Sharon Krystofiak, M.S., M.T. (A.S.C.P.), C.I.C.

  • Infection Preventionist
  • Infection Control and Hospital
  • Epidemiology
  • University of Pittsburgh Medical Center Presbyterian
  • Pittsburgh, Pennsylvania

Nutritional excesses are also recognized in the path genesis of cognitive impairment yohimbine treatment erectile dysfunction buy 100mg sildigra with visa, either through accumulative consequences Positron emission tomography Positron emission tomography has limited utility in the screening assessment of neurometabolic disorders erectile dysfunction pills cost sildigra 100mg generic, although this more accurately reflects a current lack of data for this modality amongst the heterogeneous cohort of neurometabolic disorders-for the most part limited to individual case reports and small series impotence of organic organ generic sildigra 25 mg free shipping. Neurophysiology While electrophysiological studies have limited utility in the adjunctive assessment of suspected metabolic cognitive decline erectile dysfunction from adderall best order sildigra, they are inexpensive erectile dysfunction review order sildigra 50 mg with visa, non-invasive impotence effect on relationship buy sildigra 50mg without a prescription, and may demonstrate functional aberrations not evident with neuroimaging. Electroencephalography is often normal, although background slowing consistent with an encephalopathic state is common and temporospatial changes may reflect transient cognitive impairment, a feature of many metabolic diseases. Characteristic findings may also provide diagnostic clues; triphasic waves are often considered to indicate a metabolic aetiology, most commonly present in hepatic and renal encephalopathy-although internalmedicinebook. Within the central nervous system, thiamine is critical to the processes of myelin formation, axonal conduction, and the synthesis of specific neurotransmitters. Most commonly arising in states of nutritional deficiency, classically starvation and malabsorption, thiamine depletion may also reflect reduced bioavailability due to dietary antithiamine factors, and increased metabolic consumption; hepatic stores are limited and clinical manifestations can arise in as little as one to three months. Cognitive manifestations reflect impairment of cellular energy production resulting in cytotoxic oedema and parenchymal injury. Disease features range from irritability and mild confusion, often with an apathetic quality, to frank encephalopathy and irreversible deficiencies of anterograde and retrograde amnesia (Korsakoff psychosis). Clinical suspicion is often confirmed by treatment response; fasting plasma thiamine can be measured, although it is subject to protein binding, and quantification of erythrocyte thiamine pyrophosphate levels has largely replaced this assay. Erythrocyte transketolase activity, measured pre- and post-thiamine load, remains the most sensitive indicator, with an increase of enzyme activity in excess of 25 percent indicative of deficiency. Folate deficiency and hypomagnesaemia must also be excluded as both may exacerbate thiamine deficiency. A length-dependent axonal polyneuropathy is often prominent in chronic deficiency, and non-neurological features, particularly cardiomyopathy, may result. Variability of clinical phenotype is well documented and polygenic influences have been suggested with variations in transketolase affinity and the thiamine transporter proteins implicated. Vitamin deficiency Vitamin deficiencies dominate amongst the acquired causes of neurocognitive dysfunction. Subacute cognitive impairment and psychiatric manifestations dominate, often associated with apathy. Systemic features are typically prominent, including anorexia, abdominal pain, glossitis, and a seborrheic-like dermatitis; cardiomyopathy is a feature of thiamine deficiency (wet beriberi). While a role for individual vitamin deficiencies in primary dementia and geriatric cognitive decline has been postulated. B6, B9, and B12), a clear association remains unproven and the population benefit of widespread supplementation in the non-deficient population remains unsubstantiated. Biochemical deficiency is readily confirmed via fasting assay in plasma or erythrocytes, although laboratory variability can be wide and acess to specialist assays may be limited. Indeed, clinical response to replacement is often sufficient to confirm a presumptive diagnosis, particularly when rapid intervention is indicated. Urinary organic acids may reveal excretion of characteristic metabolites such as methylmalonic acid in the presence of cobalamin deficiency, which must be excluded in any case where elevation is present. Rarely, functional enzyme studies are required to confirm increased activity following co-factor loading. Imaging is typically non-specific, with the exception of thiamine (see below) and cobalamin deficiencies, the later presenting subacute combined deficiency of the spinal cord. Vitamins D and E (-tocopherol) deficiency, while not primarily causing dementia, have also been implicated in neurocognitive decline; the latter, when severe, manifesting a phenotype of cerebellar and posterior column dysfunction, ophthalmoparesis (typically of upgaze) and axonal neuropathy resembling Friedreich ataxia. Example: Thiamine (vitamin B1) deficiency Thiamine (vitamin B1), a heterocyclic carbine, serves as a critical co-factor in carbohydrate and amino acid metabolism; its active phosphorylated form (thiamine pyrophosphate) serves internalmedicinebook. Trace elements are integral to the structure and function of many proteins (metalloproteins), and when deficient or found in excess, cognitive function is often impaired; indeed elemental deficiencies including copper, iron, selenium, and zinc, have been implicated in the causation of neuropsychiatric disease, non-specific cognitive decline and primary dementing illnesses, albeit definitive mechanisms remain poorly defined. Specific iatrogenic deficiencies may occur, as seen with chelating agents, particularly penicillamine which has wider medicinal indications, or other pharmaceutical actions such as urinary zinc losses secondary to thiazide diuretics. Chronic dialysis and dependence upon unsupplemented pareneteral nutrition are also a risk where strict monitoring is not observed; indeed, rare deficiencies of molybdenum, an essential co-factor of sulphite oxidase, xanthine oxidoreductase, and aldehyde oxidase, leading to irritability and coma have been reported in this context. Cuproproteins serve important roles in cellular energy production, free- radical scavenging, neurotransmitter metabolism, phospholipid synthesis, and iron transport, deficiency of which may also contribute to disturbed cognition and adjunct features including sensory ataxia, proprioceptive loss, and spasticity, reflecting peripheral neuropathy and myelopathic disease. Adjunct neurological findings include sensorineural deafness and spasticity of a characteristic axial and proximal appendicular distribution. In most cases neuroimaging is non-specific, although myelopathy with increased T2 signal in the dorsal columns is suggestive of copper deficiency. In all cases, prompt replacement is warranted, as delayed correction may result in permanent neurological sequalae. Gliosis in the frontotemporal regions, predominantly in the third cortical layer (Morel cortical laminar sclerosis), is often a feature. Commonly, but not absolutely described in patients with chronic alcoholism, aetiology has been attributed to non-specific nutritional deficiency and may reflect a reduction in multiple B-group compounds. A panethnic disease, cases are dominated by men, the majority arising after 45 years of age. Clinical symptoms vary; onset may be precipitous with lethargy, stupor, and rapid progression to coma, while subacute or chronic dementia, often with ideomotor apraxia and psychiatric disturbance, is also observed. Progressive corticospinal tract involvement, ataxia, and seizures evolve- with distinction from associated disease and comorbid pathology often difficult. Prognosis is poor, however early detection and supportive management including abstinence from alcohol and administration of B-complex vitamins has improved outcomes in contemporary practice. Macronutrient deficiency and excess Critical for normal neurodevelopmental outcomes, the cognitive effects of macronutrient insufficiency on the developed brain can be profound, albeit distinction from comorbid micronutrient deficiency is often difficult. Macronutrient excess is similarly linked to dementia, largely through secondary consequences of insulin resistance and chronic metabolic dysregulation. Endocrinopathy-associated cognitive decline Endocrinopathy-associated cognitive decline is well recognized as a primary