Medical Issues

Early Treatment of Ocular Hypertension May Reduce Risk for Glaucoma

2011-02-12T06:13:00.000+02:00

March 16, 2010 — Early treatment of ocular hypertension appears to reduce the risk for the development of glaucoma, especially in individuals at the highest risk, according to the results of a randomized controlled trial reported in the March issue of Archives of Ophthalmology.

"Elevated intraocular pressure (IOP) (ocular hypertension [OHT]) is a leading risk factor for the development of primary open angle glaucoma (POAG) and the only modifiable risk factor at present," write Michael A. Kass, MD, from Washington University School of Medicine in St. Louis, Missouri, and colleagues for the Ocular Hypertension Treatment Study (OHTS) Group. "It is estimated that 4% to 7% of the US population older than 40 years has OHT. There is substantial controversy on how to manage this large group of individuals who are at higher risk of developing glaucoma than the general population."

The goal of the study was to compare the safety and efficacy of earlier vs later treatment in reducing the risk for POAG in 1636 individuals with ocular hypertension, with baseline IOP ranging from 24 to 32 mm Hg in 1 eye and 21 to 32 mm Hg in the other eye. Participants were randomly assigned to observation or to receive topical ocular hypotensive medication. In the medication group, median duration of treatment was 13.0 years, whereas the observation group had a median duration of 7.5 years without treatment and then received medication for a median of 5.5 years.

To evaluate whether delaying treatment was associated with any harms, the investigators compared the cumulative proportion of participants who went on to have POAG in the original observation group and in the original medication group at a median follow-up of 13 years.

Overall, this proportion was 0.22 in the original observation group (95% confidence interval [CI], 0.19 - 0.25) vs 0.16 (95% CI, 0.13 - 0.19) in the original medication group (P =. 009), or a 27% reduction in glaucoma risk associated with early treatment. For participants at the highest tertile of baseline risk for the development of POAG, based on age, corneal thickness, and baseline IOP, the cumulative proportion of participants who went on to have POAG was 0.40 (95% CI, 0.33 - 0.46) and 0.28 (95% CI, 0.22 - 0.34), respectively.

"There was little evidence of increased adverse events associated with medication," the study authors write. "Absolute reduction was greatest among participants at the highest baseline risk of developing POAG. Individuals at high risk of developing POAG may benefit from more frequent examinations and early preventive treatment."

Limitations of the OHTS study include choice of a target IOP reduction of 20% from baseline, design not that of an epidemiologic study, use of very high thresholds for diagnosing POAG, and use of a convenience sample vs a population-based sample.

"We believe individualized assessment of the risk of developing POAG will be useful to patients and clinicians for deciding on the frequency of examinations and tests as well as the possible administration of preventive treatment," the study authors write. "Clinicians need to consider the patient's age, health status, life expectancy, and personal preferences when making such decisions. Ultimately, the full extent of the penalty for delaying treatment will require longer follow-up to ascertain the incidence and degree of visual impairment by randomization group."

In an accompanying editorial, Alfred Sommer, MD, MHS, from Bloomberg School of Public Health at Johns Hopkins University in Baltimore, Maryland, notes that clinicians should consider whether treating patients with IOP might do more harm than good.

"In the end, the physician is stuck with the persistent problem of whom to treat and whom to watch," Dr. Sommer writes. "The fascinating article by Kass et al provides interesting insights as to many of the issues at stake, but offers little definitive information to guide us. It probably still makes sense that young patients with lots of high risk factors should receive prophylaxis, while elderly patients with few risk factors should not. The endless symposia and debates on how best to manage patients with ocular hypertension will probably continue unabated."

The National Eye Institute and the National Center on Minority Health and Health Disparities, National Institutes of Health; Merck Research Laboratories; Pfizer Inc; and Research to Prevent Blindness supported this study. The study authors and Dr. Sommer have disclosed no relevant financial relationships.

Arch Ophthalmol. 2010;128:276-287.

Clinical Context

Glaucoma is one of the most common causes of blindness in the United States worldwide and has a higher incidence among African Americans than other racial groups. Elevated IOP is a leading risk factor for POAG, with 4% to 7% of the US population older than 40 years having ocular hypertension. Early medical treatment with topical hypotensive treatment in those with ocular hypertension has been shown to delay or prevent the onset of POAG but it is uncertain if duration of treatment affects the protective effects.

This is a randomized controlled trial conducted in adults with ocular hypertension to determine if medical vs delayed medical treatment in those with ocular hypertension is associated with reduced risk for POAG and if the effects differ in different risk groups.

Study Highlights

Inclusion criteria were ages 40 to 80 years, qualifying IOP of 24 mm Hg or higher or 32 mm Hg or less in 1 eye and 21 mm Hg or higher or 32 mm Hg or less in the other eye, gonioscopically open angles, 2 normal and reliable visual fields per eye, and normal optic discs.
Excluded were those with vision worse than 20/40 in either eye, with a history of ocular surgery, diabetic retinopathy, or optic disc degeneration.
The study involved 2 phases.
In phase 1, at baseline 817 participants were randomly assigned to topical ocular hypotensive agents and were observed for 13 years.
819 were randomly assigned to observation only at baseline with no ocular hypotensive agents.
In phase 2, after 7.5 years, the observation group was given ocular hypotensive treatment for the next 5.5 years and thus received delayed treatment.
Follow up visits occurred every 6 months and included a medical and ocular history, determination of refraction and visual acuity, Humphrey white-on-white 30-2 visual field test, slit-lamp examination, IOP measurement, and direct ophthalmoscopy.
Participants also completed self-administered questionnaires consisting of the Glaucoma Symptom Checklist, the National Eye Institute Visual Function Questionnaire (every 24 months from 114 months), and the Medical Outcomes Study-Short Form with 36 questions.
POAG was defined as the development of reproducible visual field abnormality or clinically significant optic disc deterioration in 1 or both eyes that was attributed to POAG.
Optic disc degeneration was defined as generalized or localized disc thinning of the neuroretinal rim vs baseline stereoscopic disc photographs.
Primary endpoint was proportion of participants in whom POAG developed.
Mean age was 55 years, and median follow-up was 13 years.
Those in the observation with delayed treatment group had no medication for 7.5 years and were treated for 5.5 years.
The cumulative proportion of participants in whom POAG developed from baseline to 13 years was 0.19 overall, 0.22 for the observation with delayed treatment group, and 0.16 for the treatment group (P = .009), with a relative risk of 0.42 (P < .001) for the medication group.
In phase 2, the cumulative proportion who had POAG to 13 years was similar in the 2 groups (hazard ratio, 1.06; P = .77).
More participants in the observation vs the treatment group went on to have bilateral POAG at 13 years (6.2% vs 3.9%).
Similarly, more participants in the observation group vs the treatment group experienced glaucomatous visual field loss (2.3% vs 1.2%).
The cumulative proportion of African Americans in whom POAG developed was higher vs other races (0.28 vs 0.16).
The protective effect of treatment was significant during phase 1 for African Americans (hazard ratio, 0.47), but the proportions were similar in phase 2 when both groups received treatment.
African American status was a significant predictor of development of POAG (hazard ratio, 1.70).
The number of Hispanic patients was too small (n = 59) to determine risk.
When examined by baseline risk tertile, the cumulative proportion of participants who had POAG to 13 years were 6%, 6% to 13%, and more than 13% for the first, second, and third tertiles, respectively.
The numbers needed to treat to prevent 1 case of POAG during 13 years of treatment were 98, 16, and 7 for the first, second, and third tertiles of risk, respectively.
There were no significant differences in adverse effects or mortality rates in the observation and treatment groups.
The authors concluded that hypotensive ocular treatment reduced the risk for POAG in those with increased IOP, and the protective effect was greatest in those at highest risk and in African Americans.

Clinical Implications

Use of ocular hypotensive agents in those with IOP is associated with a reduced risk for POAG at 13 years.
The protective effect of ocular hypotensive medications is greatest in those with the highest baseline risk for POAG.

Unintentional Therapeutic Errors Involving Insulin in the Ambulatory Setting Reported to Poison Centers

2011-02-10T18:54:00.000+02:00

Background: Adverse drug events in the ambulatory care setting are not uncommon and can cause significant morbidity. Little research has been published on the management of adverse drug events involving insulin in the outpatient setting.
Objective: To analyze data on patients with unintentional therapeutic errors involving insulin managed by 9 regional poison control centers.
Methods: A retrospective search was performed for all records involving insulin at 9 poison centers, covering the population of 4 states for the years 2000–2009. A subgroup of the study population was selected with a reason for exposure of "unintentional—therapeutic error."
Results: There were 3819 insulin exposures reported, with an increase in the annual incidence of insulin exposures of 279% (from 170 to 645 patients/year) and a mean annual increase of 18%. Of the insulin exposures, 2584 were unintentional therapeutic errors (68%). The percentage of all insulin exposures that were unintentional therapeutic errors increased progressively, from 41% to 78%. There was a 495% increase in annual incidence of unintentional therapeutic errors involving insulin, with a mean annual increase of 28%. Unintentional therapeutic errors involving insulin occurred primarily in adults >40 years (73%), with 63% occurring in women. There was a pronounced increase in unintentional therapeutic errors involving insulin in the later evening hours, with 71% occurring between 1800 and 2400 and reaching a peak at 2200. The majority (n = 1803; 70%) of patients were managed in a non–health-care facility location, primarily their own residence.
Conclusions: This is the first report of an increasing trend of insulin-related unintentional therapeutic errors in the ambulatory setting. Our study highlights a number of striking features, including: (1) a consistent and dramatic increase of unintentional therapeutic errors involving insulin over the 10-year period, (2) a high incidence of unintentional therapeutic errors involving insulin in the late evening hours, and (3) a high incidence of unintentional therapeutic errors involving insulin involving adults >40 years and females. With their 24/7 availability, poison centers appear to be an increasingly important resource for patients experiencing unintentional therapeutic errors involving insulin.

Introduction

Adverse drug events in the ambulatory care setting are not uncommon and can cause significant morbidity.^[1–4]Insulin is one of the leading medications involved in adverse drug events leading to an emergency department visit, especially in older adults.^[2] However, the published data on insulin adverse drug events have focused primarily on the hospital setting.^[1–4] There is a lack of information on the epidemiology of insulin-associated adverse drug events in the ambulatory care or non–hospital-based setting. One study of a poisons unit in Germany found that 5% of insulin overdoses were accidental, and 90% of the cases were intentional suicidal insulin overdose, with all inquiries coming from the physician caring for the patient, suggesting these cases were not being managed in the ambulatory setting.^[5]

In the US, poison control centers are able to manage the majority of their patients in the ambulatory care setting, often reducing the need for an unnecessary emergency department visit. Poison control centers manage more than 200,000 adverse drug events annually, with 88% of these patients managed outside of the hospital setting.^[3,7] The real-time database of these centers would be a rich source of information on insulin adverse drug events in the ambulatory care setting. To date, no information has been published evaluating insulin adverse drug events in this setting. The objective of this study was to delineate characteristics and outcomes of unintentional therapeutic errors involving insulin, with a focus on cases in the ambulatory care setting.

I am back!

2011-02-10T18:47:00.001+02:00

Gone for few years. I am back to continue blogging :D

Foreign Body Removal, Rectum

2008-10-19T23:42:00.001+03:00

Anorectal foreign bodies are usually inserted transanally for sexual or medicinal purposes. Rectal foreign bodies may also be observed with body packing or stuffing or after prior oral ingestion of the object. Anorectal foreign bodies are more common in men than in women.

Rectal foreign bodies may include such objects as bottles, vibrators, fruit, vegetables, and balls. Cylindrical objects are common. In addition, thermometers may accidentally break while a rectal temperature is being obtained.

Be aware that patients have usually made multiple attempts to remove the object prior to presentation in the emergency department. Patients may create unusual stories to explain how the object became lodged in the rectum.

Read more HERE

2008-10-19T12:01:00.000+03:00

Astrocytoma

2008-10-05T22:01:00.001+03:00

Background

Astrocytomas are CNS neoplasms in which the predominant cell type is derived from an immortalized astrocyte. Two classes of astrocytic tumors are recognized—those with narrow zones of infiltration (eg, pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma) and those with diffuse zones of infiltration (eg, low-grade astrocytoma, anaplastic astrocytoma, glioblastoma). Members of the latter group share various features, including the ability to arise at any site in the CNS, with a preference for the cerebral hemispheres; clinical presentation usually in adults; heterogeneous histopathological properties and biological behavior; diffuse infiltration of contiguous and distant CNS structures, regardless of histological stage; and an intrinsic tendency to progress to more advanced grades.

Numerous grading schemes based on histopathologic characteristics have been devised, including the Bailey and Cushing grading system, Kernohan grades I-IV, World Health Organization (WHO) grades I-IV, and St. Anne/Mayo grades 1-4. Regions of a tumor demonstrating the greatest degree of anaplasia are used to determine the histologic grade of the tumor. This practice is based on the assumption that the areas of greatest anaplasia determine disease progression.

This chapter focuses on the widely accepted WHO grading scheme that relies on assessments of nuclear atypia, mitotic activity, cellularity, vascular proliferation, and necrosis. WHO grade I corresponds to pilocytic astrocytoma, WHO grade II corresponds to low-grade (diffuse) astrocytoma, WHO grade III corresponds to anaplastic astrocytoma, and WHO grade IV corresponds to glioblastoma multiforme (GBM). This article is confined to low-grade and anaplastic astrocytomas. GBM and pilocytic astrocytoma are not discussed in this chapter (for more information, see Glioblastoma Multiforme).
Pathophysiology

Regional effects of astrocytomas include compression, invasion, and destruction of brain parenchyma. Arterial and venous hypoxia, competition for nutrients, release of metabolic end products (eg, free radicals, altered electrolytes, neurotransmitters), and release and recruitment of cellular mediators (eg, cytokines) disrupt normal parenchymal function. Elevated intracranial pressure (ICP) attributable to direct mass effect, increased blood volume, or increased cerebrospinal fluid (CSF) volume may mediate secondary clinical sequelae. Neurological signs and symptoms attributable to astrocytomas result from perturbation of CNS function. Focal neurological deficits (eg, weakness, paralysis, sensory deficits, cranial nerve palsies) and seizures of various characteristics may permit localization of lesions.

Infiltrating low-grade astrocytomas grow slowly compared to their malignant counterparts. Doubling time for low-grade astrocytomas is estimated at 4 times that of anaplastic astrocytomas. Several years often intervene between the initial symptoms and the establishment of a diagnosis of low-grade astrocytoma. One recent series estimated the interval to be approximately 3.5 years. The clinical course is marked by a gradual deterioration in one half of cases, a stepwise decline in one third of cases, and a sudden deterioration in 15% of cases. Seizures, often generalized, are the initial presenting symptom in about one half of patients with low-grade astrocytoma.