consequence of the precipitant disorder. Patterns of neurocognitive dysfunction vary from acute encephalopathy and subacute cognitive decline to late-onset dementing disease and neuropsychiatric manifestations. Systemic features are often prominent in thyroid and adrenal disease, with recognizable phenotypes in many cases internalmedicinebook. Biochemical confirmation is readily determined and early initiation of treatment with sustained endocrinological homeostasis the priority. Whilst not a primary endocrinopathy, the consequence of recurrent non-diabetic hypoglycaemia should also be considered in the cognitively declining patient, particularly if stepwise deterioration is evident; plasma glucose is confirmatory during an acute episode; however, transient episodes may require pre- and post-prandial sampling to substantiate, with an observed fast (up to 72 hours) most sensitive. Once confirmed, diagnostic investigations must follow and the differential causes of hypoglycaemia investigated. Disorders of carbohydrate metabolism As a primary substrate for energy production, inborn errors of carbohydrate metabolism include defects of glucose production and utilization. Neurons do not synthesize glycogen and rely upon mitochondrial oxidation of astrocyte-derived lactate, generated by glycogenolysis, to provide an alternative energy source during neuroglycopaenia. Cognitive involvement ranges from childhood intellectual impairment to acute encephalopathy, classic dementing disease, and episodic decline. Neuroglycopaenic-associated cognitive impairment and recurrent hypoglycaemic insult must also be considered in this context. Biochemical identification corresponds to the protocols for such diagnoses, excepting the glycogenoses. In several cases effective therapeutic intervention can be implemented, again emphasizing the need so far as possible to confirm diagnosis. Visceral insufficiency and cognitive decline Disordered metabolic homeostasis, as a result of visceral failure, frequently precipitates acute, recurrent encephalopathy; however, more indolent cognitive dysfunction may also occur. In each case, disease can be considered a consequence of neurotoxic metabolite accumulation-chiefly ammonia and manganese in hepatic disease and multiple renally cleared substrates (urea, phosphates, parathyroid hormone, and amino acids) in the presence of renal failure; iatrogenic neurocognitive decline in the context of long-term dialysis (dialysis dementia) has also been recognized- the result of aluminium toxicity, now rarely observed, with removal of this contaminant from dialysate. Moreover, in all cases of visceral failure, comorbid electrolyte disturbance and micronutrient insufficiency are often present; indeed, co- morbid thiamine deficiency has been implicated in both hepatic- and pancreatic-associated encephalopathies. In all cases acute management pertains to reduction of the accumulating toxins, through dietary, pharmacotherapeutic, and other means including dialysis, in addition to treatment of the underling systemic pathology. Example: the cerebral glycogenoses Characterized by the intracellular accumulation of polyglucosan-an abnormal storage form of glycogen-the cerebral glycogenoses45,46 are an important consideration in the dementing adult. Neurocognitive decline, with a frontal dementia pattern ensues with progression to myoclonic status, and death within 10 years of onset. Accurate epidemiological data are lacking-in part due to underdiagnosis-however it is notable that the greatest burden is within young adult presentations and amongst those with adjunct neurological and/or systemic disease. A contemporary view of inborn metabolic diseases includes other genetic disorders affecting metabolic function, a premise which could be extended to almost all neurodegenerative processes. Childhood onset dominates but late-onset decline, often with specific deficits of visual construction, attention, and abstraction (in the absence of general intellectual deterioration) has been reported in mutations involving both the mitochondrial genome. Searching for these mutations should be considered in work-up of early-onset dementing patients. These diseases typically occur in childhood, however, adult presenting disease is recognized, often during periods of metabolic stress, and in many cases preceeded by prolonged periods of normal health. Cognitive involvement is rare in adult disease and hypertrophic cardiomyopathy and skeletal muscle involvement, often with rhabdomyolysis, dominate the clinical picture. Disorders of amino acid metabolism and transport Disorders of amino acid metabolism and transport are a large group of intermediate metabolism defects, reflecting the importance of amino acids in cellular function. These diseases occur principally in infancy and childhood; however, adult-onset variants, typically of an attenuated phenotype, are increasingly recognized. Many of these prove amenable to therapeutic intervention, necessitating timely and accurate diagnosis. Disease is largely attributed to toxic accumulation of specific amino acids, their precursors, and derivatives, including secondary impairment of complicit metabolic pathways such as disruption of the tricarboxylic acid cycle in many of the organic acidopathies and urea cycle disorders. Porphyria- like decompensation, characteristic of tyrosinemia type 1, is another example, reflecting inhibition of aminolevulinate dehydratase, an enzyme in haem biosynthesis, by pathogenic metabolites. These are protean disorders, particularly amongst attenuated, lateonset variants: detailed summaries can be obtained from dedicated texts, nevertheless several common features may inform diagnosis. Dietary aversion to protein-rich diets may be discovered, particularly in phenylketonuria, the organic acidopathies, and urea cycle disorders, which may present following protein loading. Mutations in the transporter, citrin (citrullinaemia type 2) are a notable exception; here carbohydrate-rich diets trigger decompensation. Neurocognitive decline in the context of childhood intellectual impairment should also suggest an undiagnosed aminoacidopathy. Insidious cognitive impairment in the context of known diagnoses may also occur, prompting consideration of either lack of compliance or iatrogenic restriction of essential nutrients, as a result of inappropriate dietary therapy. In general, psychiatric and neurobehavioural manifestations are common and additional neurological and systemic features often occur. Stroke-like episodes may be identified, particularly in patients with branched chain aminoacidopathies and urea cycle disorders; while peripheral thromboembolism is a feature of homocystinuria-most commonly due to deficiency of the pyridoxine-dependent enzyme, cystathionine -synthase, which causes disrupted methionine transsulfuration (classical homocystinuria). In this condition, unique amongst the aminoacidopathies, there is a prominent Marfanoid phenotype which is a distinguishing feature in hyperhomocysteinaemia. In the case of several aminoacidopathies, a characteristic body odour may be reported, reflecting accumulation of the odiferous compound. Diagnosis relies upon quantification of pathological compounds and their derivatives in biological fluids-typically plasma and urine, including ammonia and the aminoacids-detection of the latter has been advanced through contemporary refinement of chromatographic techniques and mass spectrometry. In the case of the organic acidopathies, patterns of aberrant acylcarnitine conjugation may assist diagnosis. Caution should be exercised in the diagnosis of hyperammonaemia in this context, as the presentation of many organic acidemias may suggest a urea cycle anomaly, consequent to accumulation of CoA derivatives which inhibit the formation of N-acetylglutamate, the activator of hepatic carbamoyl phosphate synthetase. It is important to be aware of assay limitations, including factors which lead to artefactual results and, where possible, sampling should be performed during symptomatic states or under conditions of metabolic stress as this will improve detection of pathogenic metabolites, which may fall below levels of detection internalmedicinebook. Iatrogenic B12 deficiency may account for the dementing phenylketonuria patient-a consequence of low-protein diet without supplementation of this essential vitamin. Given the potential for decompensation, timed collections under conditions of substrate load should only be performed under careful clinical observation; while occasionally required to confirm diagnoses, the advent of genetic analyses has rendered such tests increasingly unnecessary. Many of the aminoacidopathies are treatable, however, particularly when neurological disease is advanced, not all sequalae are reversible. Example: Phenylketonuria and disordered biopterin metabolism Phenylketonuria is the most prevalent of the aminoacidopathies and is usually the result of an autosomal recessive deficiency of phenylalanine hydroxylase, which catalyses the conversion of phenylalanine (an essential amino acid) to tyrosine. Central nervous system pathology ensues when excess phenylalanine accumulates and, while the exact mechanism of disease is uncertain, consequences include disruption of synaptogenesis and dendritic arborization, glial cell dysfuncton, and oligodendrocyte toxicity-the latter resulting in dysmyelination and white matter vacuolization. Insulin resistance impairs glucose utilization by insulin-sensitive tissues and increases hepatic glucose output; both effects contribute to the hyperglycemia. Initially, the insulin secretory defect is mild and selectively involves glucose-stimulated insulin secretion, including a greatly reduced first secretory phase. The assumption is that a second genetic defect- superimposed upon insulin resistance-leads to beta cell failure. For example, chronic hyperglycemia paradoxically impairs islet function ("glucose toxicity") and leads to a worsening of hyperglycemia. In addition, elevation of free fatty acid levels ("lipotoxicity") and dietary fat may also worsen islet function. Increased hepatic glucose production occurs early in the course of diabetes, although likely after the onset of insulin secretory abnormalities and insulin resistance in skeletal muscle.

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Hematomas may expand for several hours following the initial hemorrhage erectile dysfunction doctors tucson az order online sildigra, even in patients without coagulopathy erectile dysfunction treatment perth order sildigra without prescription. The theoretical risk of acutely elevated blood pressure on hematoma expansion forms the basis of the consideration for recently completed and ongoing clinical trials of acute blood pressure lowering erectile dysfunction doctors in alexandria va buy sildigra online from canada. Evacuation of supratentorial hematomas does not appear to improve outcome for most patients erectile dysfunction age 36 purchase sildigra master card. No benefit was found in the early surgery arm erectile dysfunction weed buy sildigra canada, although analysis was complicated by the fact that 26% of patients in the initial medical management group ultimately had surgery for neurologic deterioration erectile dysfunction juice purchase sildigra online pills. Therefore, existing data do not support routine surgical evacuation of supratentorial hemorrhages in stable patients. However, many centers still consider surgery for patients deemed salvageable and who are having progressive neurologic deterioration due to herniation. For cerebellar hemorrhages, a neurosurgeon should be consulted immediately to assist with the evaluation; most cerebellar hematomas >3 cm in diameter will require surgical evacuation. If the patient is alert without focal brainstem signs and if the hematoma is <1 cm in diameter, surgical removal is usually unnecessary. Blood vessels forming the tangle interposed between arteries and veins are usually abnormally thin and histologically resemble both arteries and veins. Bleeding, headache, and seizures are most common between the ages of 10 and 30, occasionally as late as the fifties. In most, the hemorrhage is mainly intraparenchymal with extension into the subarachnoid space in some cases. Blood is usually not deposited in the basal cisterns, and symptomatic cerebral vasospasm is rare. Hemorrhages may be massive, leading to death, or may be as small as 1 cm in diameter, leading to minor focal symptoms or no deficit. The presence of deep venous drainage, venous outflow stenosis, and intranidal aneurysms may increase rupture risk. The trial was stopped prematurely for harm, with the medical arm achieving the combined endpoint of death or symptomatic stroke in 10. This highly significant finding argues against routine intervention for patients presenting without hemorrhage, although debate ensues regarding the generalizability of these results. Venous anomalies are the result of development of anomalous cerebral, cerebellar, or brainstem venous drainage. They are of little clinical significance and should be ignored if found incidentally on brain imaging studies. Surgical resection of these anomalies may result in venous infarction and hemorrhage. Venous anomalies may be associated with cavernous malformations (see below), which do carry some bleeding risk. Capillary telangiectasias are true capillary malformations that often form extensive vascular networks through an otherwise normal brain structure. The pons and deep cerebral white matter are typical locations, and these capillary malformations can be seen in patients with hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber) syndrome. Cavernous angiomas are typically <1 cm in diameter and are often associated with a venous anomaly. Surgical resection eliminates bleeding risk and may reduce seizure risk, but it is usually reserved for those malformations that form near the brain surface. Dural arteriovenous fistulas are acquired connections usually from a dural artery to a dural sinus. Patients may complain of a pulse-synchronous cephalic bruit ("pulsatile tinnitus") and headache. Fistulas have been observed to appear months to years following venous sinus thrombosis, suggesting that angiogenesis factors elaborated from the thrombotic process may cause these anomalous connections to form. Alternatively, dural arteriovenous fistulas can produce venous sinus occlusion over time, perhaps from the high pressure and high flow through a venous structure. Raskin the general principles around headache as a cardinal symptom are covered elsewhere (Chap. The most common are migraine, tension-type headache, and the trigeminal autonomic cephalalgias, notably cluster headache; the complete list is summarized in Table 447-1. It is usually an episodic headache associated with certain features such as sensitivity to light, sound, or movement; nausea and vomiting often accompany the headache. A useful description of migraine is a recurring syndrome of headache associated with other symptoms of neurologic dysfunction in varying admixtures (Table 447-2). The brain of the migraineur is particularly sensitive to environmental and sensory stimuli; migraine-prone patients do not habituate easily to sensory stimuli. Headache can be initiated or amplified by various triggers, including glare, bright lights, sounds, or other afferent stimulation; hunger; let-down from stress; physical exertion; stormy weather or barometric pressure changes; hormonal fluctuations during menses; lack of or excess sleep; and alcohol or other chemical stimulation, such as with nitrates. Pathogenesis the sensory sensitivity that is characteristic of migraine is probably due to dysfunction of monoaminergic sensory control systems located in the brainstem and hypothalamus. Centrally, the second-order trigeminal neurons cross the midline and project to ventrobasal and posterior nuclei of the thalamus for further processing. Additionally, there are projections to the periaqueductal gray and hypothalamus, from which reciprocal descending systems have established antinociceptive effects. Other brainstem regions likely to be involved in descending modulation of trigeminal pain include the nucleus locus coeruleus in the pons and the rostroventromedial medulla. Triptans arrest nerve signaling in the nociceptive pathways of the trigeminovascular system, at least in the trigeminal nucleus caudalis and trigeminal sensory thalamus, in addition to cranial vasoconstriction, while ditans, now shown conclusively to be effective in acute migraine, act only at neural targets. An interesting range of neural targets is now being actively pursed for the acute and preventive management of migraine. Moreover, there is dopamine receptor hypersensitivity in migraineurs, as demonstrated by the induction of yawning, nausea, vomiting, hypotension, and other symptoms of a migraine attack by dopaminergic agonists at doses that do not affect nonmigraineurs. Dopamine receptor antagonists are effective therapeutic agents in migraine, especially when given parenterally or concurrently with other antimigraine agents. These neurons in turn project in the quintothalamic tract and, after decussating in the brainstem, synapse on neurons in the thalamus. Important modulation of the trigeminovascular nociceptive input comes from the dorsal raphe nucleus, locus coeruleus, and nucleus raphe magnus. Diagnosis and Clinical Features Diagnostic criteria for migraine headache are listed in Table 447-3. Patients with episodes of migraine that occur daily or near-daily are