For patients with anaplastic astrocytomas, the growth rate and interval between onset of symptoms and diagnosis is intermediate between low-grade astrocytomas and glioblastomas. Although highly variable, a mean interval of approximately 1.5-2 years between onset of symptoms and diagnosis frequently is reported. Compared to low-grade lesions, seizures are less common among patients with anaplastic astrocytomas. Initial presenting symptoms most commonly are headache, depressed mental status, and focal neurological deficits.
Mortality/Morbidity

Morbidity and mortality, as defined by the length of a patient's history and the odds of recurrence-free survival, are correlated most highly with the intrinsic properties of the astrocytoma in question. Typical ranges of survival are approximately 10 years from the time of diagnosis for pilocytic astrocytomas (WHO grade I), more than 5 years for patients with low-grade diffuse astrocytomas (WHO grade II), 2-5 years for those with anaplastic astrocytomas (WHO grade III), and less than 1 year for patients with glioblastoma (WHO grade IV).
Race

Although genetic determinants are recognized in astrocytoma development and progression, astrocytomas do not differ intrinsically in incidence or behavior among racial groups. Demographic and sociological factors, such as population, age, ethnic attitude toward disease, and access to care, have been reported to influence measured distributions.
Sex

No clear sex predominance has been identified in the development of pilocytic astrocytomas. A slight male predominance, with a male-to-female ratio of 1.18:1 for development of low-grade astrocytomas, has been reported. A more significant male predominance, with a male-to-female ratio of 1.87:1 for the development of anaplastic astrocytomas, has been identified.
Age

Most cases of pilocytic astrocytoma present in the first 2 decades of life. In contrast, the peak incidence of low-grade astrocytomas, representing 25% of all cases in adults, occurs in people aged 30-40 years. Ten percent of low-grade astrocytomas occur in people younger than 20 years; 60% of low-grade astrocytomas occur in people aged 20-45 years; and 30% of low-grade astrocytomas occur in people older than 45 years. The mean age of patients undergoing a biopsy of anaplastic astrocytoma is 41 years.

Read more HERE

2008-09-08T16:43:00.001+03:00

2008-09-03T19:57:00.001+03:00

2008-09-01T15:29:00.000+03:00

2008-08-09T15:44:00.001+03:00

Sexual and Gender Identity Disorders

2008-08-01T18:18:00.003+03:00

History

The study of sexual deviancy began just before the turn of the 20th century as the taboo of discussing sexuality was beginning to lift. Early pioneers included Richard von Kraff-Ebing, Albert Moll, August Forel, Iwan Bloch, Magnus Hirschfield, Havelock Ellis, and Sigmund Freud. Their work was not well accepted, and they were regarded with disdain.

Several psychiatric concepts were prominent at this time. One of them was a constitutional predisposition of unknown origin called degeneration, which refers to an innate neurologic weakness that is transmitted with increased severity to future generations and produces deviations from the norm. Masturbation was blamed for a list of diseases including insanity, suicide, self-mutilation, and tuberculosis. The law of association of ideas suggests that when sex and another experience occur, one stimulus sets off the other.

Ellis worked against the prudish view of sex that existed at the time, and he advocated the decriminalization of homosexuality. Freud wrote on fetishism, masochism, and the theory of perversions. These early investigators of sexual deviation provide an important principal: "Not only must the act be studied, but also the person. The personal roots of deviance spring from an interaction of the individual's biological nature and his early life experiences."

Disorders of human behavior remain difficult to understand, identify, and treat. Few data are available, too much of our knowledge is based on speculation and unsupported theory, and societal stereotypes influence our perceptions. Good science-based research remains difficult, and monetary, ethical, and legal concerns complicate such research.

PARAP
Sexual deviation is a term applicable to a subclass of sexual disorders termed paraphilias. Paraphilias are associated with arousal in response to sexual objects or stimuli not associated with normal behavior patterns and that may interfere with the establishment of sexual relationships. In modern classification systems, the term paraphilia is preferable to sexual deviation because it clarifies the essential nature of this group of behaviors (ie, arousal in response to an inappropriate stimulus).

The American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), the prevailing resource for diagnostic criteria of paraphilias, describes the essential feature of paraphilias as recurrent, intense, sexual urges and sexually arousing fantasies generally involving nonhuman objects, the suffering or humiliation of oneself or partner, or children or other nonconsenting persons. The DSM-IV-TR describes 8 of the more commonly observed paraphilias and makes reference to several other examples. People who experience one paraphilia may also experience other paraphilias, although the paraphilia may occur as an isolated event. Commonly, people who manifest paraphilias also exhibit personality disorders, substance abuse problems, or affective disorders.

Prevalence

Paraphilias are rarely diagnosed in clinical settings. Large commercial markets in paraphiliac pornography and paraphernalia are testaments that prevalence is high. Pedophilia, voyeurism, and exhibitionism are the most commonly observed behaviors in clinics that specialize in paraphilia treatment. Sexual masochism and sexual sadism are much less commonly observed. Approximately half of patients observed in clinics for treatment of paraphilias are married.

Differentials

Nonparaphiliacs may describe nonpathological use of sexual fantasies, behaviors, or objects as stimuli for sexual excitement.

In patients with mental retardation, paraphilia should be distinguished from dementia, personality change due to general medical condition, substance intoxication, manic episode, or schizophrenia in which judgment, social skills, or impulse control are compromised.

When appropriate, public urination should be distinguished from exhibitionism.

Exhibitionism

The DSM-IV-TR diagnostic criteria for exhibitionism are as follows:

The patient reports recurrent, intense, sexual urges and sexually arousing fantasies related to exposing the genitals to a stranger. Symptoms must be present for at least 6 months.
The patient experiences significant distress or impairment in social, occupational, or other important areas of functioning because of the fantasies, urges, or behaviors.
Generally, no attempt at further sexual activity with the stranger occurs, although a desire to shock the stranger sometimes exists or the exhibitionist may have a fantasy that the observer will become sexually aroused. Onset usually occurs in persons younger than 18 years but may occur later. The disorder causes significant stress or impairment in social, occupational, or other important areas of functioning. In 1975, Rooth classified 2 types of exhibitionism: Type I is the inhibited flaccid exposer, and type II is the sociopathic exposer who may have a history of other conduct. About half of adult women have witnessed indecent exposure sometime in their lives.

Exhibitionists, whether timid or brash, feel dominated by women and resent it. By exposing themselves, exhibitionists turn the table on women, dominating rather than being dominated. Exhibitionists view this act as making women their helpless victims, rather than being helpless before them. Some researchers have suggested that exhibitionists have a fragile sense of masculinity. Threats to masculinity are countered by demonstrations of manliness.

Exhibitionists have difficulty relating to women as whole people. Rather, women are present merely to provide both gratification and proof against castration. Many exhibitionists are very prudish with their wives. They go to great efforts to never look at their wives or be seen by them in the nude. Intercourse tends to be rigid and conventional.

Common to all exhibitionists is some abnormality in handling aggression and hostility. On the one hand, they must keep their anger under tight control, yet on the other hand they may become tyrannical with their family because they feel safe from retaliation.

Male genital exhibitionism is an indicator of future sexual offenses in some individuals. In a 1980 longitudinal study, Bluglass found that 7% of exhibitionists were later convicted of contact sexual offenses, including rape.

Genital exhibitionism is rare among women. This has been explained by the differences between the sexes in the development of the castration complex and the absence of a reassuring effect from showing a penis because of anatomic differences in women. Eber in a 1977 report and Kohut in a 1978 report view female exhibitionism as a disorder of bodily narcissism.

Presentation to physicians is common and may result from a sense of guilt and an inability to control the behavior. Sometimes the behavior is revealed as the result of a criminal offense. More serious underlying pathology is suggested when preferred scenes include defecation or small children.

Fetishism

The DSM-IV-TR lists the following diagnostic criteria for fetishism:

The patient experiences recurrent and intense sexual urges and sexually arousing fantasies involving the use of nonliving objects by themselves. Symptoms must be present for at least 6 months.
The patient experiences significant distress or impairment in social, occupational, or other important areas of functioning because of the fantasies, urges, or behaviors.
The fetishes are not limited to articles of female clothing used in cross-dressing (transvestic fetishism) or devices designed for genital stimulation (eg, vibrators).
Common fetishistic objects include female underwear; rubber, plastic, or leather garments; specific articles of clothing such as shoes or boots; and bodily items such as hair, odors, or feces. The disorder is more common among males than females. Prevalence is unknown. It can often be traced from adolescence and usually persists.

In the context of psychoanalytic theory, in a 1996 publication Greenacre associates fetishism with a severe castration complex in males and a more complicated and less readily recognized set of relational reactions in females. For men, the fetish serves a defensive function, a reinforcing adjunct for a penis of uncertain potency. The fetish serves to increase the efficiency of the penis, which does not perform well without it. In women, fetishism is less common, largely because of anatomic differences that allow women to conceal inadequate sexual response more readily than men. Women can develop symptoms more comparable to male fetishism when the illusion of having a phallus has gained sufficient strength to approach delusional proportions. This occurs in rare cases in which severe disturbances in the sense of reality exist.

Treatment of the specific condition (fetish), rather than the primary underlying disorder (eg, organic pathology, personality disorder) generally is unsuccessful. A variety of treatment approaches have been tried, such as aversive conditioning, cognitive therapy, and psychotherapy.

Frotteurism

The DSM-IV-TR lists the following diagnostic criteria for frotteurism:

The patient experiences intense, recurrent, sexual urges and sexually arousing fantasies involving touching and rubbing against a nonconsensual person. Symptoms must be present for at least 6 months.
The patient experiences significant distress or impairment in social, occupational, or other important areas of functioning because of the fantasies, urges, or behaviors, or the patient has acted on the sexual urges.
Frotteurs typically act out their fantasies in crowded places (eg, public transportation vehicles, busy sidewalks), which allows for escape; the frotteur can claim that the touching was accidental. The frotteur rubs his genital area against the (usually female) victim's thighs or buttocks, or the frotteur fondles a woman's genitalia or breasts with his hands. While committing the act, the offender typically fantasizes about an exclusive, caring relationship with the victim.

Most acts occur in perpetrators aged 15-25 years, after which frequency gradually declines. Frotteurism has been noted to be equally common among older, shy, inhibited individuals. Fantasies of frotteuristic behavior without action have been reported as a stimulant to sexual arousal.

Voyeurism

The term voyeurism, from the French word meaning to see, refers to the fairly common desire to view nudity and acts of coition. Differentiating innocent enjoyment of nudity from behavior that is similar but deviant in other circumstances can be difficult.

The DSM-IV-TR diagnostic criteria for voyeurism are as follows:

The patient has recurrent and intense sexual urges and sexually arousing fantasies involving the act of observing an unsuspecting person who is naked, in the process of disrobing, or engaging in sexual activity. Symptoms must be present for at least 6 months.
The patient experiences significant distress or impairment in social, occupational, or other important areas of functioning because of the fantasies, urges, or behaviors.
When severe, the act of peeping constitutes the exclusive form of sexual activity. Onset usually is in persons younger than 15 years, and the disorder tends to be chronic. The wide extent of voyeuristic tendencies in the general population is evidenced in the common desire to indulge in exploitative activities such as live shows and pornography.

Pedophilia

The essential features of this disorder as described by the DSM-IV-TR include the following:

The patient reports recurrent and intense sexually arousing fantasies, sexual urges, or behaviors involving sexual activity with a prepubescent child or children, generally aged 13 years or younger.
Pedophiles must be aged 16 years or older and be at least 5 years older than the victim.
The disorder causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
The clinician should specify if the person is attracted to males, females, or both; if the acts are limited to incest; and if the patient is attracted to children only (exclusive type) or both children and adults (nonexclusive type).
While female pedophiles are considered to be rare, discrepancies between the numbers of male and female offenders are tied to sexual stereotypes. Masculinity connotes sexual qualities, while femininity connotes maternal qualities and nurturance. When a female pets a child, she is nurturing. When a male pets a child, he is molesting. The majority of men who have had sexual contact with a woman when they were boys viewed it positively rather than negatively. Consequently, these acts were probably unreported. In one study, 16% of college males and 46% of prisoners reported having had sexual contact with older females, and half of the encounters involved intercourse. Mean age of males at the time of sexual contact was 12 years, and the females with whom they were involved were aged 20-30 years.

Many pedophiles have a personal history of unstable parent-child relationships as children and sexual abuse. The majority of pedophiles have a clear sexual preference. The undifferentiated or bisexual group accounts for only 5-25% of pedophiles. Most studies indicate that 60-90% of incidents of abuse involve girls.

Great variation exists among men who use children sexually. One third to one half prefer children as sexual partners. Others are attracted to children but act on their impulses only under stress. Some, who typically are younger than 30 years, are sociosexually underdeveloped, lack age-appropriate experience, and have feelings of shyness and inferiority. Unable to attain adult female contact, they continue prepubescent sexual patterns. Amoral delinquent youths (younger than pedophiles proper), lacking control when aroused, use whoever is close at hand. Patients with the situational type of pedophilia have no special preference for children, although they have sexual contact with children because of convenience or coincidence. Contact typically is brief and nonrecurrent. A residual category of offenders includes people with mental retardation, psychosis, alcoholism, senility, or dementia.

Approximately 37% of sexual assault victims reported to law enforcement agencies were juveniles ( <18 y); 34% of all victims were younger than 12 years. One in 7 victims is younger than 6 years. Forty percent of offenders who victimized children younger than 6 years were juveniles ( <18 y).

Sexual masochism

The essential features of this disorder as described by the DSM-IV-TR include the following:

The patient reports recurrent and intense sexual urges and sexually arousing fantasies involving the act (real, not simulated) of being humiliated, beaten, bound, or otherwise made to suffer. Symptoms must be present for at least 6 months.
The fantasies, urges, or behaviors cause significant distress or impairment in social, occupational, or other important areas of functioning.
Masochistic acts commonly involve a wide range of activities, such as restraint, blindfolding, beating, electrical shock, cutting, piercing, and humiliation (eg, being urinated or defecated on, forced to bark, verbally abused, forced to cross-dress). Some sexual masochists inflict pain through self-mutilation, and some engage in group activity or use services provided by prostitutes.

Hypoxyphilia is a dangerous form of masochism that involves sexual arousal by oxygen deprivation achieved by means of chest compression, noose, ligature, plastic bag, mask, or chemicals. Oxygen deprivation may be accomplished alone or with a partner. Data from the United States, England, Australia, and Canada indicate that 1-2 deaths per million population are reported each year.

Some sexually masochistic males also exhibit fetishism, transvestic fetishism, or sexual sadism. Masochistic sexual fantasies are likely present in childhood. Masochistic activities commonly begin by early adulthood, tend to be chronic, and the same act is generally repeated. Some individuals increase the severity of the act over time, which may lead to injury or death.

In 1926, Sadger observed a common association between homosexuality and masochism. In a 1977 report, Spengler found that 38% of exclusive homosexuals were sadomasochists, which provides some support for Sadger's observation.

Ritualized behavior is a noted feature of masochistic scenes; the slightest deviation from the script may result in failure to achieve the desired result. This feature is also viewed as a mechanism through which the masochist maintains control.

Sexual sadism

The DSM-IV-TR diagnostic criteria for sexual sadism are as follows:

The patient reports recurrent and intense sexual urges and sexually arousing fantasies involving the act (real, not simulated) in which the psychological or physical suffering (including humiliation) of one person is sexually arousing to another person. Symptoms must be present for at least 6 months.
The fantasies, urges, or behaviors cause significant distress or impairment in social, occupational, or other important areas of functioning.
Sadistic fantasies or acts may involve activities such as dominance, restraint, blindfolding, beating, pinching, burning, electrical shock, rape, cutting, stabbing, strangulation, torture, mutilation, or killing. Sadistic sexual fantasies are likely present in childhood. Onset of sadistic activities commonly occurs by early adulthood, and it tends to be chronic.

Some individuals do not increase the severity of their sadistic acts; however, severity of the sadistic acts does usually increase over time. When practiced with nonconsenting partners, the activity is likely to be repeated until the perpetrator is apprehended. When sexual sadism is severe and associated with antisocial personality disorder, victims may be seriously injured or killed.

No clear lines divide sexual sadism and sexual masochism, and the predispositions are often interchangeable. The conditions may coexist in the same individual, sometimes in association with other paraphilias. This relationship is supported by the finding that those who entertain masochistic fantasies also engage in sadistic fantasies. In the context of psychoanalytic theory, Panken in a 1973 publication does not find that the conditions coexist in an individual and claims that the dynamics are different.