considered to have chronic migraine (see "Chronic Daily Headache" in Chap. Migraine must be differentiated from tension-type headache (discussed below), the most common primary headache syndrome seen in the population. Migraine has several forms that have been defined (Table 447-1): migraine with and without aura and chronic migraine, the latter occurring 15 days or more a month, as the most important. Migraine at its most basic level is headache with associated features, and tension-type headache is headache that is featureless. Vertigo can be prominent; it has been estimated that one-third of patients referred for vertigo or dizziness have a primary diagnosis of migraine. Migraine aura can have prominent brainstem symptoms, and the terms basilar artery and basilar-type migraine have now been replaced by migraine with brainstem aura (Table 447-1). Hypothalamic, dorsal midbrain, and dorsolateral pontine activation is seen in triggered attacks in the premonitory phase before pain, whereas in migraine attacks, dorsolateral pontine activation persists, as it does in chronic migraine (not shown). The dorsolateral pontine area, which includes the noradrenergic locus coeruleus, is fundamental to the expression of migraine. Moreover, lateralization of changes in this region of the brainstem correlates with lateralization of the head pain in hemicranial migraine; the scans shown in panels C and D are of patients with acute migraine headache on the right and left side, respectively. Posterior hypothalamic gray matter activation by positron emission tomography in a patient with acute cluster headache. High-resolution T1-weighted magnetic resonance image obtained using voxel-based morphometry demonstrates increased gray matter activity, lateralized to the side of pain in a patient with cluster headache. It is helpful for patients to understand that migraine is an inherited tendency to headache; that migraine can be modified and controlled by lifestyle adjustments and medications, but it cannot be eradicated; and that, except in some occasions in women on oral estrogens or contraceptives, migraine is not associated with serious or life-threatening illnesses. Most patients benefit by the identification and avoidance of specific headache triggers. A regulated lifestyle is helpful, including a healthy diet, regular exercise, regular sleep patterns, avoidance of excess caffeine and alcohol, and avoidance of acute changes in stress levels, being particularly wary of the let-down effect. The measures that benefit a given individual should be used routinely because they provide a simple, cost-effective approach to migraine management. Patients with migraine do not encounter more stress than headache-free individuals; over-responsiveness to changes in stress appears to be the issue. If these measures fail to prevent an attack, pharmacologic approaches are then needed to abort an attack. The selection of the optimal regimen for a given patient depends on a number of factors, the most important of which is the severity of the attack. In general, an adequate dose of whichever agent is chosen should be used as soon as possible after the onset of an attack. If additional medication is required within 60 min because symptoms return or have not abated, the initial dose should be increased for subsequent attacks or a different class of drug tried as first-line treatment. Migraine therapy must be individualized; a standard approach for all patients is not possible. A therapeutic regimen may need to be constantly refined until one is identified that provides the patient with rapid, complete, and consistent relief with minimal side effects (Table 447-5). However, the effectiveness of these agents in migraine is usually less than optimal in moderate or severe migraine attacks. The combination of acetaminophen, aspirin, and caffeine has been approved for use by the U. The combination of aspirin and metoclopramide has been shown to be comparable to a single dose of oral sumatriptan. Ergotamine and dihydroergotamine are nonselective receptor Source: Adapted from the International Headache Society Classification (Headache Classification Committee of the International Headache Society, 2013). On how many days in the last 3 months did you miss work or school because of your headaches How many days in the last 3 months was your productivity at work or school reduced by half or more because of your headaches (do not include days you counted in question 1 where you missed work or school). On how many days in the last 3 months did you not do household work because of your headaches How many days in the last 3 months was your productivity in household work reduced by half or more because of your headaches (do not include days you counted in question 3 where you did not do household work). On how many days in the last 3 months did you miss family, social, or leisure activities because of your headaches Because the clinical studies demonstrating the efficacy of ergotamine in migraine predated the clinical trial methodologies used with the triptans, it is difficult to assess the clinical efficacy of ergotamine versus the triptans. In general, ergotamine appears to have a much higher incidence of nausea than triptans but less headache recurrence. Nasal Nasal formulations of dihydroergotamine (Migranal), zolmitriptan (Zomig nasal), or sumatriptan can be useful in patients requiring a nonoral route of administration. Studies with a new inhalational formulation of dihydroergotamine indicate that its absorption problems can be overcome to produce rapid onset of action with good tolerability. Drug absorption is impaired during migraine because of reduced gastrointestinal motility. Delayed absorption occurs even in the absence of nausea and is related to the severity of the attack and not its duration. Each drug in the triptan class has similar pharmacologic properties but varies slightly in terms of clinical efficacy. Rizatriptan and eletriptan are the most efficacious of the triptans currently available in the United States. Sumatriptan and zolmitriptan have similar rates of efficacy as well as time to onset, with an advantage of having multiple formulations, whereas almotriptan has a similar rate of efficacy to sumatriptan and is better tolerated, and frovatriptan and naratriptan are somewhat slower in onset and are better tolerated. Clinical efficacy appears to be related more to the tmax (time to peak plasma level) than to the potency, half-life, or bioavailability. This observation is consistent with a large body of data indicating that fasteracting analgesics are more effective than slower-acting agents. Triptans are generally not effective in migraine with aura unless given after the aura is completed and the headache initiated. Recurrence of headache, within usual time course of an attack, is another important limitation of triptan use and occurs at least occasionally in most patients. A nonnauseating dose of ergotamine should be sought because a dose that provokes nausea is too high and may intensify head pain. This condition is likely not a separate headache entity but a reaction of the migraine patient to a particular medicine. Migraine patients who have two or more headache days a week should be cautioned about frequent analgesic use (see "Chronic Daily Headache" in Chap. In general, a preventive medication should be considered in the subset of patients with four or more attacks a month. Significant side effects are associated with the use of many of these agents; furthermore, determination of dose can be difficult because the recommended doses have been derived for conditions other than migraine. The mechanism of action of these drugs is unclear; it seems likely that the brain sensitivity that underlies migraine is modified. Patients are usually started on a low dose of a chosen treatment; the dose is then gradually increased, up to a reasonable maximum, to achieve clinical benefit. Drugs must be taken daily, and there is usually a lag of between 2 to 12 weeks before an effect is seen. This group includes amitriptyline, nortriptyline, flunarizine, phenelzine, gabapentin, and cyproheptadine. Placebo-controlled trials of onabotulinum toxin type A in episodic migraine were negative, whereas, overall, placebo-controlled trials in chronic migraine were positive. Phenelzine and methysergide are usually reserved for recalcitrant cases because of their serious potential side effects. Methysergide may cause retroperitoneal or cardiac valvular fibrosis when it is used for >6 months, and thus monitoring is required for patients using this drug; the risk of fibrosis is about 1:1500 and is likely to reverse after the drug is stopped. Many patients are managed adequately with low-dose amitriptyline, propranolol, candesartan, topiramate, or valproate.