Transvestic fetishism

Transvestic fetishism is defined by DSM-IV-TR diagnostic criteria as follows:

The patient is a heterosexual male who has recurrent, intense, sexually arousing fantasies, urges, or behaviors involving cross-dressing. Symptoms must be present for at least 6 months.
These fantasies, urges, or behaviors cause significant distress or impairment in social, occupational, or other important areas of functioning.
If gender dysphoria is present, it should be specified.
Fetishistic transvestism is essentially unheard of in females. Women may cross-dress, but no literature (English) describes cross-dressing females who become sexually excited by the activity.

Other paraphilias

Sexual arousal may be obtained from a wide array of additional behaviors. Some are provided with the assistance of prostitutes, others find willing partners when needed. Other paraphilias include the following:

Scatologia (obscene phone calls)
Necrophilia (corpses)
Partialism (exclusive focus on part of body)
Zoophilia (animals)
Coprophilia (feces)
Klismaphilia (enemas)
Urophilia (urine)

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Botulism

2008-08-01T18:01:00.001+03:00

Botulism is an acute neurologic disorder with potentially life-threatening neuroparalysis that is caused by a neurotoxin produced by Clostridium botulinum (CB). The toxin binds irreversibly to the presynaptic membranes of peripheral neuromuscular and autonomic nerve junctions. Toxin binding blocks acetylcholine release, resulting in weakness, flaccid paralysis, and (often) respiratory arrest. Cure occurs following sprouting of new nerve terminals.

The 3 main clinical presentations of botulism include infant, food-borne, and wound. Additionally, because of the potency of the toxin, the possibility of botulism as a bioterrorism agent or biological weapon is a great concern.

Infant botulism (IB) arises from ingested botulism spores that germinate in the intestine and produce toxin. These spores typically come from bee honey or the environment. Most infants fully recover with supportive treatment; the infant mortality rate is less than 1%. Improperly canned or home-prepared foods are common sources of the toxin that can result in food-borne botulism (FBB). Wound botulism (WB) results from contamination of the wound with toxin-producing CB. FBB and WB occur predominantly in adults and are the focus of this article.

CB is an anaerobic gram-positive rod that survives in soil and marine sediment by forming spores. Under anaerobic conditions that permit germination, it synthesizes and releases a potent exotoxin. Microbiologically, the organism stains gram-positive in cultures less than 18 hours old. The organism may stain gram-negative after 18 hours of incubation, potentially complicating attempts at diagnosis. On a molecular weight basis, botulinum toxins are the most potent toxins known.

Eight antigenically distinct CB toxins are known, including A, B, C (alpha), C (beta), D, E, F, and G. Each strain of CB is limited to producing a single toxin type. Types A, B, E, and (rarely) F cause human disease. Toxins A and B are the most potent, and the consumption of small amounts of food contaminated with them has resulted in full-blown disease. During the last 20 years, toxin A has been the most frequent cause of food-borne outbreaks; toxins B and E follow in frequency. In 15% of CB outbreaks, the toxin type is not determined. Toxins C and D cause disease in a variety of animals. Type G toxin has been associated with sudden death but not with neuroparalytic illness. It was isolated from autopsy material from 5 patients in Switzerland in 1977.

Pathophysiology
The mechanism of action involves toxin-mediated blockade of neuromuscular transmission in cholinergic nerve fibers. This is accomplished by either inhibiting acetylcholine release at the presynaptic clefts of the myoneural junctions or by binding acetylcholine itself. Toxins are absorbed from the stomach and small intestine where they are not denatured by digestive enzymes. Subsequently, they are hematogenously disseminated and block neuromuscular transmission in cholinergic nerve fibers. The nervous, gastrointestinal, endocrine, and metabolic systems are predominantly affected. Because the motor end plate responds to acetylcholine, botulinum toxin ingestion results in hypotonia that manifests as descending symmetric flaccid paralysis and is usually associated with gastrointestinal symptoms of nausea, vomiting, and diarrhea. Cranial nerves are affected early in the course of disease. Later complications include paralytic ileus, severe constipation, and urinary retention.

WB results when wounds are contaminated with CB spores. It has occurred (1) after traumatic injury that involved soil contamination, (2) among injection drug users, particularly those who use black-tar heroin, and (3) after cesarean delivery. The wound may appear deceptively benign. Traumatized and devitalized tissue provides an anaerobic medium for the spores to germinate into vegetative organisms and produce neurotoxin, which then disseminates hematogenously. The nervous, endocrine, and metabolic systems are predominantly affected. Symptoms develop after an incubation period of 4-14 days, with a mean of 10 days. The clinical symptoms of WB are similar to those of FBB except that gastrointestinal symptoms (including nausea, vomiting, diarrhea) are uncommon.

Frequency
United States
The frequency is 0.034 cases out of 100,000 population, of which nearly 75% are associated with IB.

FBB incidences total 24 cases per year. WB incidences total 3 cases per year and 3 cases per year from the young adult cohort (aged 18-25 y). IB incidences total 71 cases per year, with a mean age of 3 months. FBB incidence totals 24 cases per year drawn from all age cohorts.

Toxin A is found predominantly west of the Mississippi River. Toxin B is found most commonly in the eastern United States. Toxin E is found in northern latitudes, such as the Pacific Northwest, the Great Lakes region, and Alaska. The native peoples have some of the highest rates of botulism in the world. Toxin E outbreaks frequently are associated with fish products.

International
Human botulism is found worldwide. Spores from organisms producing type A or B toxins are distributed widely in the soil and have been found throughout the world. Toxin type B commonly is found in Europe. Toxin G originally was isolated in Switzerland.

Mortality/Morbidity

Mortality rates vary according to age of the patient and the type of botulism observed. In FBB, a 25% mortality rate exists overall; however, the rate is 10% in patients younger than 20 years. In WB, the mortality rate varies (15-17%); in IB, the mortality rate usually is less than 1%.
The recovery period from botulism often is quite long (30-100 d). Some patients demonstrate residual weakness or autonomic dysfunction for 1 year after the onset of the illness. However, full neurologic recovery is usual. Permanent deficits may occur in those who sustain significant hypoxic insults.

Sex
Males present more frequently with WB than females. Males and females present with FBB in equal numbers.

Age
FBB and WB predominately occur in adults.

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Diabetes Mellitus, Type 1

2008-08-01T17:58:00.001+03:00

Diabetes mellitus (DM) is a multisystem disease with both biochemical and anatomical consequences. It is a chronic disease of carbohydrate, fat, and protein metabolism caused by the lack of insulin. In type 1 diabetes, insulin is functionally absent because of the destruction of the beta cells of the pancreas. Type 1 DM occurs most commonly in juveniles but can occur in adults, especially in those in their late 30s and early 40s. Unlike people with type 2 DM, those with type 1 DM generally are not obese and may present initially with diabetic ketoacidosis (DKA).

Pathophysiology
Type 1 DM is a catabolic disorder in which circulating insulin is very low or absent, plasma glucagon is elevated, and the pancreatic beta cells fail to respond to all insulin-secretory stimuli. Patients need exogenous insulin to reverse this catabolic condition, prevent ketosis, decrease hyperglucagonemia, and normalize lipid and protein metabolism.

Type 1 DM is an autoimmune disease. The pancreas shows lymphocytic infiltration and destruction of insulin-secreting cells of the islets of Langerhans, causing insulin deficiency. Approximately 85% of patients have circulating islet cell antibodies, and the majority also have detectable anti-insulin antibodies before receiving insulin therapy. Most islet cell antibodies are directed against glutamic acid decarboxylase (GAD) within pancreatic B cells.

One theory regarding the etiology of type 1 DM is that it results from damage to pancreatic beta cells from an infectious or environmental agent. It triggers the immune system in a genetically susceptible individual to develop an autoimmune response against altered pancreatic beta cell antigens or molecules in beta cells that resemble a viral protein. Currently, autoimmunity is considered the major factor in the pathophysiology of type 1 DM. Prevalence is increased in patients with other autoimmune diseases, such as Graves disease, Hashimoto thyroiditis, and Addison disease. Approximately 95% of patients with type 1 DM have either human leukocyte antigen (HLA)-DR3 or HLA-DR4. HLA-DQs are considered specific markers of type 1 DM susceptibility.

Environmental agents that have been hypothesized to induce an attack on beta cell function include viruses (eg, mumps, rubella, Coxsackie B4), toxic chemicals, exposure to cow's milk in infancy, and cytotoxins.

Recent evidence suggests a role for vitamin D in the pathogenesis and prevention of diabetes mellitus.

Frequency
United States
Roughly 5-15% of all cases of diabetes are type 1 DM. It is the most common metabolic disease of childhood, with a yearly incidence of 15 cases per 100,000 people younger than 18 years. Approximately 1 million Americans have type 1 DM, and physicians diagnose 10,000 new cases every year.

According to the American Diabetes Association, there are 20.8 million children and adults in the United States, or 7% of the population, who have diabetes. While an estimated 14.6 million have been diagnosed, unfortunately, 6.2 million people (or nearly one-third) are undiagnosed. Fifty-four million people are prediabetes status. In people younger than 20 years, 176,500 cases, or 0.22% of all people in this age group, have diabetes. About one in every 400-600 children and adolescents has type 1 DM. Two million adolescents (or 1 in 6 overweight adolescents) aged 12-19 years have prediabetes status. In people aged 20 years or older, 1.5 million new cases of diabetes were diagnosed in 2005.

International
Scandinavia has the highest prevalence rates for type 1 DM (ie, approximately 20% of the total number of people with DM), while China and Japan have the lowest prevalence rates, with less than 1% of all people with diabetes. Some of these differences may relate to definitional issues and the completeness of reporting.

Mortality/Morbidity
Type 1 DM is associated with a high morbidity and premature mortality due to complications. The annual financial cost from diabetes overall exceeds $100 billion, almost $1 of every $7 dollars of US health expenditures in terms of medical care and loss of productivity. Advances in treatment that permit tight glycemic control and control of comorbidities (hyperlipidemia) can greatly reduce the incidence of microvascular and macrovascular complications.

As a result of these complications, people with diabetes have an increased risk of developing ischemic heart disease, cerebral vascular disease, peripheral vascular disease with gangrene of lower limbs, chronic renal disease, reduced visual acuity and blindness, and autonomic and peripheral neuropathy.

Race
Type 1 DM is more common among non-Hispanic whites, followed by African Americans and Hispanic Americans. It is comparatively uncommon among Asians.

Sex
Type 1 DM is more common in men than in women.

Age
Type 1 DM usually starts in children aged 4 years or older, with the peak incidence of onset at age 11-13 years, coinciding with early adolescence and puberty. Also, a relatively high incidence exists in people in their late 30s and early 40s, when it tends to present in a less aggressive manner, ie, early hyperglycemia without ketoacidosis and gradual onset of ketosis.

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Diabetes Mellitus, Type 1 (pedia)

2008-07-31T17:36:00.002+03:00

Diabetes mellitus (DM) is a chronic metabolic disorder caused by an absolute or relative deficiency of insulin, an anabolic hormone. Insulin is produced by the beta cells of the islets of Langerhans located in the pancreas, and the absence, destruction, or other loss of these cells results in type 1 diabetes (insulin-dependent diabetes mellitus [IDDM]). Most children with diabetes have IDDM and a lifetime dependence on exogenous insulin.

Type 2 diabetes (non–insulin-dependent diabetes mellitus [NIDDM]) is a heterogeneous disorder. Most patients with NIDDM have insulin resistance, and their beta cells lack the ability to overcome this resistance. Although this form of diabetes was previously uncommon in children, in some, countries 20% or more of new patients with diabetes in childhood and adolescence have NIDDM, a change associated with increased rates of obesity. Other patients may have inherited disorders of insulin release leading to maturity onset diabetes of the young (MODY).

This chapter addresses only IDDM.

Pathophysiology
Insulin is essential to process carbohydrates, fat, and protein. Insulin reduces blood glucose levels by allowing glucose to enter muscle cells and by stimulating the conversion of glucose to glycogen (glycogenesis) as a carbohydrate store. Insulin also inhibits the release of stored glucose from liver glycogen (glycogenolysis) and slows the breakdown of fat to triglycerides, free fatty acids, and ketones. It also stimulates fat storage. Additionally, insulin inhibits the breakdown of protein and fat for glucose production (gluconeogenesis) in both liver and kidneys.

Hyperglycemia (ie, random blood glucose concentration more than 200 mg/dL or 11 mmol/L) results when insulin deficiency leads to uninhibited gluconeogenesis and prevents the use and storage of circulating glucose. The kidneys cannot reabsorb the excess glucose load, causing glycosuria, osmotic diuresis, thirst, and dehydration. Increased fat and protein breakdown leads to ketone production and weight loss. Without insulin, a child with IDDM wastes away and eventually dies from diabetic ketoacidosis (DKA).

An excess of insulin prevents the release of glucose into the circulation and results in hypoglycemia (blood glucose concentrations of <60 mg/dL or 3.5 mmol/L). Glucose is the sole energy source for erythrocytes, kidney medulla, and the brain.

Frequency
United States
Overall incidence is approximately 15 cases per 100,000 individuals annually and probably increasing. An estimated 3 children out of 1000 develop IDDM by age 20 years.

International
DM exhibits wide geographic variation in incidence and prevalence. Annual incidence varies from 0.61 cases per 100,000 persons in China, to 41.4 cases per 100,000 in Finland. Substantial variations exist between nearby countries with differing lifestyles, such as Estonia and Finland, and between genetically similar populations such as those in Iceland and Norway. Even more striking are the differences in incidence between mainland Italy (8.4/100,000) and the Island of Sardinia (36.9/100,000). These variations strongly support the importance of environmental factors in the development of IDDM. Most countries report that incidence rates have at least doubled or more in the last 20 years. Incidence appears to increase with distance from the equator.

Mortality/Morbidity
Information on mortality rates is difficult to ascertain without complete national registers of childhood diabetes, although age-specific mortality is probably double that of the general population. Particularly at risk are children aged 1-4 years who may die with DKA at the time of diagnosis. Adolescents are also a high-risk group. Most deaths result from delayed diagnosis or neglected treatment and subsequent cerebral edema during treatment for DKA, although untreated hypoglycemia also causes some deaths. Unexplained death during sleep may also occur.

IDDM complications are comprised of 3 major categories: acute complications, long-term complications, and complications caused by associated autoimmune diseases.

Acute complications reflect the difficulties of maintaining a balance between insulin therapy, dietary intake, and exercise. Acute complications include hypoglycemia, hyperglycemia, and DKA.
Long-term complications arise from the damaging effects of prolonged hyperglycemia and other metabolic consequences of insulin deficiency on various tissues. While long-term complications are rare in childhood, maintaining good control of diabetes is important to prevent complications from developing in later life. The likelihood of developing complications appears to depend on the interaction of factors such as metabolic control, genetic susceptibility, lifestyle (eg, smoking, diet, exercise), pubertal status, and gender.Long-term complications include the following:
Retinopathy
Cataracts
Hypertension
Progressive renal failure
Early coronary artery disease
Peripheral vascular disease
Neuropathy, both peripheral and autonomic
Increased risk of infection
Associated autoimmune diseases are common with IDDM, particularly in children who have the human leukocyte antigen DR3 (HLA-DR3). Some conditions may precede development of diabetes; others may develop later. As many as 20% of children with diabetes have thyroid autoantibodies.

Race

Different environmental effects on IDDM development complicate the influence of race, but racial differences clearly exist.
Whites have the highest reported incidence of IDDM; Chinese have the lowest.
IDDM is 1.5 times more likely to develop in American whites than in American blacks or Hispanics.
Current evidence suggests that when immigrants from an area with low incidence move to an area with higher incidence, their IDDM rates tend to increase toward the higher level.

Sex

The influence of sex varies with the overall incidence rates.
Males are at greater risk in regions of high incidence, particularly older males, whose incidence rates often show seasonal variation.
Females appear to be at a greater risk in low-incidence regions.

Age

Generally, incidence rates increase with age until mid-puberty then decline after puberty, but IDDM can occur at any age. Onset in the first year of life, though unusual, can occur and must be considered in any infant or toddler, because these children have the greatest risk for mortality if diagnosis is delayed. Their symptoms may include the following:
Severe monilial diaper/napkin rash
Unexplained malaise
Poor weight gain or weight loss
Increased thirst
Vomiting and dehydration, with a constantly wet napkin/diaper
Where prevalence rates are high, a bimodal variation of incidence has been reported that shows a definite peak in early childhood (ie, 4-6 y) and a second, much greater peak of incidence during early puberty (ie, 10-14 y).

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Mesenteric Ischemia

2008-07-30T15:00:00.000+03:00

Mesenteric ischemia is a relatively rare disorder seen in the emergency department (ED); however, it is an important diagnosis to make because of its high mortality rate. Vague and nonspecific clinical findings and limitations of diagnostic studies make the diagnosis a significant challenge. Moreover, delays in diagnosis lead to increased mortality rates. Despite recent advances in diagnosis and treatment, mortality rates continue to remain high.

Pathophysiology
Mesenteric ischemia is caused by decreased intestinal blood flow that can be caused by a number of mechanisms. Decreased intestinal blood flow results in ischemia and subsequent reperfusion damage at the cellular level that may progress to the development of mucosal injury, tissue necrosis, and metabolic acidosis.

The blood supply to the intestine is derived predominantly from 3 major gastrointestinal arteries that arise from the abdominal aorta: the celiac axis, the superior mesenteric artery (SMA), and the inferior mesenteric artery (IMA). The intestine has significant collateral circulation at all levels that allows for some protection from ischemia and is able to compensate for approximately a 75% acute reduction in mesenteric blood flow for up to 12 hours, without substantial injury.

The pathophysiology of intestinal ischemia can be divided into arterial and venous etiologies and acute and chronic ischemia. The vast majority of cases are secondary to arterial causes. All diseases and conditions that affect arteries, including atherosclerosis, arteritis, aneurysms, arterial infections, dissections, arterial emboli, and thrombosis, are reported to occur in the intestinal arteries.

Acute mesenteric ischemia (AMI) can be further divided into embolic, thrombotic, or nonocclusive causes.

Arterial embolism
Arterial embolism accounts for approximately one third of acute cases of AMI.
Emboli to the mesenteric arteries are usually from a dislodged cardiac thrombus.
The SMA is most commonly affected with the IMA rarely affected due to its small caliber.
Arterial thrombosis
Arterial thrombosis accounts for approximately one third of acute cases of AMI.
It is usually due to acute worsening of ischemia in patients who have preexisting atherosclerosis of the mesenteric arteries.
Thrombosis often involves at least 2 of the major splanchnic vessels.
Nonocclusive etiology
Nonocclusive etiology accounts for approximately one third of acute cases of AMI.
The primary mechanism is severe and prolonged intestinal vasoconstriction.
The most common setting is severe systemic illness with systemic shock usually secondary to reduced cardiac output.
Intestinal vasospasm has also been seen to occur in cocaine ingestion, ergot poisoning, digoxin use, and with alpha-adrenergic agonists.
A small proportion of cases are from venous thrombosis, seen mostly in patients with hypercoagulable states.
Venous thrombosis of the visceral vessels may precipitate an acute ischemic event as compromised venous return leads to interstitial swelling of the bowel wall, with subsequent impedance of arterial flow and eventual tissue necrosis.

Chronic mesenteric ischemia (CMI) usually results from long-standing atherosclerotic disease of 2 or more mesenteric vessels. Other nonatheromatous causes of CMI include the vasculitides such as Takayasu arteritis. Symptoms are caused by the gradual reduction in blood flow to the intestine that occurs during eating since total blood flow to the intestine can increase by 15% during meals.

Frequency
United States
AMI is involved in up to 0.1% of all hospital admissions, although this number is likely to rise as the population ages.

Mortality/Morbidity

Mortality rates are high and range from 60-100% depending on the source of obstruction. Early and aggressive diagnosis and treatment has been shown to significantly decrease the mortality rate if the diagnosis is made prior to the development of peritonitis.
One report of 21 patients with SMA embolus, intestinal viability was achieved in 100% of patients before diagnosis if the duration of symptoms was less than 12 hours, in 56% if it was between 12 and 24 hours, and in only 18% if symptoms were more than 24 hours in duration.
Another study found that even at hospital centers with angiography available 24 hours, mortality rates still were approximately 70%.

Sex
No sex predilection exists.

Age
Mesenteric ischemia is generally a disease of the older population, with the typical age of onset being older than 60 years; however, with risk factors and other predisposing factors, it may be seen in younger patients.

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Aortic Stenosis

2008-07-30T12:00:00.001+03:00

Aortic stenosis (AS) is the obstruction of blood flow across the aortic valve. AS has several etiologies: congenital unicuspid or bicuspid valve, rheumatic fever, and degenerative calcific changes of the valve.

Pathophysiology
When the aortic valve becomes stenotic, resistance to systolic ejection occurs and a systolic pressure gradient develops between the left ventricle and the aorta. Stenotic aortic valves have a decreased aperture that leads to a progressive increase in left ventricular systolic pressure. This leads to pressure overload in the left ventricle, which, over time, causes an increase in ventricular wall thickness (ie, concentric hypertrophy). At this stage, the chamber is not dilated and ventricular function is preserved, although diastolic compliance may be affected.

Eventually, however, the left ventricle dilates. This, coupled with a decrease in compliance, is associated with an increase in left ventricular end-diastolic pressure, which is increased further by a rise in atrial systolic pressure. A sustained pressure overload eventually leads to myocardial decompensation. The contractility of the myocardium diminishes, which leads to a decrease in cardiac output. The elevated left ventricular end-diastolic pressure causes a corresponding increase in pulmonary capillary arterial pressures and a decrease in ejection fraction and cardiac output. Ultimately, congestive heart failure (CHF) develops.

Frequency
United States
Aortic stenosis is a relatively common congenital cardiac defect. Incidence is 4 in 1000 live births.

Mortality/Morbidity
Sudden cardiac death occurs in 3-5% of patients with AS. Adults with AS have a 9% mortality rate per year. Once symptoms develop, the incidence of sudden death increases to 15-20%, with average survival duration of less than 5 years. Patients with exertional angina or syncope survive an average of 3 years. After the development of left ventricular failure, life expectancy is slightly greater than 1 year.

Sex
Among children, 75% of cases of AS are in males.

Age
AS usually is not detected until individuals are school aged. AS exists in up to 2% of those who are younger than 70 years. The etiology of AS in those aged 30-70 years can be rheumatic disease or calcification of a congenital bicuspid valve. In those older than 70 years, degenerative calcification is the primary cause of AS. Among people older than 75 years, 3% have critical AS.

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ART

2008-07-30T07:12:00.001+03:00

Angina Pectoris

2008-07-30T07:00:00.000+03:00

Angina pectoris (AP) represents the clinical syndrome occurring when myocardial oxygen demand exceeds supply. The term is derived from Latin; the literal meaning is "the choking of the chest;" angere, meaning "to choke" and pectus, meaning "chest." The first English-written account of recurrent angina pectoris was by English nobleman Edward Hyde, Earl of Clarendon. He described his father as having, with exertion, "a pain in the left arm…so much that the torment made him pale".1 The first description of angina as a medical disorder came from William Heberden. Heberden, a prodigious physician, made many noteworthy contributions to medicine during his career. He presented his observations on "dolor pectoris" to the Royal College of Physicians in 1768. Much of his classic description retains its validity today.2

Angina pectoris has a wide range of clinical expressions. The symptoms most often associated to angina pectoris are substernal chest pressure or tightening, frequently with radiating pain to the arms, shoulders, or jaw. The symptoms may also be associated with shortness of breath, nausea, or diaphoresis. Symptoms stem from inadequate oxygen delivery to myocardial tissue. No definitive diagnostic tools that capture all patients with angina pectoris exist. This, combined with its varied clinical expression, makes angina pectoris a distinct clinical challenge to the emergency physician. The disease state can manifest itself in a variety of forms:

Stable angina pectoris is classified as a reproducible pattern of anginal symptoms that occur during states of increased exertion.
Unstable angina pectoris (UA) manifests either as an increasing frequency of symptoms or as symptoms occurring at rest.
Prinzmetal angina or variant angina occurs as a result of transient coronary artery spasms. These spasms can occur either at rest or with exertion. Unlike stable or unstable angina, no pathological plaque or deposition is present within the coronary arteries that elicits the presentation. On angiography, the coronary arteries are normal in appearance.
Cardiac syndrome X occurs when a patient has all of the symptoms of angina pectoris without coronary artery disease or spasm.

Pathophysiology
The past 2 decades has greatly expanded our overall understanding of the pathophysiology of myocardial ischemic syndromes. The primary dysfunction in angina pectoris is decreased oxygen delivery to myocardial muscle cells. The 2 predominant mechanisms by which delivery is impaired appear to be coronary artery narrowing and endothelial dysfunction. Any other mechanism that affects oxygen delivery can also precipitate symptoms.

Extracardiac causes of angina include, but are by no means limited to, anemia, hypoxia, hypotension, bradycardia, carbon monoxide exposure, and inflammatory disorders.3 The end result is a shift to anaerobic metabolism in the myocardial cells. This is followed by a stimulation of pain receptors that innervate the heart. These pain receptors ultimately are referred to afferent pathways, which are carried in multiple nerve roots from C7 through T4. The referred/radiating pain of angina pectoris is believed to occur because these afferent pathways also carry pain fibers from other regions (eg, the arm, neck, and shoulders).

Coronary artery narrowing

Coronary artery narrowing appears to be the etiology of cardiac ischemia in the preponderance of cases. This has clinical significance when atherosclerotic disease diminishes or halts blood flow through the coronary arterial circulation, interfering with normal laminar blood flow. The significance of even a small change in the diameter of a blood vessel can be profound. The Poiseuille law predicts this outcome—the rate of flow is decreased exponentially by any change in the radius of the lumen. As with a smaller pediatric airway, even relatively minute changes in diameter have dramatic consequences in flow rates. Thus, when a lumen is narrowed by one fifth, the flow rate is decreased by about one half. This predicts that even a small change in a coronary artery plaque size can affect the oxygenation through that vessel's territory.

The epicardial vessel, where atherosclerosis often takes place, has the capacity to dilate via autoregulatory mechanisms to respond to increased demand. Angina occurs as this compensatory mechanism is overwhelmed either by large plaques (typically considered 70% or greater obstruction) or by significantly increased myocardial demand.4

Endothelial factors

Endothelial factors also play an important role in angina pectoris. During sympathetic stimulation, the endothelium is subjected to mediators of both vasoconstriction and vasodilatation. Alpha-agonists (catecholamines) directly cause vasoconstriction, while endothelial nitrous oxide synthase creates nitrous oxide (NO), which counteracts this constricting force via vasodilatation.

In the diseased coronary artery, NO production is reduced or absent. In this setting, the catecholamine drive can overwhelm the autoregulatory mechanisms. In addition, the endothelium of the plaque-laden artery may, in itself, be dysfunctional. This limits the ability of the intra-arterial endothelium to produce mediators, which, in a healthy artery, would protect against further vasoconstriction, assist dilatation, and provide protection from platelet aggregation. Small lesions in these vessels may produce incompletely obstructing aggregates of platelets. This would further impede flow through the affected vessel.4

In the diseased heart, these 2 factors, coronary artery narrowing and endothelial dysfunction, synergistically result in reduced oxygen delivery to the myocardium. The net result is angina pectoris.

Extrinsic factors

Extrinsic factors can also play a role in specific circumstances. The oxygen-carrying capacity of blood is based on a number of factors. The most important of which is the amount of hemoglobin. Any alteration in the ability of blood to carry oxygen can precipitate angina. Anemia of any degree can result in anginal symptoms. Given a scenario where demand is increased, such as climbing a flight of stairs, increased stress, or even sexual intercourse, the anginal symptoms may appear.5 Abnormal hemoglobin, such as methemoglobin, carboxyhemoglobin, or any of a number of hemoglobinopathies, creates an environment at greater risk for precipitating angina.

Other extrinsic factors that affect hemoglobin formation, such as lead poisoning or iron-deficiency states, also lead to a similar decrease in oxygen-carrying capacity. Any mechanism that impedes oxygen delivery to the red blood cells has a similar effect. Therefore, any number of pulmonary causes, such as pulmonary embolism, pulmonary fibrosis or scarring, pneumonia, or congestive heart failure, can exacerbate angina. A decreased oxygen environment, such as travel to a higher elevation, has similar consequences due to the decrease in concentration of atmospheric oxygen.

Variant angina

The etiology of variant angina is currently not well understood. Research suggests that inflammatory mediators may result in focal coronary artery vasospasm. Another possibility is that perfusion is decreased through microvascular circulation. Spasm or intermittent narrowing of this microscopic lumen may result in transient areas of hypoperfusion and oxygen deprivation.6

Syndrome X

Syndrome X is the triad of angina pectoris, a positive ECG stress test result, and a normal coronary angiogram. The pathophysiology of this disease is not well understood. Many theories exist as to the underlying pathology. Decreased oxygenation of the underlying myocardium may be the result of impaired vasodilatation, dysfunctional smooth muscle cells, poor or deficient microvascular circulation, or even structural problems on a cellular level (eg, an inappropriately functioning sodium ion channel).6

Frequency
United States

An estimated 6,500,000 people in the United States experience angina pectoris.

Each year 400,000 new cases of angina pectoris develop.

Mortality/Morbidity
More than 479,000 people died from coronary heart disease (both angina and myocardial infarction) in 2003.

The estimated direct and indirect cost for Americans with coronary heart disease in 2006 was $142.5 billion.

Race

The Centers for Disease Control and Prevention (CDC) note that the prevalence of angina and/or coronary heart disease is highest in Hispanics followed by whites and black non-Hispanics (5%, 4.2%, 3.7%, respectively). This information includes the 50 US states, the District of Columbia, Puerto Rico, and the US Virgin Islands.7

Sex
According to National Health and Nutrition Examination Survey (NHANES) data, the age-adjusted prevalence of self-reported angina appears to be higher in woman than in men. Although 2005 CDC data suggest that men (5.5%) have a higher prevalence of angina and/or coronary heart disease than women (3.4%).7

Age
The incidence of new and recurrent angina increases with age but then declines at around 85 years.

Statistics from American Heart Association and Centers for Disease Control and Prevention.

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Allergic Rhinitis

2008-07-29T16:17:00.001+03:00

Rhinitis is defined as inflammation of the nasal membranes1 and is characterized by a symptom complex that consists of any combination of the following: sneezing, nasal congestion, nasal itching, and rhinorrhea. The eyes, ears, sinuses, and throat can also be involved. Allergic rhinitis is the most common cause of rhinitis. It is an extremely common condition, affecting approximately 20% of the population. While allergic rhinitis is not a life-threatening condition, complications can occur and the condition can significantly impair quality of life, which leads to a number of indirect costs. The total direct and indirect cost of allergic rhinitis was recently estimated to be $5.3 billion per year.

Pathophysiology
Allergic rhinitis involves inflammation of the mucous membranes of the nose, eyes, eustachian tubes, middle ear, sinuses, and pharynx. The nose invariably is involved, and the other organs are affected in certain individuals. Inflammation of the mucous membranes is characterized by a complex interaction of inflammatory mediators but ultimately is triggered by an immunoglobulin E (IgE)–mediated response to an extrinsic protein.