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Diagnostic criteria require at least 1 month of concern or worry about the attacks or a change in behavior related to them impotence at 30 years old sildigra 25 mg lowest price. Panic attacks have a sudden onset young healthy erectile dysfunction discount sildigra 100mg on-line, developing within 10 min and usually resolving over the course of an hour erectile dysfunction ka desi ilaj purchase sildigra, and they occur in an unexpected fashion erectile dysfunction at the age of 24 buy online sildigra. The frequency and severity of panic attacks vary impotence clinics purchase sildigra 50mg with amex, ranging from once a week to clusters of attacks separated by months of well-being erectile dysfunction commercials buy cheap sildigra 120 mg on line. The first attack is usually outside the home, and onset is typically in late adolescence to early adulthood. In some individuals, anticipatory anxiety develops over time and results in a generalized fear and a progressive avoidance of places or situations in which a panic attack might recur. Agoraphobia, which occurs commonly in patients with panic disorder, is an acquired irrational fear of being in places where one might feel trapped or unable to escape. Typically, it leads the patient into a progressive restriction in lifestyle and, in a literal sense, in geography. Frequently, patients are embarrassed that they are housebound and dependent on the company of others to go out into the world and do not volunteer this information; thus, physicians will fail to recognize the syndrome if direct questioning is not pursued. Differential Diagnosis A diagnosis of panic disorder is made after a medical etiology for the panic attacks has been ruled out. A variety of cardiovascular, respiratory, endocrine, and neurologic conditions can present with anxiety as the chief complaint. Patients with true panic disorder will often focus on one specific feature to the exclusion of others. For example, 20% of patients who present with syncope as a primary medical complaint have a primary diagnosis of a mood, anxiety, or substance abuse disorder, the most common being panic disorder. The differential diagnosis of panic disorder is complicated by a high rate of comorbidity with other psychiatric conditions, especially alcohol and benzodiazepine abuse, which patients initially use in an attempt at self-medication. Some 75% of panic disorder patients will also satisfy criteria for major depression at some point in their illness. When the history is nonspecific, physical examination and focused laboratory testing must be used to rule out anxiety states resulting from medical disorders such as pheochromocytoma, thyrotoxicosis, or hypoglycemia. In two studies, panic disorder was the primary diagnosis in 43% of patients with chest pain who had normal coronary angiograms and was present in 9% of all outpatients referred for cardiac evaluation. Panic disorder has also been diagnosed in many patients referred for pulmonary function testing or with symptoms of irritable bowel syndrome. Etiology and Pathophysiology the etiology of panic disorder is unknown but appears to involve a genetic predisposition, altered autonomic responsivity, and social learning. Acute panic attacks appear to be associated with increased noradrenergic discharges in the locus coeruleus. It is hypothesized that each of these stimuli activates a pathway involving noradrenergic neurons in the locus coeruleus and serotonergic neurons in the dorsal raphe. Insomnia, orthostatic hypotension, and the need to maintain a low-tyramine diet (avoidance of cheese and wine) have limited their use, however. Because of anticipatory anxiety and the need for immediate relief of panic symptoms, benzodiazepines are useful early in the course of treatment and sporadically thereafter (Table 466-4). Early psychotherapeutic intervention and education aimed at symptom control enhance the effectiveness of drug treatment. Homework assignments and monitored compliance are important components of successful treatment. Onset is usually before age 20 years, and a history of childhood fears and social inhibition may be present. Comorbid substance abuse is common in these patients, particularly alcohol and/or sedative/hypnotic abuse. The cornerstone of drug therapy is antidepressant medication (Tables 466-1 through 466-3). These drugs should be started at onethird to one-half of their usual antidepressant dose. A short course of a benzodiazepine is usually indicated, preferably lorazepam, oxazepam, or alprazolam. Benzodiazepines differ in their milligram per kilogram potency, half-life, lipid solubility, metabolic pathways, and presence of active metabolites. Agents that are absorbed rapidly and are lipid soluble, such as diazepam, have a rapid onset of action and a higher abuse potential. It is important to warn patients that concomitant use of alcohol or other sedating drugs may exacerbate side effects and impair their ability to function. An optimistic approach that encourages the patient to clarify environmental precipitants, anticipate his or her reactions, and plan effective response strategies is an essential element of therapy. Longer-acting agents, such as diazepam, chlordiazepoxide, flurazepam, and clonazepam, tend to accumulate active metabolites, with resultant sedation, impairment of cognition, and poor psychomotor performance. Shorter-acting compounds, such as alprazolam, lorazepam, and oxazepam, can produce daytime anxiety, early morning insomnia, and, with discontinuation, rebound anxiety and insomnia. Although patients develop tolerance to the sedative effects of benzodiazepines, they are less likely to habituate to the adverse psychomotor effects. It is usually more difficult to taper patients off shorter-acting benzodiazepines. Increase dose or drug holiday; add amantadine, 100 mg bid, buspirone, 10 mg tid, or pindolol, 2. Insomnia Sedation Headache Weight gain Loss of therapeutic benefit over time adjunctive medication such as a beta blocker or carbamazepine, before attempting to discontinue the benzodiazepine. Withdrawal reactions vary in severity and duration; they can include depression, anxiety, lethargy, diaphoresis, autonomic arousal, and, rarely, seizures. It is nonsedating, does not produce tolerance or dependence, does not interact with benzodiazepine receptors or alcohol, and has no abuse or disinhibition potential. However, it requires several weeks to take effect and requires thrice-daily dosing. Patients who were previously responsive to a benzodiazepine are unlikely to rate buspirone as equally effective, but patients with head injury or dementia who have symptoms of anxiety and/or agitation may do well with this agent. Gabapentin, oxcarbazepine, tiagabine, pregabalin, and divalproex have all shown some degree of benefit in a variety of anxiety-related syndromes in off-label usage. Excessive anxiety and worry (apprehensive expectation), occurring more days than not for at least 6 months, about a number of events or activities (such as work or school performance). The anxiety and worry are associated with three (or more) of the following