The tendency to develop allergic, or IgE-mediated, reactions to extrinsic allergens (proteins capable of causing an allergic reaction) has a genetic component. In susceptible individuals, exposure to certain foreign proteins leads to allergic sensitization, which is characterized by the production of specific IgE directed against these proteins. This specific IgE coats the surface of mast cells, which are present in the nasal mucosa. When the specific protein (eg, a specific pollen grain) is inhaled into the nose, it can bind to the IgE on the mast cells, leading to immediate and delayed release of a number of mediators.

The mediators that are immediately released include histamine, tryptase, chymase, kinins, and heparin. The mast cells quickly synthesize other mediators, including leukotrienes and prostaglandin D2. These mediators, via various interactions, ultimately lead to the symptoms of rhinorrhea (ie, nasal congestion, sneezing, itching, redness, tearing, swelling, ear pressure, postnasal drip). Mucous glands are stimulated, leading to increased secretions. Vascular permeability is increased, leading to plasma exudation. Vasodilation occurs, leading to congestion and pressure. Sensory nerves are stimulated, leading to sneezing and itching. All of these events can occur in minutes; hence, this reaction is called the early, or immediate, phase of the reaction.

Over 4-8 hours, these mediators, through a complex interplay of events, lead to the recruitment of other inflammatory cells to the mucosa, such as neutrophils, eosinophils, lymphocytes, and macrophages. This results in continued inflammation, termed the late-phase response. The symptoms of the late-phase response are similar to those of the early phase, but less sneezing and itching and more congestion and mucus production tend to occur. The late phase may persist for hours or days.

Systemic effects, including fatigue, sleepiness, and malaise, can occur from the inflammatory response. These symptoms often contribute to impaired quality of life.

Frequency
United States
Allergic rhinitis affects approximately 40 million people in the United States. Recent US figures suggest a 20% cumulative prevalence rate.

International
Scandinavian studies have demonstrated a cumulative prevalence rate of 15% in men and 14% in women. The prevalence of allergic rhinitis may vary within and among countries. This may be due to geographic differences in the types and potency of different allergens and the overall aeroallergen burden.

Mortality/Morbidity
While allergic rhinitis itself is not life-threatening (unless accompanied by severe asthma or anaphylaxis), morbidity from the condition can be significant. Allergic rhinitis often coexists with other disorders, such as asthma, and may be associated with asthma exacerbations. It is also associated with otitis media, eustachian tube dysfunction, sinusitis, nasal polyps, allergic conjunctivitis, and atopic dermatitis. Allergic rhinitis may also contribute to learning difficulties, sleep disorders, and fatigue.

A number of complications that can lead to increased morbidity or even mortality can occur secondary to allergic rhinitis. Possible complications include otitis media, eustachian tube dysfunction, acute sinusitis, and chronic sinusitis.
Allergic rhinitis can be associated with a number of comorbid conditions, including asthma, atopic dermatitis, and nasal polyps. Evidence now suggests that uncontrolled allergic rhinitis can actually worsen the inflammation associated with asthma or atopic dermatitis. This could lead to further morbidity and even mortality.
Allergic rhinitis can frequently lead to significant impairment of quality of life. Symptoms such as fatigue, drowsiness (due to the disease or to medications), and malaise can lead to impaired work and school performance, missed school or work days, and traffic accidents. The overall cost (direct and indirect) of allergic rhinitis was recently estimated to be $5.3 billion per year.

Race
Allergic rhinitis occurs in persons of all races. Prevalence of allergic rhinitis seems to vary among different populations and cultures, which may be due to genetic differences, geographic factors or environmental differences, or other population-based factors.

Sex
In childhood, allergic rhinitis is more common in boys than in girls, but in adulthood, the prevalence is approximately equal between men and women.

Age
Onset of allergic rhinitis is common in childhood, adolescence, and early adult years, with a mean age of onset 8-11 years, but allergic rhinitis may occur in persons of any age. In 80% of cases, allergic rhinitis develops by age 20 years. The prevalence of allergic rhinitis has been reported to be as high as 40% in children, subsequently decreasing with age. In the geriatric population, rhinitis is less commonly allergic in nature.

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Cholera

2008-07-29T15:35:00.001+03:00

The word cholera is derived from a Greek term that means "flow of bile." Cholera is caused by Vibrio cholerae, the most feared epidemic diarrheal disease because of its severity. Dehydration and death can occur within hours of infection.

Robert Koch discovered V cholerae in 1883 during an outbreak in Egypt. The organism is a comma-shaped, gram-negative aerobic bacillus whose size varies from 1-3 µm in length by 0.5-0.8 µm in diameter. Its antigenic structure consists of a flagellar H antigen and a somatic O antigen. The differentiation of the latter allows for separation into pathogenic and nonpathogenic strains. V cholerae O1 and V cholerae O139 are associated with epidemic cholera. V cholerae O1 is classified into 2 major biotypes: classic and El Tor. Currently, El Tor is the predominant cholera pathogen. Organisms in both biotypes are subdivided into serotypes according to the structure of the O antigen, as follows:

Serotype Inaba - O antigens A and C
Serotype Ogawa - O antigens A and B
Serotype Hikojima - O antigens A, B, and C

Pathophysiology
The infectious dose of bacteria required to cause clinical disease varies by the mode of administration. If ingested with water, the infectious dose is 103-106 organisms. When ingested with food, fewer organisms (102-104 organisms) are required to produce disease.

The use of antacids, histamine receptor blockers, and proton pump inhibitors increases the risk of cholera infection and predisposes patients to more severe disease as a result of reduced gastric acidity. The same applies to patients with chronic gastritis secondary to Helicobacter pylori infection or those who have undergone a gastrectomy.

V cholerae O1 and V cholerae O139 cause clinical disease by producing an enterotoxin that promotes the secretion of fluid and electrolytes into the lumen of the small intestine. The enterotoxin is a protein molecule composed of 5 B subunits and 2 A subunits. The B subunits are responsible for binding to a ganglioside (monosialosyl ganglioside, GM1) receptor located on the surface of the cells that line the intestinal mucosa.

The activation of the A1 subunit by adenylate cyclase is responsible for the net increase in cyclic adenosine monophosphate (cAMP). cAMP blocks the absorption of sodium and chloride by the microvilli and promotes the secretion of chloride and water by the crypt cells. The result is watery diarrhea with electrolyte concentrations isotonic to those of plasma.

Fluid loss originates in the duodenum and upper jejunum; the ileum is less affected. The colon is usually in a state of absorption because it is relatively insensitive to the toxin. However, the large volume of fluid produced in the upper intestine overwhelms the absorptive capacity of the lower bowel, resulting in severe diarrhea.

The enterotoxin acts locally and does not invade the intestinal wall. As a result, few neutrophils are found in the stool.

Frequency
United States

Among the millions of Americans who travel to endemic areas in foreign countries, only 42 imported cases of cholera were reported from 1965-1991. However, in August 1986, 4 cases of cholera were acquired in Louisiana and 1 case was acquired in Florida. These patients were hospitalized with severe diarrhea and had stool cultures that yielded toxigenic V cholerae O1 Inaba. Although the vehicle of transmission was not specifically identified, the patients had consumed seafood within 5 days prior to symptom onset. Toxigenic V cholerae O1 El Tor Inaba appears to have an environmental reservoir on the US Gulf Coast.

Sixty-one cases of cholera were reported from January 1, 1995, through December 31, 2000, in 18 states and 2 US territories. Thirty-seven were travel-associated cases; the other 24 cases were acquired in the United States.1 Individuals living in the United States most often acquire cholera through travel to cholera-endemic areas or through consumption of undercooked seafood from the Gulf Coast or foreign waters.

In 2005, 12 cases were reported to the World Health Organization (WHO) and, of these, 8 were imported.

International

Since 1817, 7 cholera pandemics have occurred. The first 6 occurred from 1817-1923 and were probably the result of V cholerae O1 of the classic biotype. The pandemics originated in Asia, with subsequent spread to Europe and the Americas.

The seventh pandemic was caused by V cholerae O1 El Tor, which was first isolated in Egypt in 1905. The pandemic originated from the Celebes Islands, Indonesia, in 1961; this pandemic affected more countries and continents than the previous 6 pandemics. The last extension of this pandemic was into Latin America. The total number of cases officially reported from 1997 through March 26, 1998, was 120,867; 89% of these cases were reported in Africa.

In 2002, all regions of the world continued to report cholera caused by V cholerae O1 El Tor; that year, 142,311 cases and 4564 deaths were reported to the WHO by 52 countries. Compared with 2001, the number of reported cases almost doubled.

Between 2002 and 2004, the number of cases reported to the WHO decreased worldwide. In 2005, however, the number reported increased 30% to a total of 131,943 cases in 52 countries.

In October 1992, an epidemic of cholera emerged from Madras, India, as a result of a new serogroup, O139 (also known as Bengal). This Bengal strain has now spread throughout Bangladesh and India and into neighboring countries in Asia. Some experts regard this as an eighth pandemic. Thus far, 11 countries in Southeast Asia have reported isolation of this Vibrio serogroup.

Mortality/Morbidity
If untreated, the disease rapidly results in dehydration and can result in death in more than 50% of infected individuals. The mortality rate is increased in pregnant women and children.

Age
People of all ages are susceptible, although infants are protected through maternally transmitted antibodies during breastfeeding. An attack of the classic biotype of V cholerae usually protects against recurrent infection by either biotype, but El Tor cholera does not protect against further attacks.

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Cardiac Cirrhosis

2008-07-16T12:02:00.001+03:00

Background
Cardiac cirrhosis (congestive hepatopathy) includes a spectrum of hepatic derangements that occur in the setting of right-sided heart failure. Clinically, the signs and symptoms of congestive heart failure (CHF) dominate the disorder. Unlike cirrhosis caused by chronic alcohol use or viral hepatitis, the effect of cardiac cirrhosis on overall prognosis is unknown. Because of this, treatment is aimed at managing the patient's underlying heart failure.

Distinguish cardiac cirrhosis from ischemic hepatitis. The latter condition may involve massive hepatocellular necrosis caused by sudden cardiogenic shock or other hemodynamic collapse. Typically, sudden and dramatic serum hepatic transaminase elevations lead to its discovery. Although cardiac cirrhosis and ischemic hepatitis arise from distinct underlying cardiac lesions (right-sided heart failure in the former and left-sided failure in the latter), in clinical practice they may present together.

Despite its name, cardiac cirrhosis rarely satisfies strict pathologic criteria for cirrhosis. The terms congestive hepatopathy and chronic passive liver congestion are more accurate, but the name cardiac cirrhosis has become convention.

Pathophysiology
Decompensated right ventricular or biventricular heart failure causes transmission of elevated central venous pressures directly to the liver via the inferior vena cava and hepatic veins. At a cellular level, venous congestion impedes efficient drainage of sinusoidal blood flow into terminal hepatic venules. Sinusoidal stasis results in accumulation of deoxygenated blood, parenchymal atrophy, necrosis, collagen deposition, and, ultimately, fibrosis.

A separate theory proposes that cardiac cirrhosis is not simply a response to chronically increased pressure and sinusoidal stasis. That intrahepatic vascular lesions are confined to areas of the liver with higher fibrotic burden suggests that cardiac cirrhosis requires a higher grade of vascular obstruction, such as intrahepatic thrombosis, for its development. The theory proposes that thrombosis of sinusoids and terminal hepatic venules propagates to medium-sized hepatic veins and to portal vein branches, resulting in parenchymal extinction and fibrosis.

Frequency
United States
Cardiac cirrhosis rarely occurs in the United States. Its true prevalence is difficult to estimate, since the disease typically remains subclinical and undiagnosed. The incidence of cardiac cirrhosis at autopsy has decreased significantly over the past several decades. This may be due to lower rates of uncorrected rheumatic heart disease and constrictive pericardial disease.

Mortality/Morbidity
The effect of cardiac cirrhosis on mortality and morbidity rates is unknown. The severity of the patient's underlying cardiac disease, which is typically advanced and chronic, is the major determinant of overall outcome.

Sex
Comparative sex data for cardiac cirrhosis do not exist. However, because CHF is more common in men than women in the United States, the same is likely for cardiac cirrhosis.

Age
No published data exist. However, the prevalence of cardiac cirrhosis in the United States, like that of CHF, almost certainly increases with age.

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Adrenal Carcinoma

2008-07-01T23:08:00.003+03:00

Adrenocortical cancers (ACs) are uncommon malignancies that can have protean clinical manifestations. Adrenocortical masses are common; autopsy studies show that approximately 5-15% of the general adult population may have adrenal incidentalomas. Adrenal incidentalomas are biochemically and clinically asymptomatic adrenal masses found incidentally as a result of unrelated imaging investigations such as abdominal CT or MRI scans. Findings from abdominal CT scans suggest that the prevalence rate is 1-5%. Only a small number of adrenal tumors are functional and an even smaller number (approximately 1%) are malignant.
Regardless of size, approximately 1 per 1500 adrenal tumors is malignant. The evaluation of these incidentalomas, therefore, focuses on (1) identifying functional masses and treating them appropriately (including surgical removal); (2) identifying adrenal carcinomas early, with the intent of attempting complete surgical extirpation; and (3) reassuring the patients who do not fit either of these classes and arranging for their subsequent follow-up.
Although the means of identifying ACs from this subpopulation still are controversial, virtually all authorities agree about removing all nonfunctional adrenal tumors larger than or equal to 6 cm because of the significant potential cancer risk. Authorities also generally agree that nonfunctional adrenal tumors (£3 cm) have a very low probability of being adrenal cancer; therefore, they can be removed safely.
The management strategy for adrenal masses larger than 3 cm and less than 6 cm is disputed. Some authorities suggest lowering the threshold for surgical removal of nonfunctional masses from 6 cm to 4-5 cm. Others individualize the follow-up of these patients depending on their clinical status, CT scan characteristics, and age. Particularly important is the fact that these criteria do not apply to children, who generally have smaller ACs. A review of the available data suggests that the incidence rate of malignancy is small Frequency
International
AC tumors are uncommon. The incidence is approximately 0.6-1.67 cases per million persons per year. Some reports suggest an inordinately high frequency (up to 10-fold higher) of cases among children in southern Brazil, for unknown reasons. Overall, AC accounts for 0.02-0.2% of all cancer-related deaths; therefore, it is relatively rare.
Race
AC has no specific racial predilection.
Sex
The female-to-male ratio is approximately 2.5-3:1. Male patients tend to be older and have a worse overall prognosis than female patients. Female patients are more likely than male patients to have an associated endocrine syndrome. Nonfunctional ACs are distributed equally between the sexes.
Age
AC occurs in 2 major peaks: in the first decade of life and again in the fourth to fifth decades. Approximately 75% of the children with AC are younger than 5 years. Functional tumors also are more common in children, while nonfunctional tumors are more common in adults.

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Hydrocephalus

2008-06-29T23:01:00.001+03:00

Hydrocephalus can be defined broadly as a disturbance of formation, flow, or absorption of cerebrospinal fluid (CSF) that leads to an increase in volume occupied by this fluid in the central nervous system (CNS). This condition also could be termed a hydrodynamic disorder of CSF. Acute hydrocephalus occurs over days, subacute over weeks, and chronic over months or years. Conditions such as cerebral atrophy and focal destructive lesions also lead to an abnormal increase of CSF in CNS. In these situations, loss of cerebral tissue leaves a vacant space that is filled passively with CSF. Such conditions are not the result of a hydrodynamic disorder and therefore are not classified as hydrocephalus. An older misnomer used to describe these conditions was hydrocephalus ex vacuo.

Normal pressure hydrocephalus (NPH) describes a condition that rarely occurs in patients younger than 60 years. Enlarged ventricles and normal CSF pressure at lumbar puncture (LP) in the absence of papilledema led to the term NPH. However, intermittent intracranial hypertension has been noted during monitoring of patients in whom NPH is suspected, usually at night. The classic Hakim triad of symptoms includes gait apraxia, incontinence, and dementia. Headache is not a typical symptom in NPH.

Benign external hydrocephalus is a self-limiting absorption deficiency of infancy and early childhood with raised intracranial pressure (ICP) and enlarged subarachnoid spaces. The ventricles usually are not enlarged significantly, and resolution within 1 year is the rule.

Communicating hydrocephalus occurs when full communication exists between the ventricles and subarachnoid space. It is caused by overproduction of CSF (rarely), defective absorption of CSF (most often), or venous drainage insufficiency (occasionally).

Noncommunicating hydrocephalus occurs when CSF flow is obstructed within the ventricular system or in its outlets to the arachnoid space, resulting in ventricular/subarachnoid space noncommunication.

Obstructive hydrocephalus results from obstruction of the flow of CSF (intraventricular or extraventricular). Most hydrocephalus is obstructive, and the term is used to contrast the hydrocephalus caused by overproduction of CSF.

Arrested hydrocephalus is defined as stabilization of known ventricular enlargement, probably secondary to compensatory mechanisms. These patients may decompensate, especially following minor head injuries.

Pathophysiology
Normal CSF production is 0.20-0.35 mL/min; a majority is produced by the choroid plexus, which is located within the ventricular system, mainly the lateral and fourth ventricles. The capacity of the lateral and third ventricles in a healthy person is 20 mL. Total volume of CSF in an adult is 120 mL.

Normal route of CSF from production to clearance is the following: From the choroid plexus, the CSF flows to the lateral ventricle, then to the interventricular foramen of Monro, the third ventricle, the cerebral aqueduct of Sylvius, the fourth ventricle, the 2 lateral foramina of Luschka and 1 medial foramen of Magendie, the subarachnoid space, the arachnoid granulations, the dural sinus, and finally into the venous drainage.

ICP rises if production of CSF exceeds absorption. This occurs if CSF is overproduced, resistance to CSF flow is increased, or venous sinus pressure is increased. CSF production falls as ICP rises. Compensation may occur through transventricular absorption of CSF and also by absorption along nerve root sleeves. Temporal and frontal horns dilate first, often asymmetrically. This may result in elevation of the corpus callosum, stretching or perforation of the septum pellucidum, thinning of the cerebral mantle, or enlargement of the third ventricle downward into the pituitary fossa (which may cause pituitary dysfunction).

The mechanism of NPH has not been elucidated completely. Current theories include increased resistance to flow of CSF within the ventricular system or subarachnoid villi; intermittently elevated CSF pressure, usually at night; and ventricular enlargement caused by an initial rise in CSF pressure; the enlargement is maintained despite normal pressure because of the Laplace law. Although pressure is normal, the enlarged ventricular area reflects increased force on the ventricular wall.

Frequency
United States
Incidence of congenital hydrocephalus is 3 per 1,000 live births, while the incidence of acquired hydrocephalus is not known exactly.

International
Incidence of acquired hydrocephalus is unknown. About 100,000 shunts are implanted each year in the developed countries, but little information is available for other countries.

Mortality/Morbidity
In untreated hydrocephalus, death may occur by tonsillar herniation secondary to raised ICP with compression of the brain stem and subsequent respiratory arrest.

Shunt dependence occurs in 75% of all cases of treated hydrocephalus and in 50% of children with communicating hydrocephalus.
Patients are hospitalized for scheduled shunt revisions or for treatment of shunt complications or shunt failure.
Poor development of cognitive function in infants and children, or loss of cognitive function in adults, can complicate untreated hydrocephalus. It may persist after treatment.
Visual loss can complicate untreated hydrocephalus and may persist after treatment.

Sex
Generally, incidence is equal in males and females. The exception is Bickers-Adams syndrome, an X-linked hydrocephalus transmitted by females and manifested in males. NPH has a slight male preponderance.

Age
Incidence of human hydrocephalus presents a bimodal age curve. One peak occurs in infancy and is related to the various forms of congenital malformations. Another peak occurs in adulthood, mostly resulting from NPH. Adult hydrocephalus represents approximately 40% of total cases of hydrocephalus.

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Treadmill and Pharmacologic Stress Testing

2008-06-27T08:39:00.000+03:00

Cardiovascular exercise stress testing in conjunction with an ECG has been established as one of the focal points in the diagnosis and prognosis of cardiovascular disease, specifically coronary artery disease (CAD).

Feil and Seigel first noticed the significance of cardiovascular exercise stress testing in 1928; they reported ST and T changes following exercise in 3 patients with chronic stable angina.1 The following year, Master and Oppenheimer introduced a standardized exercise protocol to assess functional capacity and hemodynamic response.

Continued research into causal mechanisms of ST displacement, refinement of exercise protocols, and determination of diagnostic and prognostic exercise variables in clinical patient subsets have continued to evolve since 1929.

After the establishment of coronary angiography as a diagnostic tool, the limitation of exercise-induced ST-segment depression as a diagnostic marker for obstructive CAD in patient populations with a low disease prevalence became apparent.

Introduction

Exercise testing is a cardiovascular stress test using treadmill bicycle exercise with ECG and blood pressure monitoring. Pharmacologic stress testing, established after exercise testing, is a diagnostic procedure in which cardiovascular stress induced by pharmacologic agents is demonstrated in patients with decreased functional capacity or in patients who cannot exercise. Pharmacologic stress testing is used in combination with imaging modalities such as radionuclide imaging and echocardiography.

Exercise stress testing, which is now widely available at a relatively low cost, is currently used most frequently to estimate prognosis and determine functional capacity, to assess the probability and extent of coronary disease, and to assess the effects of therapy. Ancillary techniques, such as metabolic gas analysis, radionuclide imaging, and echocardiography, can provide further information that may be needed in selected patients, such as those with moderate or prior risk.

Exercise physiology

The initiation of dynamic exercise results in increases in the ventricular heart rate, stroke volume, and cardiac output due to vagal withdrawal and sympathetic stimulation. Also, alveolar ventilation and venous return increase as a result of sympathetic vasoconstriction. The overall hemodynamic response depends on the amount of muscle mass involved, exercise efficiency, conditioning, and exercise intensity.

In the initial phases of exercise in the upright position, cardiac output is increased by an augmentation in stroke volume mediated through the use of the Frank-Starling mechanism and heart rate. The increase in cardiac output in the later phases of exercise is due primarily to an increase in ventricular rate.

During strenuous exertion, sympathetic discharge is maximal and parasympathetic stimulation is withdrawn, resulting in autoregulation with generalized vasoconstriction, except in the vital organs (cerebral and coronary circulations).

Venous and arterial norepinephrine release from sympathetic postganglionic nerve endings is increased, and epinephrine levels are increased at peak exertion, resulting in an increase in ventricular contractility. As exercise progresses, skeletal muscle blood flow increases; oxygen extraction increases as much as 3-fold; peripheral resistance decreases; and systolic blood pressure (SBP), mean arterial pressure, and pulse pressure usually increase. Diastolic blood pressure (DBP) remains unchanged or may increase or decrease by approximately 10 mm Hg. The pulmonary vascular bed can accommodate as much as a 6-fold increase in cardiac output, with only modest increases in pulmonary arterial pressure, pulmonary capillary wedge pressure, and right atrial pressure; this is not a limiting determinant of peak exercise capacity in healthy subjects.

The maximum heart rate and cardiac output are decreased in older individuals, related in part to decreased beta-adrenergic responsiveness. Maximum heart rate can be calculated by subtracting the patient's age (y) from 220 (has a standard deviation of 10-12 beats per minute [bpm]). The age-predicted maximum heart rate is a useful measurement for safety reasons and as an estimate of the adequacy of the stress to evoke inducible ischemia. A patient who reaches 80% of the age-predicted maximum is considered to have a good test result, and an age-predicted maximum of 90% or better is considered excellent.

In the postexercise phase, hemodynamics return to baseline within minutes of discontinuing exercise. The return of vagal stimulation is an important cardiac deceleration mechanism after exercise and is more pronounced in well-trained athletes but blunted in patients with chronic congestive heart failure. Intense physical work or important cardiorespiratory impairment may interfere with achievement of a steady state, and an oxygen deficit occurs during exercise. The oxygen debt is the total oxygen uptake in excess of the resting oxygen uptake during the recovery period.

Cor pulmonale

2008-06-26T08:36:00.000+03:00

Cor pulmonale is defined as an alteration in the structure and function of the right ventricle caused by a primary disorder of the respiratory system. Pulmonary hypertension is the common link between lung dysfunction and the heart in cor pulmonale. Right-sided ventricular disease caused by a primary abnormality of the left side of the heart or congenital heart disease is not considered cor pulmonale, but cor pulmonale can develop secondary to a wide variety of cardiopulmonary disease processes. Although cor pulmonale commonly has a chronic and slowly progressive course, acute onset or worsening cor pulmonale with life-threatening complications can occur.
Pathophysiology: Several different pathophysiologic mechanisms can lead to pulmonary hypertension and, subsequently, to cor pulmonale. These pathogenetic mechanisms include (1) pulmonary vasoconstriction due to alveolar hypoxia or blood acidemia; (2) anatomic compromise of the pulmonary vascular bed secondary to lung disorders, eg, emphysema, pulmonary thromboembolism, interstitial lung disease; (3) increased blood viscosity secondary to blood disorders, eg, polycythemia vera, sickle cell disease, macroglobulinemia; and (4) idiopathic primary pulmonary hypertension. The result is increased pulmonary arterial pressure.
The right ventricle (RV) is a thin-walled chamber that is more a volume pump than a pressure pump. It adapts better to changing preloads than afterloads. With an increase in afterload, the RV increases systolic pressure to keep the gradient. At a point, further increase in the degree of pulmonary arterial pressure brings significant RV dilation, an increase in RV end-diastolic pressure, and circulatory collapse. A decrease in RV output with a decrease in diastolic left ventricle (LV) volume results in decreased LV output. Since the right coronary artery, which supplies the RV free wall, originates from the aorta, decreased LV output diminishes blood pressure in the aorta and decreases right coronary blood flow. This is a vicious cycle between decreases in LV and RV output.
Right ventricular overload is associated with septal displacement toward the left ventricle. Septal displacement, which is seen in echocardiography, can be another factor that decreases LV volume and output in the setting of cor pulmonale and right ventricular enlargement. Several pulmonary diseases cause cor pulmonale, which may involve interstitial and alveolar tissues with a secondary effect on pulmonary vasculature or may primarily involve pulmonary vasculature. Chronic obstructive pulmonary disease (COPD) is the most common cause of cor pulmonale in the United States.
Cor pulmonale usually presents chronically, but 2 main conditions can cause acute cor pulmonale: massive pulmonary embolism (more common) and acute respiratory distress syndrome (ARDS). The underlying pathophysiology in massive pulmonary embolism causing cor pulmonale is the sudden increase in pulmonary resistance. In ARDS, 2 factors cause RV overload: the pathologic features of the syndrome itself and mechanical ventilation. Mechanical ventilation, especially higher tidal volume, requires a higher transpulmonary pressure. In chronic cor pulmonale, right ventricular hypertrophy (RVH) generally predominates. In acute cor pulmonale, right ventricular dilatation mainly occurs.
Frequency:
In the US: Cor pulmonale is estimated to account for 6-7% of all types of adult heart disease in the United States, with chronic obstructive pulmonary disease (COPD) due to chronic bronchitis or emphysema the causative factor in more than 50% of cases. Although the prevalence of COPD in the United States is about 15 million, the exact prevalence of cor pulmonale is difficult to determine because it does not occur in all cases of COPD and the physical examination and routine tests are relatively insensitive for the detection of pulmonary hypertension. In contrast, acute cor pulmonale usually is secondary to massive pulmonary embolism. Acute massive pulmonary thromboembolism is the most common cause of acute life-threatening cor pulmonale in adults. In the United States, 50,000 deaths are estimated to occur per year from pulmonary emboli and about half occur within the first hour due to acute right heart failure.
Internationally: Incidence of cor pulmonale varies among different countries depending on the prevalence of cigarette smoking, air pollution, and other risk factors for various lung diseases.
Mortality/Morbidity: Development of cor pulmonale as a result of a primary pulmonary disease usually heralds a poorer prognosis. For example, patients with COPD who develop cor pulmonale have a 30% chance of surviving 5 years. However, whether cor pulmonale carries an independent prognostic value or it is simply reflecting the severity of underlying COPD or other pulmonary disease is not clear. Prognosis in the acute setting due to massive pulmonary embolism or ARDS has not been shown to be dependent on presence or absence of cor pulmonale.

Brugada Syndrome

2008-06-25T07:34:00.001+03:00

Background
Brugada syndrome is a disorder characterized by coved or saddle-shaped ST-segment elevation in leads V1 through V3 on ECG. It is associated with complete or incomplete right bundle-branch block and T-wave inversion. In its initial description, the heart was reported to be structurally normal, but this has recently been challenged (Frustaci, 2005). Moreover, subtle structural abnormalities in the right ventricular outflow tract can also be observed. The ECG abnormality may not be evident until it is unmasked by infusion of flecainide or procainamide, or is augmented by a beta-blocker.
Patients with Brugada syndrome are prone to develop ventricular tachyarrhythmias, which may lead to syncope, cardiac arrest, or sudden cardiac death (Martini, 1989; Brugada, 1992; Brugada, 2001). Brugada syndrome is genetically determined and has an autosomal dominant pattern of transmission in about 50% of familial cases. About 5% of survivors of cardiac arrest have no clinically identified cardiac abnormality; about half of these cases are thought to be due to Brugada syndrome (Alings, 1999).
Pathophysiology
Dysfunction in cardiac ion channels underlies the clinical manifestations of Brugada syndrome (cardiac channelopathy). In 10-30% of patients and families, mutations in the gene SCN5A, encoding the cardiac voltage-gated sodium channel Nav1.5, have been reported. Another locus has also been reported on chromosome 3. Most SCN5A mutations lead to loss of function of the Nav1.5 channel by reducing the sodium current (INa) available during the phases 0 (upstroke) and 1 (early repolarization) of the cardiac action potential. Gain-of-function SCN5A mutations may also cause long QT syndrome type 3.
Repolarization disorder hypothesis
ECG alterations in Brugada syndrome have been proposed to be due to an imbalance between the depolarizing and repolarizing currents during phase 1 of the action potential, most particularly in cells expressing a large, transient outward Ito current, such as the epicardial cells of the right ventricle free wall. In patients with loss-of-function SCN5A mutations that result in less INa during phase 1, the large Ito current may prematurely repolarize the membrane and produce a loss of the dome (phase 2) of the action potential (see Image 1).
When such premature shortening of the action potential heterogeneously occurs in the myocardium, it may generate phase 2 reentries that can cause ventricular tachycardia and ventricular fibrillation. The large transmural voltage gradients generated by the short action potentials in the right ventricular outflow epicardium are thought to be the basis of the ECG patterns of Brugada syndrome. These specific alterations in cardiac electrical activity, which mainly affect the right ventricle, manifest at ST-segment elevation in precordial leads V1 through V3, with a QRS morphology resembling that of a right bundle-branch block (RBBB). Such a pattern may also be due to a J point elevation. This pattern is called coved-type when ST elevation is the most prominent feature, and it is called saddleback-type when J point elevation occurs without ST elevation (see Image 2).
Depolarization disorder model
An alternative hypothesis for the ECG alterations is based on conduction delay in the right ventricular outflow tract compared with the right ventricle free wall. The mechanisms underlying the Brugada syndrome ECG pattern are reviewed by Meregalli (Meregalli, 2005).
The ECG pattern in Brugada syndrome may only be intermittent. The ECG alterations may fluctuate with changes in autonomic balance or body temperature. The abnormality may only be apparent during administration of drugs that block the sodium channel (eg, flecainide, procainamide, ajmaline). The ECG abnormality may disappear with infusion of isoprenaline or with exercise, and it may increase with beta-blockers. These effects are explained by a reduced sodium current in the etiology of Brugada syndrome.