six symptoms (with at least some symptoms present for more days than not for the past 6 months): (1) restlessness or feeling keyed up or on edge; (2) being easily fatigued; (3) difficulty concentrating or mind going blank; (4) irritability; (5) muscle tension; (6) sleep disturbance (difficulty falling or staying asleep, or restless, unsatisfying sleep). The anxiety, worry, or physical symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. Benzodiazepines can be helpful in reducing fearful avoidance, but the chronic nature of phobic disorders limits their usefulness. Behaviorally focused psychotherapy is an important component of treatment because relapse rates are high when medication is used as the sole treatment. Cognitive-behavioral strategies are based on the finding that distorted perceptions and interpretations of fear-producing stimuli play a major role in perpetuation of phobias. In desensitization therapy, hierarchies of feared situations are constructed, and the patient is encouraged to pursue and master gradual exposure to the anxiety-producing stimuli. Patients with social phobia, in particular, have a high rate of comorbid alcohol abuse, as well as of other psychiatric conditions. In both syndromes, individuals experience associated symptoms of detachment and loss of emotional responsivity. The patient may feel depersonalized and unable to recall specific aspects of the trauma, although typically it is reexperienced through intrusions in thought, dreams, or flashbacks, particularly when cues of the original event are present. Patients often actively avoid stimuli that precipitate recollections of the trauma and demonstrate a resulting increase in vigilance, arousal, and startle response. Patients with stress disorders are at risk for the development of other disorders related to anxiety, mood, and substance abuse (especially alcohol). The patient avoids the phobic stimulus, and this avoidance usually impairs occupational or social functioning. Unlike patients with other anxiety disorders, individuals with phobias usually experience anxiety only in specific situations. Common phobias include fear of closed spaces (claustrophobia), fear of blood, and fear of flying. Social phobia is distinguished by a specific fear of social or performance situations in which the individual is exposed to unfamiliar individuals or to possible examination and evaluation by others. Examples include having to converse at a party, use public restrooms, and meet strangers. In each case, the affected individual is aware that the experienced fear is excessive and unreasonable given the circumstance. The specific content of a phobia may vary across gender, ethnic, and cultural boundaries. Full criteria for diagnosis are usually satisfied first in early adulthood, but behavioral avoidance of unfamiliar people, situations, or objects dating from early childhood is common. In one study of female twins, concordance rates for agoraphobia, social phobia, and animal phobia were found to be 23% for monozygotic twins and 15% for dizygotic twins. Animal studies of fear conditioning have indicated that processing of the fear stimulus occurs through the lateral nucleus of the amygdala, extending through the central nucleus and projecting to the periaqueductal gray region, lateral hypothalamus, and paraventricular hypothalamus. Learning that the traumatic event(s) occurred to a close family member or close friend. In cases of actual or threatened death of a family member or friend, the event(s) must have been violent or accidental. Experiencing repeated or extreme exposure to aversive details of the traumatic event(s). Presence of one (or more) of the following intrusion symptoms associated with the traumatic event(s), beginning after the traumatic event(s) occurred: 1. Recurrent, involuntary, and intrusive distressing memories of the traumatic event(s). Recurrent distressing dreams in which the content and/or affect of the dream are related to the traumatic event(s). Intense or prolonged psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event(s). Marked physiologic reactions to internal or external cues that symbolize or resemble an aspect of the traumatic event(s). Persistent avoidance of stimuli associated with the traumatic event(s), beginning after the traumatic event(s) occurred, as evidenced by one or both of the following: 1. Avoidance of or efforts to avoid distressing memories, thoughts, or feelings about or closely associated with the traumatic event(s). Negative alterations in cognitions and mood associated with the traumatic event(s), beginning or worsening after the traumatic event(s) occurred as evidenced by two (or more) of the following: 1. Inability to remember an important aspect of the traumatic event(s) (typically due to dissociative amnesia and not to other factors such as head injury, alcohol, or drugs). Irritable behavior and angry outbursts (with little or no provocation) typically expressed as verbal or physical aggression toward people or objects. Carbamazepine, valproic acid, and alprazolam have also independently produced improvement in uncontrolled trials. Patients often conceal their symptoms, usually because they are embarrassed by the content of their thoughts or the nature of their actions. Physicians must ask specific questions regarding recurrent thoughts and behaviors, particularly if physical clues such as chafed and reddened hands or patchy hair loss (from repetitive hair pulling, or trichotillomania) are present. Comorbid conditions are common, the most frequent being depression, other anxiety disorders, eating disorders, and tics. Onset is usually gradual, beginning in early adulthood, but childhood onset is not rare. The disorder usually has a waxing and waning course, but some cases may show a steady deterioration in psychosocial functioning. The anatomy of obsessive-compulsive behavior is thought to include the orbital frontal cortex, caudate nucleus, and globus pallidus. Fears of contamination and germs are common, as are handwashing, counting behaviors, and having to check and recheck such actions as whether a door is locked. The degree to which the disorder is disruptive for the individual varies, but in all cases, obsessive-compulsive activities take up >1 h per day and are 2714 and maintenance of habit and skill learning, and interventions that are successful in reducing obsessive-compulsive behaviors also decrease metabolic activity measured in the caudate. In treatment-resistant cases, augmentation with other serotonergic agents such as buspirone, or with a neuroleptic or benzodiazepine, may be beneficial, and in severe cases, deep brain stimulation has been found to be effective. When a therapeutic response is achieved, long-duration maintenance therapy is usually indicated. For many individuals, particularly those with time-consuming compulsions, behavior therapy will result in as much improvement as that afforded by medication. Effective techniques include the gradual increase in exposure to stressful situations, maintenance of a diary to clarify stressors, and homework assignments that substitute new activities for compulsive behaviors.

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Onset is usually in infancy or early childhood impotent rage quotes sildigra 25 mg generic, but avoidant behaviors may persist into adulthood impotence marijuana facts sildigra 25 mg for sale. The disorder is equally prevalent in males and females and is frequently comorbid with anxiety and cognitive and attentiondeficit disorders and situations of familial stress erectile dysfunction drugs and heart disease buy cheapest sildigra and sildigra. Developmental delay and functional deficits may be significant if the disorder is long-standing and unrecognized erectile dysfunction latest treatment order sildigra 50mg free shipping. The condition is further characterized by differentiating those who achieve their weight loss predominantly through restricting intake or by excessive exercise (restricting type) from those who engage in recurrent binge eating and/or subsequent purging impotence vacuum treatment generic sildigra 100 mg line, selfinduced vomiting disease that causes erectile dysfunction order discount sildigra online, and usage of enemas, laxatives, or diuretics (bingeeating/purging type). Such subtyping is more state than trait specific, as individuals may transition from one profile to the other over time. Determination of whether an individual satisfies the primary criterion of significant low weight is complex and must be individualized, using all available historical information and comparison of body habitus to international body mass norms and guidelines. Individuals with anorexia nervosa frequently lack insight into their condition and are in denial about possible medical consequences; they often are not comforted by their achieved weight loss and persist in their behaviors despite having met previously self-designated weight goals. Recent research has identified alterations in the circuitry of reward sensitivity and executive function in anorexia and implicated disturbances in frontal cortex and anterior insula regulation of interoceptive awareness of satiety and hunger. Many more females than males are affected, with a lifetime prevalence in women of up to 4%. The disorder appears Chapter 466 Mental Disorders Somatic Symptom diSorder and related diSorderS Patients with somatic symptom disorder are frequently subjected to many diagnostic tests and exploratory surgeries in an attempt to find their "real" illness. Visits can be brief and should not be associated with a need for a diagnostic or treatment action. Although the literature is limited, some patients may benefit from antidepressant treatment. Any attempt to confront the patient usually creates a sense of humiliation and causes the patient to abandon treatment from that caregiver. A better strategy is to introduce psychological causation as one of a number of possible explanations in the differential diagnoses that are discussed. Without directly linking psychotherapeutic intervention to the diagnosis, the patient can be offered a face-saving means by which the pathologic relationship with the health care system can be examined and alternative approaches to life stressors developed. Specific medical treatments also may be indicated and effective in treating some of the functional consequences of conversion disorder. Binge-eating disorder is also now included as a formal diagnosis; the intent of each of these modifications is to encourage clinicians to be more specific in their codification of eating and feeding pathology. The medical consequences of prolonged anorexia nervosa are multisystemic and can be life-threatening in severe presentations. Changes in blood chemistry include leukopenia with lymphocytosis, elevations in blood urea nitrogen, and metabolic alkalosis and hypokalemia when purging is present. History and physical examination may reveal amenorrhea in females, skin abnormalities (petechiae, lanugo hair, dryness), and signs of hypometabolic function, including hypotension, hypothermia, and sinus bradycardia. Endocrine effects include hypogonadism, growth hormone resistance, and hypercortisolemia. The course of the disorder is variable, with some individuals recovering after a single episode, while others exhibit recurrent episodes or a chronic course. Maudsley family-based therapy has proven to be an effective therapy in younger individuals, with strict behavioral contingencies used when weight loss becomes critical. No pharmacologic intervention has proven to be specifically beneficial, but comorbid depression and anxiety should be treated. Most individuals are able to achieve remission within 5 years of the original diagnosis. Binge eating itself is defined as excessive food intake in a prescribed period of time, usually <2 h. As in anorexia nervosa, disturbances in body image occur and promote the behavior, but unlike in anorexia, individuals are of normal weight or even somewhat overweight. Subjects typically describe a loss of control and express shame about their actions, and often relate that their episodes are triggered by feelings of negative self-esteem or social stresses. The lifetime prevalence in women is approximately 2%, with a 10:1 female-to-male ratio. The disorder typically begins in adolescence and may be persistent over a number of years. Many of the medical risks associated with bulimia nervosa parallel those of anorexia nervosa and are a direct consequence of purging, including fluid and electrolyte disturbances and conduction abnormalities. Physical examination often results in no specific findings, but dental erosion and parotid gland enlargement may be present. Other features are similar, including distress over the behavior and the experience of loss of control, resulting in eating more rapidly or in greater amounts than intended or eating when not hungry. Little is known about the course of the disorder, given its recent categorization, but its prognosis is markedly better than for other eating disorders, both in terms of its natural course and response to treatment. This distinction is often difficult to make in clinical practice, because personality change may be the first sign of serious neurologic, endocrine, or other medical illness. Patients with frontal lobe tumors, for example, can present with changes in motivation and personality while the results of the neurologic examination remain within normal limits. Individuals with personality disorders are often regarded as "difficult patients" in clinical medical practice because they are seen as excessively demanding and/or unwilling to follow recommended treatment plans. It includes individuals who are odd and eccentric and who maintain an emotional distance from others. Patients with schizotypal personality disorder frequently have unusual perceptual experiences and express magical beliefs about the external world. The essential feature of paranoid personality disorder is a pervasive mistrust and suspiciousness of others to an extent that is unjustified by available evidence. Cluster B disorders include antisocial, borderline, histrionic, and narcissistic types and describe individuals whose behavior is impulsive, excessively emotional, and erratic. Cluster C incorporates avoidant, dependent, and obsessive-compulsive personality types; enduring traits are anxiety and fear. The boundaries between cluster types are to some extent artificial, and many patients who meet criteria for one personality disorder also meet criteria for aspects of another. The risk of a comorbid major mental disorder is increased in patients who qualify for a diagnosis of personality disorder. Anxious or fearful cluster C patients often respond to medications used for axis I anxiety disorders (see above). The syndrome commonly begins in late adolescence, has an insidious (and less commonly acute) onset, and, often, a poor outcome, progressing from social withdrawal and perceptual distortions to recurrent delusions and hallucinations. Patients may present with positive symptoms (such as conceptual disorganization, delusions, or hallucinations) or negative symptoms (loss of function, anhedonia, decreased emotional expression, impaired concentration, and diminished social engagement) and must have at least two of these for a 1-month period and continuous signs for at least 6 months to meet formal diagnostic criteria. Disorganized thinking or speech and grossly disorganized motor behavior, including catatonia, may also be present. As individuals age, positive psychotic symptoms tend to attenuate, and some measure of social