Frequency
United States
Because of its recent identification, the incidence of the Brugada syndrome is not well established. It may cause 4-10 sudden deaths per 10,000 population per year.
International
In Asia (eg, the Philippines, Thailand, Japan), Brugada syndrome seems to be the most common cause of natural death in men younger than 50 years. It is known as Lai Tai (Thailand), Bangungut (Philippines), and Pokkuri (Japan). In Northeast Thailand, the mortality rate from Lai Tai is approximately 30 per 100,000 population per year (Nademanee, 1997).
Mortality/Morbidity
Brugada syndrome may lead to polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation and cause sudden cardiac death.
Prolonged syncope and aborted cardiac arrest may cause nightmares, seizures, other neurologic deficits, or brain damage.

Race
Brugada syndrome is most common in people from Asia. The reason for this observation is not yet fully understood but may be due to an Asian-specific sequence in the promoter region of SCN5A (Bezzina, 2005).
Sex
Brugada syndrome is 8-10 times more prevalent in men than in women, although the probability of having a mutated gene does not differ by sex. The penetrance of the mutation appears to be much higher in men than in women.
Age
Brugada syndrome most commonly affects otherwise healthy men aged 30-50 years, but affected patients aged 0-84 years have been reported. The mean age of patients who die suddenly is 41 years (Antzelevitch, 2005).

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Varicose Veins and Spider Veins

2008-06-24T16:57:00.000+03:00

Varicose veins and telangiectasia (spider veins) are the visible surface manifestations of an underlying venous insufficiency syndrome. Venous insufficiency syndromes allow venous blood to escape from a normal flow path and flow in a retrograde direction into an already congested leg.

Mild forms of venous insufficiency are merely uncomfortable, annoying, or cosmetically disfiguring, but severe venous disease can produce serious systemic consequences and can lead to loss of life or limb.

Most patients with venous insufficiency have subjective symptoms that may include pain, soreness, burning, aching, throbbing, cramping, muscle fatigue, and restless legs. Over time, chronic venous insufficiency leads to cutaneous and soft tissue breakdown that can be debilitating.

Chronic venous insufficiency eventually produces chronic skin and soft tissue changes that begin with mild swelling and then progress to include discoloration, inflammatory dermatitis, recurrent or chronic cellulitis, cutaneous infarction, ulceration, and even malignant degeneration.

Chronic nonhealing leg ulcers, bleeding from varicose veins, and recurrent phlebitis are serious problems that are caused by venous insufficiency and can be relieved by the correction of venous insufficiency.

Pathophysiology
Varicose veins and spider veins are normal veins that have dilated under the influence of increased venous pressure.

In healthy veins, one-way valves direct the flow of venous blood upward and inward. Blood is collected in superficial venous capillaries, flows into larger superficial veins, and eventually passes through valves into the deep veins and then centrally to the heart and lungs. Superficial veins are suprafascial, while deep veins are within the muscle fascia. Perforating veins allow blood to pass from the superficial veins into the deep system.

Within muscle compartments, muscular contraction compresses deep veins and causes a pumping action that can produce transient deep venous pressures as high as 5 atmospheres. Deep veins can withstand this pressure because of their construction and because their confining fascia prevents them from becoming excessively distended. In contrast to deep veins, the venous pressure in superficial veins normally is very low. Exposure to high pressures causes superficial veins of any size to become dilated and tortuous.

Perfectly normal veins dilate and become tortuous in response to continued high pressure, as is observed in patients with dialysis shunts or with spontaneous arteriovenous malformations. In a subset of patients with hereditary vein wall weakness, even normal venous pressures produce varicose changes and venous insufficiency.

Elevated venous pressure most often is the result of venous insufficiency due to valve incompetence in the deep or superficial veins. Varicose veins are the undesirable pathways by which venous blood refluxes back into the congested extremity. Ablation of the varicose pathways invariably improves overall venous circulation.

Chronically increased venous pressure can also be caused by outflow obstruction, either from intravascular thrombosis or from extrinsic compression. In patients with outflow obstruction, varicosities must not be ablated because they are an important bypass pathway allowing blood to flow around the obstruction. Specific diagnostic tests can distinguish between patients who will benefit from ablation of dilated superficial veins and those who will be harmed by the same procedure.

Deep vein thrombosis initially produces an obstruction to outflow, but in most cases the thrombosed vessel eventually recanalizes and becomes a valveless channel delivering high pressures from above downward.

Superficial venous valve failure may result from direct trauma or from thrombotic valve injury, but most commonly is simply due to the effects of high pressure within the superficial venous system. When exposed to high pressure for a long enough period, superficial veins dilate so much that their delicate valve leaflets no longer meet.

In the most common scenario, a single venous valve fails and creates a high-pressure leak between the deep and superficial systems. High pressure within the superficial system causes local dilatation, which leads to sequential failure (through over-stretching) of other nearby valves in the superficial veins. After a series of valves have failed, the involved veins are no longer capable of directing blood upward and inward. Without functioning valves, venous blood flows in the direction of the pressure gradient: outward and downward into an already congested leg.

As increasing numbers of valves fail under the strain, high pressure is communicated into a widening network of dilated superficial veins in a recruitment phenomenon. Over time, large numbers of incompetent superficial veins acquire the typical dilated and tortuous appearance of varicosities.

Varicose veins of pregnancy most often are caused by hormonal changes that render the vein wall and the valves themselves more pliable. The sudden appearance of new dilated varicosities during pregnancy still warrants a full evaluation because of the possibility that these may be new bypass pathways related to acute deep vein thrombosis.

The sequelae of venous insufficiency are related to the venous pressure and to the volume of venous blood that is carried in a retrograde direction through incompetent veins. Unfortunately, the presence and size of visible varicosities are not reliable indicators of the volume or pressure of venous reflux. A vein that is confined within fascial planes or is buried beneath subcutaneous tissue can carry massive amounts of high-pressure reflux without being visible at all. Conversely, even a small increase in pressure can eventually produce massive dilatation of an otherwise normal superficial vein that carries very little flow.

Frequency
United States
The incidence and prevalence of venous insufficiency disease depend on the age and sex of the population. Varicosities were observed in 72% of women aged 60-69 years but in only 1% of men aged 20-29 years in the Tecumseh community health study.

International
The prevalence of venous disease is higher in Westernized and industrialized countries, most likely due to alterations in lifestyle and activity.

Mortality/Morbidity
Death can occur because of bleeding from friable varicose veins, but the mortality associated with varicose veins is almost entirely due to the association of this condition with venous thromboembolism. When treating a patient with varicose veins, the possibility of associated deep venous thrombosis must always be considered because the mortality rate of unrecognized and untreated thromboembolism is 30-60%.

Patients with varicose veins are at increased risk of deep vein thrombosis because venous stasis and injury often cause superficial phlebitis that can pass through perforating vessels to involve the deep venous system.
Varicose veins may arise after an unrecognized episode of deep vein thrombosis that causes damage to venous valves. Such patients have some underlying risk factor for thromboembolism and are at especially high risk for recurrence.
Varicose veins may sometimes serve as an important pathway for venous return in a patient with acute blockage of the deep venous system from any cause. This most often occurs after an episode of deep vein thrombosis, but it may also be a response to tumor growth or to impaired portal flow through a cirrhotic liver.

Sex
Because of hormonal factors, varicosities and telangiectasia are more common in women than in men at any age.

Age

Most varicose and spider veins in adults have their genesis in childhood. Serial examinations of children aged 10-12 years and again 4 and 8 years later showed that symptoms are experienced (and venous test results are abnormal) before any abnormal veins are visible at the surface of the skin.
When abnormal veins do become visible, reticular veins usually appear first and are followed after several years by incompetent perforators. Smaller telangiectatic webs and large varicose veins usually become visible only in adulthood, many years after the true onset of disease.
Although varicosities continue to worsen and to recruit new areas of involvement throughout life, only a small number of new cases appear after the childbearing years.

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The US Visa

2008-06-23T07:26:00.000+03:00

Prices of Gas skyrocketting

2008-06-20T17:24:00.001+03:00

Acute Renal Failure

2008-06-20T12:07:00.001+03:00

Background
Acute renal failure (ARF) or acute kidney injury (AKI), as it is now referred to in the literature, is defined as an abrupt or rapid decline in renal filtration function. This condition is usually marked by a rise in serum creatinine concentration or azotemia (a rise in blood urea nitrogen [BUN] concentration). However, immediately after a kidney injury, BUN or creatinine levels may be normal, and the only sign of a kidney injury may be decreased urine production. A rise in the creatinine level can result from medications (eg, cimetidine, trimethoprim) that inhibit the kidney’s tubular secretion. A rise in the BUN level can occur without renal injury, such as in GI or mucosal bleeding, steroid use, or protein loading, so a careful inventory must be taken before determining if a kidney injury is present.
Pathophysiology
AKI may occur in 3 clinical patterns, including the following: (1) as an adaptive response to severe volume depletion and hypotension, with structurally intact nephrons; (2) in response to cytotoxic, ischemic, or inflammatory insults to the kidney, with structural and functional damage; and (3) with obstruction to the passage of urine. Therefore, in general terms, AKI may be classified as prerenal, intrinsic, and postrenal. While these classifications are useful in establishing a differential diagnosis, many pathophysiologic features are shared among the different categories.
Patients who develop AKI can be oliguric or nonoliguric, have a rapid or slow rise in creatinine levels, and may have qualitative differences in urine solute concentrations and cellular content. The reason for this lack of a uniform clinical presentation is a reflection of the variable nature of the injury. Classifying AKI as oliguric or nonoliguric based on daily urine excretion has prognostic value. Oliguria is defined as a daily urine volume of less than 400 mL/d and has a worse prognosis, except in prerenal failure. Anuria is defined as a urine output of less than 100 mL/d and, if abrupt in onset, is suggestive of bilateral obstruction or catastrophic injury to both kidneys. Stratification of renal failure along these lines helps in decision-making (eg, timing of dialysis) and can be an important criterion for patient response to therapy.
Prerenal AKIPrerenal AKI represents the most common form of kidney injury and often leads to intrinsic AKI if it is not promptly corrected. Volume loss from GI, renal, cutaneous (eg, burns), and internal or external hemorrhage can result in this syndrome. Prerenal AKI can also result from decreased renal perfusion in patients with heart failure or shock (eg, sepsis, anaphylaxis). Special classes of medications that can induce prerenal AKI in volume-depleted states are angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), which are otherwise safely tolerated and beneficial in most patients with chronic kidney disease. Arteriolar vasoconstriction leading to prerenal AKI can occur in hypercalcemic states, with the use of radiocontrast agents, nonsteroidal anti-inflammatory drugs (NSAIDs), amphotereicin, calcineurin inhibitors, norepinephrine, and other pressor agents. The hepatorenal syndrome can also be considered a form of prerenal AKI because functional renal failure develops from diffuse vasoconstriction in vessels supplying the kidney.Intrinsic AKI
Structural injury in the kidney is the hallmark of intrinsic AKI, and the most common form is acute tubular injury (ATN), either ischemic or cytotoxic. Frank necrosis is not prominent in most human cases of ATN and tends to be patchy. Less obvious injury includes loss of brush borders, flattening of the epithelium, detachment of cells, formation of intratubular casts, and dilatation of the lumen. Although these changes are observed predominantly in proximal tubules, injury to the distal nephron can also be demonstrated. The distal nephron may also be subjected to obstruction by desquamated cells and cellular debris. In contrast to necrosis, the principal site of apoptotic cell death is the distal nephron. During the initial phase of ischemic injury, loss of integrity of the actin cytoskeleton leads to flattening of the epithelium, with loss of the brush border, loss of focal cell contacts, and subsequent disengagement of the cell from the underlying substratum.
Many endogenous growth factors that participate in the process of regeneration have not been identified; however, administration of growth factors exogenously has been shown to ameliorate and hasten recovery from AKI. Depletion of neutrophils and blockage of neutrophil adhesion reduce renal injury following ischemia, indicating that the inflammatory response is responsible, in part, for some features of ATN, especially in postischemic injury after transplant.
Intrarenal vasoconstriction is the dominant mechanism for the reduced glomerular filtration rate (GFR) in patients with ATN. The mediators of this vasoconstriction are unknown, but tubular injury seems to be an important concomitant finding. Urine backflow and intratubular obstruction (from sloughed cells and debris) are causes of reduced net ultrafiltration. The importance of this mechanism is highlighted by the improvement in renal function that follows relief of such intratubular obstruction. In addition, when obstruction is prolonged, intrarenal vasoconstriction is prominent in part due to the tubuloglomerular feedback mechanism, which is thought to be mediated by adenosine and activated when there is proximal tubular damage and the macula densa is presented with increased chloride load.
Apart from the increase in basal renal vascular tone, the stressed renal microvasculature is more sensitive to potentially vasoconstrictive drugs and otherwise-tolerated changes in systemic blood pressure. The vasculature of the injured kidney has an impaired vasodilatory response and loses its autoregulatory behavior. This latter phenomenon has important clinical relevance because the frequent reduction in systemic pressure during intermittent hemodialysis may provoke additional damage that can delay recovery from ATN. Often, injury results in atubular glomeruli, where the glomerular function is preserved, but the lack of tubular outflow precludes its function.A physiologic hallmark of ATN is a failure to maximally dilute or concentrate urine (isosthenuria). This defect is not responsive to pharmacologic doses of vasopressin. The injured kidney fails to generate and maintain a high medullary solute gradient because the accumulation of solute in the medulla depends on normal distal nephron function. Failure to excrete concentrated urine, even in the presence of oliguria, is a helpful diagnostic clue to distinguish prerenal from intrinsic renal disease, in which urine osmolality is less than 300 mOsm/kg. In prerenal azotemia, urine osmolality is typically more than 500 mOsm/kg. Glomerulonephritis can be a cause of AKI and usually falls into a class referred to as rapidly progressive glomerulonephritis (RPGN). The pathologic correlation of RPGN is the presence of glomerular crescents (glomerular injury) on biopsy; if more than 50% of glomeruli contain crescents, this usually results in a significant decline in renal function. Although comparatively rare, acute glomerulonephritides should be part of the diagnostic consideration in cases of AKI.Postrenal AKI
Mechanical obstruction of the urinary collecting system, including the renal pelvis, ureters, bladder, or urethra, results in obstructive uropathy or postrenal AKI.
If the site of obstruction is unilateral, then a rise in the serum creatinine level may not be apparent due to contralateral renal function. Although the serum creatinine level may remain low with unilateral obstruction, a significant loss of GFR occurs, and patients with partial obstruction may develop progressive loss of GFR if the obstruction is not relieved. Causes of obstruction include stone disease; stricture; and intraluminal, extraluminal, or intramural tumors.
Bilateral obstruction is usually a result of prostate enlargement or tumors in men and urologic or gynecologic tumors in women.
Patients who develop anuria typically have obstruction at the level of the bladder or downstream to it.