and occupational function may be regained. The observed behaviors are not secondary to another mental disorder, nor are they precipitated by substance abuse or a general medical condition. However, marked variability in the course and individual character of symptoms is typical. The term schizophreniform disorder describes patients who meet the symptom requirements but not the duration requirements for schizophrenia, and schizoaffective disorder is used for those who manifest symptoms of schizophrenia and independent periods of mood disturbance. The terms "schizotypal" and "schizoid" refer to specific personality disorders and are discussed in that section. The diagnosis of delusional disorder is used for individuals who have delusions of various content for at least 1 month but who otherwise do not meet criteria for schizophrenia. Patients who experience a sudden onset of a brief (<1 month) alteration in thought processing, characterized by delusions, hallucinations, disorganized speech, or gross motor behavior, are most appropriately designated as having a brief psychotic disorder. Catatonia is recognized as a nonspecific syndrome that can occur as a consequence of other severe psychiatric/medical disorders and is diagnosed by the documentation of three or more of a cluster of motor and behavioral symptoms, including stupor, cataplexy, mutism, waxy flexibility, and stereotypy, among others. Prognosis depends not on symptom severity but on the response to antipsychotic medication. An estimated 300,000 episodes of acute schizophrenia occur annually in the United States, resulting in direct and indirect costs of $62. Drug reactions that cause hallucinations, paranoia, confusion, or bizarre behavior may be dose-related or idiosyncratic; parkinsonian medications, clonidine, quinacrine, and procaine derivatives are the most common prescription medications associated with these symptoms. The general neurologic examination in patients with schizophrenia is usually normal, but motor rigidity, tremor, and dyskinesias are noted in one-quarter of untreated patients. Genetic factors are involved in at least a subset of individuals who develop schizophrenia. The concordance rate for monozygotic twins is 50%, compared to 10% for dizygotic twins. Schizophrenia-prone families are also at risk for other psychiatric disorders, including schizoaffective disorder and schizotypal and schizoid personality disorders, the latter terms designating individuals who show a lifetime pattern of social and interpersonal deficits characterized by an inability to form close interpersonal relationships, eccentric behavior, and mild perceptual distortions. The mechanism of action involves, at least in part, binding to dopamine D2/D3 receptors in the ventral striatum; the clinical potencies of traditional antipsychotic drugs parallel their affinities for the D2 receptor, and even the newer "atypical" agents exert some degree of D2 receptor blockade. All neuroleptics induce expression of the immediate-early gene c-fos in the nucleus accumbens, a dopaminergic site connecting prefrontal and limbic cortices. Older agents, such as chlorpromazine and thioridazine, are more sedating and anticholinergic and more likely to cause orthostatic hypotension, whereas higher potency antipsychotics, such as haloperidol, perphenazine, and thiothixene, are more likely to induce extrapyramidal side effects. Paliperidone is a recently approved agent that is a metabolite of risperidone and shares many of its properties. Approximately 30% of patients who do not benefit from conventional antipsychotic agents will have a better response to this drug, which also has a demonstrated superiority to other antipsychotic agents in preventing suicide; however, its side effect profile makes it most appropriate for treatment-resistant cases. Risperidone is not as effective as clozapine in treatment-resistant cases but does not carry a risk of blood dyscrasias. Olanzapine is similar neurochemically to clozapine but has a significant risk of inducing weight gain. Quetiapine is distinct in having a weak D2 effect but potent 1 and histamine blockade. Aripiprazole also has little risk of weight gain or prolactin increase but may increase anxiety, nausea, and insomnia as a result of its partial agonist properties. Asenapine is associated with minimal weight gain and anticholinergic effect but may have a higher than expected risk of extrapyramidal symptoms. Antipsychotic agents are effective in 70% of patients presenting with a first episode. The choice of agent depends principally on the side effect profile and cost of treatment or on a past personal or family history of a favorable response to the drug in question. Atypical agents appear to be more effective in treating negative symptoms and improving cognitive function. An equivalent treatment response can usually be achieved with relatively low doses of any drug selected. Doses in this range result in >80% D2 receptor blockade, and there is little evidence that higher doses increase either the rapidity or degree of response. Maintenance treatment requires careful attention to the possibility of relapse and monitoring for the development of a movement disorder. Intermittent drug treatment is less effective than regular dosing, but gradual dose reduction is likely to improve social functioning in many schizophrenic patients who have been maintained at high doses. If medications are completely discontinued, however, the relapse rate is 60% within 6 months. Long-acting injectable preparations (risperidone, paliperidone, olanzapine, aripiprazole) are considered when noncompliance with oral therapy leads to relapses but should not be considered interchangeable, because the agents differ in their indications, injection intervals and sites/volumes, and possible adverse reactions, among other factors. In treatment-resistant patients, a transition to clozapine usually results in rapid improvement, but a prolonged delay in response in some cases necessitates a 6- to 9-month trial for maximal benefit to occur. Antipsychotic medications can cause a broad range of side effects, including lethargy, weight gain, postural hypotension, constipation, and dry mouth. In rare cases, more serious and occasionally life-threatening side effects may emerge, including hyperprolactinemia, ventricular arrhythmias, gastrointestinal obstruction, retinal pigmentation, obstructive jaundice, and neuroleptic malignant syndrome (characterized by hyperthermia, autonomic dysfunction, muscular rigidity, and elevated creatine phosphokinase levels). The most serious adverse effects of clozapine are agranulocytosis, which has an incidence of 1%, and induction of seizures, which has an incidence of 10%. Weekly white blood cell counts are required, particularly during the first 3 months of treatment. The risk of type 2 diabetes mellitus appears to be increased in schizophrenia, and second-generation agents as a group produce greater adverse effects on glucose regulation, independent of effects on obesity, than traditional agents. Clozapine, olanzapine, and quetiapine seem more likely to cause hyperglycemia, weight gain, and hypertriglyceridemia than other atypical antipsychotic drugs. Close monitoring of plasma glucose and lipid levels are indicated with the use of these agents. A serious side effect of long-term use of first-generation antipsychotic agents is tardive dyskinesia, characterized by repetitive, involuntary, and potentially irreversible movements of the tongue and lips (bucco-linguo-masticatory triad) and, in approximately half of cases, choreoathetosis. The prevalence increases with age, total dose, and duration of drug administration. The cause may involve formation of free radicals and perhaps mitochondrial energy failure. Vitamin E may reduce abnormal involuntary movements if given early in the syndrome. Olanzapine showed greater effectiveness than quetiapine, risperidone, perphenazine, or ziprasidone but also a higher discontinuation rate due to weight gain and metabolic effects. Surprisingly, perphenazine, a first-generation agent, showed little evidence of inferiority to newer drugs. Educational efforts directed toward families and relevant community resources have proved to be necessary to maintain stability and optimize outcome. A treatment model involving a multidisciplinary casemanagement team that seeks out and closely follows the patient in the community has proved particularly effective.

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