Frequency
United States
Approximately 1% of patients admitted to hospitals have AKI at the time of admission, and the estimated incidence rate of AKI is 2-5% during hospitalization. Approximately 95% of consultations with nephrologists are related to AKI. Feest and colleagues calculated in their report that the appropriate nephrologist referral rate is approximately 70 cases per million population.1
Mortality/Morbidity
The mortality rate estimates vary from 25-90%. The in-hospital mortality rate is 40-50%; in intensive care settings, the rate is 70-80%. Increments of 0.3 mg/dL in serum creatinine have important prognostic significance.
Race
No racial predilection is recognized.
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Firsts

2008-06-19T18:00:00.000+03:00

Syndrome of Inappropriate Secretion of Antidiuretic Hormone

2008-06-19T12:06:00.000+03:00

Background
Water balance is an important regulatory function involving the hypothalamus and the kidneys (among other organs). Various hormones are also involved, of which the antidiuretic hormone (ADH) arginine vasopressin is most important.
The syndrome of inappropriate secretion of ADH (SIADH) is characterized by the nonphysiologic release of ADH, resulting in impaired water excretion with normal sodium excretion.
SIADH was first described by Schwartz and associates in 2 patients with bronchogenic carcinoma and was later further characterized by Bartter and Schwartz.
Pathophysiology
ADH is a polypeptide synthesized in the supraoptic and paraventricular nuclei in the hypothalamus and is released in response to a number of stimuli. ADH is rapidly metabolized in the liver and kidneys and has a half-life of 15-20 minutes.
In the kidneys, ADH acts on the principal cells of the cortical and medullary collecting tubules to increase water permeability. Other renal actions include local production of prostaglandins in a variety of renal cells, including the glomerulus and the thick ascending limb of the loop of Henle. Elsewhere, ADH causes vasoconstriction in a number of vascular beds and releases factor VIII and von Willebrand factor from vascular endothelium.
Three known receptors bind ADH at the cell membrane: V1a, V1b (also known as V3), and V2. The vasopressin (AVP, ADH) receptor subtypes belong to the G protein–coupled receptor superfamily. The V1a and V1b receptors signal by activation of phospholipase C and elevation in intracellular calcium, which, in turn, stimulates protein kinase C.
V1a subtype is ubiquitous and found on cells, such as vascular smooth muscle cells, hepatocytes, platelets, brain cells, and uterus cells. V1b receptors are found predominantly in the anterior pituitary.
V2 receptors are coupled to adenylate cyclase, causing a rise in intracellular cyclic adenosine monophosphate (cAMP), which serves as the second messenger. V2 receptors are found predominantly in the principal cells of the renal collecting duct, where they mediate antidiuretic response. V2 receptors are also found in endothelial cells and induce the secretion of von Willebrand factor.
ADH activates the V2 receptor on the basolateral membrane of the principal cells of the renal collecting duct. This activates cyclic adenosine monophosphate through heterotrimeric G proteins, which results in insertion of aquaporin-2 water channels in the luminal membrane, thus making it more permeable to water.
The major stimuli to ADH are hyperosmolality and effective circulating volume depletion. Normally, ADH secretion ceases when plasma osmolality falls below 275 mOsm/kg. This fall causes increased water excretion, which leads to a dilute urine with an osmolality of 40-100 mOsm/kg. In addition to the hypothalamic osmoreceptors, hypothalamic neurons secreting ADH also receive input from baroreceptors in the great vessels and the atria. This results in nonosmotic release of ADH. Other stimuli for ADH secretion include pain and nausea.
In general, the plasma sodium concentration is the primary osmotic determinant of ADH release. However, in persons with SIADH, a nonphysiologic secretion of ADH results in enhanced water reabsorption, leading to dilutional hyponatremia. Sodium excretion is intact, and the amount of sodium excreted in the urine varies with diet. Ingestion of water is an essential prerequisite to the development of dilutional hyponatremia; regardless of cause, hyponatremia does not occur if water is restricted.
The continued presence of ADH with water intake causes retention of ingested water. While a large fraction of this water is intracellular, the extracellular fraction causes volume expansion. Volume receptors are activated and peptides (eg, atrial natriuretic peptide) are secreted, which causes natriuresis with some degree of accompanying kaliuresis and diuresis. Thus, these patients are euvolemic or are slightly volume-expanded.
If water and sodium intake remain constant, a steady state is reached and sodium excretion equals sodium intake. Experimental evidence indicates that several days after ADH-induced water retention, escape from its effect occurs. This results in the establishment of a water balance and a newer, stable (although lower) sodium concentration. This is thought to be mediated via pressure-induced natriuresis and diuresis. Other authorities attribute this escape phenomenon to a decrease in the aquaporin-2 channel expression in the renal collecting duct.
In addition to the inappropriate ADH secretion, persons with this syndrome also may have an inappropriate thirst sensation, which leads to an intake of water that is in excess of the free water excreted. This increase in water ingested may then contribute to the maintenance of hyponatremia.
Before the diagnosis of SIADH is made, other causes for a decreased diluting capacity (eg, renal, pituitary, adrenal, thyroid, cardiac, or hepatic disease) must be excluded. In addition, nonosmotic stimuli for arginine vasopressin release, particularly hemodynamic derangements (eg, due to hypotension, nausea, uncontrolled pain, or drugs) must be excluded.
Frequency
United States
SIADH is usually observed in patients in hospital settings, and the frequency may be as high as 35%.
Mortality/Morbidity
The mortality rate for acute symptomatic hyponatremia has been noted to be as high as 55% and as low as 5%, depending on the reference source. The mortality rate associated with chronic hyponatremia has been reported to be 14-27%.
In a retrospective case note review by Clayton and colleagues, patients with a multifactorial cause for hyponatremia in an inpatient setting had a significantly higher mortality rate. The outcome was least favorable in patients who were normonatremic at admission and became hyponatremic during the course of their hospitalization. The etiology of hyponatremia was a more important prognostic indicator than the level of absolute serum sodium in the patients.

2008-06-18T16:56:00.000+03:00

Azotemia

2008-06-18T12:03:00.000+03:00

Background
Each human kidney contains approximately 1 million functional units, called nephrons, which are primarily involved in formation. Formation ensures that the body eliminates the final products of metabolic activities and excess water in an attempt to maintain a constant internal environment (homeostasis).
Urine formation by each nephron involves 3 main processes, as follows: filtration at the glomerular level, selective reabsorption from the filtrate passing along the renal tubules, and secretion by the cells of the tubules into this filtrate. Perturbation of any of these processes impairs the kidney's excretory function, resulting in azotemia, which is elevation of blood urea nitrogen (BUN) (reference range, 8-20 mg/dL) and serum creatinine (normal value, 0.7-1.4 mg/dL) levels.
The quantity of glomerular filtrate produced each minute by all nephrons in both kidneys is referred to as the glomerular filtration rate (GFR). Average GFR is about 125 mL/min (10% less for women) or 180 L/d. About 99% (178 L/d) is reabsorbed, and the rest (2 L/d) is excreted.
Measuring renal function
Radionuclide assessment of GFR is the criterion standard for measuring kidney function. However, because it is expensive and not widely available, serum creatinine concentration and creatinine clearance (CrCl) more commonly are used.
An inverse relationship between serum creatinine and GFR exists. However, the serum creatinine and CrCl are not sensitive measures of kidney damage for two reasons. First, substantial renal damage can take place before any decrease in GFR occurs. Second, a substantial decline in GFR may lead to only slight elevation in serum creatinine, as shown in Media file 1. An elevation in serum creatinine is apparent only when the GFR falls to about 60-70 mL/min. This is due to compensatory hypertrophy and hyperfiltration of the remaining healthy nephrons.
Because creatinine normally is filtered as well as secreted into the renal tubules, the CrCl may cause the GFR to be substantially overestimated, especially as kidney failure progresses because of maximal tubular excretion. More accurate determinations of GFR require the use of inulin clearance or a radiolabeled compound, such as iothalamate. In practice, precise knowledge of the GFR is not required, and disease process usually can be monitored by the estimated GFR (eGFR) using different methods, as shown below.
The CrCl is best calculated by obtaining a 24-hour collection for creatinine and volume and then using the following formula: CrCl (mL/min) = U/P X V where U is the 24-hour creatinine in mg/dL, P is the serum creatinine in mg/dL, and V is the 24-hour volume/1440 (number of min in 24 h). Using the 24-hour creatinine in grams and the serum creatinine in milligrams, CrCl (mL/min) = creatinine [g/d]/serum creatinine [mg/dL]) X 70. An adequate 24-hour collection usually reflects a creatinine generation of 15-20 mg/kg in women and 20-25 mg/kg in men. When 24-hour creatinine is measured, the adequacy of the collection must be established prior to calculation of the creatinine clearance.
Alternatively, a bedside formula (Cockroft and Gault) using the patient's serum creatinine, age, and lean weight (in kg) can be used to estimate the GFR, as follows: CrCl (mL/min) = (140 - age) X weight (kg) / (72 X serum creatinine) in mg/dL (X 0.85 for women).Another formula was derived from data collected in a large study called the Modification of Diet in Renal Disease (MDRD). This formula is known as the MDRD formula or the Levey formula. It is now widely accepted as more accurate than the Cockroft and Gault formula and is an alternative to radioisotope clearance. Because serum creatinine levels alone cannot detect earlier stages of chronic kidney disease (CKD), the MDRD formula also takes into account the patient's age and race. Although more accurate, it is much more difficult to calculate manually. However, software for estimating GFR by the MDRD formula is available on most pocket digital assistants (PDA) or can be found on the Internet.

Pathophysiology
There are three pathophysiologic states in azotemia, as follows: prerenal azotemia, intrarenal azotemia, and postrenal azotemia.
Prerenal azotemia
Prerenal azotemia refers to elevation in BUN and creatinine levels because of problems in the systemic circulation that decrease flow to the kidneys. In prerenal azotemia, decrease in renal flow stimulates salt and water retention to restore volume and pressure. When volume or pressure is decreased, the baroreceptor reflexes located in the aortic arch and carotid sinuses are activated. This leads to sympathetic nerve activation, resulting in renal afferent arteriolar vasoconstriction and renin secretion through b1-receptors. Constriction of the afferent arterioles causes a decrease in the intraglomerular pressure, reducing GFR proportionally. Renin converts angiotensin I to angiotensin II, which, in turn, stimulates aldosterone release. Increased aldosterone levels results in salt and water absorption in the distal collecting tubule.
A decrease in volume or pressure is a nonosmotic stimulus for antidiuretic hormone production in the hypothalamus, which exerts its effect in the medullary collecting duct for water reabsorption. Through unknown mechanisms, activation of the sympathetic nervous system leads to enhanced proximal tubular reabsorption of salt and water, as well as BUN, creatinine, calcium, uric acid, and bicarbonate. The net result of these 4 mechanisms of salt and water retention is decreased output and decreased urinary excretion of sodium (<20 mEq/L).
Intrarenal azotemia
Intrarenal azotemia, also known as acute renal failure (ARF), renal-renal azotemia, and acute kidney injury (AKI), refers to elevation in BUN and creatinine levels because of problems in the kidney itself. There are several definitions, including a rise in serum creatinine levels of about 30% from baseline or a sudden decline in output below 500 mL/d. If output is preserved, it is called nonoliguric ARF. If output falls below 500 mL/d, it is called oliguric ARF. Any form of ARF may be so severe to virtually stop formation, a condition called anuria (<100 mL/d).
The most common causes of nonoliguric ARF are acute tubular necrosis (ATN), aminoglycoside nephrotoxicity, lithium toxicity, or cisplatin nephrotoxicity. Tubular damage is less severe than in oliguric ARF. Normal output in nonoliguric ARF does not reflect normal GFR. Patients may still make 1440 mL/d of urine even when the GFR falls to about 1 mL/min because of decreased tubular reabsorption.
Some studies indicate that nonoliguric forms of ARF are associated with less morbidity and mortality than oliguric ARF. Uncontrolled studies also suggest that volume expansion, potent diuretic agents, and renal vasodilators can convert oliguric to nonoliguric ARF if administered early.
The pathophysiology of acute oliguric or nonoliguric ARF depends on the anatomical location of the injury. In ATN, epithelial damage leads to functional decline in the ability of the tubules to reabsorb salt, water, and other electrolytes. Excretion of acid and potassium also is impaired. In more severe ATN, the tubular lumen is filled with epithelial casts, causing intraluminal obstruction, resulting in the decline of GFR.
Acute interstitial nephritis is characterized by inflammation and edema, resulting in azotemia, hematuria, sterile pyuria, white cell casts with variable eosinophiluria, proteinuria, and hyaline casts. The net effect is a loss of urinary concentrating ability, with low osmolality (usually <500>40 mEq/L), and, occasionally, hyperkalemia and renal tubular acidosis. However, in the presence of a superimposed prerenal azotemia, the specific gravity, osmolality, and sodium may be misleading.
Glomerulonephritis or vasculitis is suggested by the presence of hematuria, red cells, white cells, granular and cellular casts, and a variable degree of proteinuria. Nephrotic syndrome usually is not associated with active inflammation and often presents as proteinuria greater than 3.5 g/24 h.
Glomerular diseases may reduce GFR due to changes in basement membrane permeability, as well as stimulation of the renin-aldosterone axis. Glomerular diseases often manifest as nephrotic or nephric syndrome. In nephrotic syndrome, the urinary sediment is inactive, and there is gross proteinuria (>3.5 g/d), hypoalbuminemia, hyperlipidemia, and edema. Azotemia and hypertension are uncommon initially, but their presence may indicate advanced disease.
In nephritic syndrome, the urinary sediment is active with white or red cell casts, granular casts, and azotemia. Proteinuria is less obvious, but increased salt and water retention in glomerulnephritis can lead to hypertension, edema formation, decreased output, low urinary excretion of sodium, and increased specific gravity.
Acute vascular diseases include vasculitis syndromes, malignant hypertension, scleroderma renal crisis, and thromboembolic disease, all of which cause renal hypoperfusion and ischemia leading to azotemia. Chronic vascular diseases are due to hypertensive benign nephrosclerosis, which has not been conclusively associated with end-stage renal disease and ischemic renal disease from bilateral renal artery stenosis.
In bilateral renal artery stenosis, maintenance of adequate intraglomerular pressure for filtration greatly depends on efferent arteriolar vasoconstriction. Azotemia sets in when angiotensin-converting enzyme (ACE) inhibitors or angiotensin type 2 receptor blockers cause efferent arteriolar dilatation, thereby decreasing intraglomerular pressure and filtration. Therefore, converting enzyme inhibitors and receptor blockers are contraindicated in bilateral renal artery stenosis.
In addition to accumulation of urea creatinine and other waste products, a substantial reduction in GFR in CKD results in decreased production of erythropoietin (causing anemia) and vitamin D-3 (causing hypocalcemia, secondary hyperparathyroidism, hyperphosphatemia, and renal osteodystrophy); reduction in acid, potassium, salt, and water excretion (causing acidosis, hyperkalemia, hypertension, and edema); and platelet dysfunction, which leads to increased bleeding tendencies.
The syndrome associated with the signs and symptoms of accumulation of toxic waste products (uremic toxins) is termed uremia and often occurs at a GFR of about 10 mL/min. Some of the uremic toxins (ie, urea, creatinine, phenols, guanidines) have been identified, but none has been found responsible for all the manifestations of uremia.
Postrenal azotemia
Postrenal azotemia refers to elevation in BUN and creatinine levels because of obstruction in the collecting system. Obstruction to flow leads to a reversal of Starling forces responsible for glomerular filtration. Progressive bilateral obstruction causes hydronephrosis with an increase in the Bowman capsular hydrostatic pressure and tubular blockage resulting in progressive decline and ultimate cessation in glomerular filtration, azotemia, acidosis, fluid overload, and hyperkalemia.
Unilateral obstruction rarely causes azotemia. With relief of complete ureteral obstruction within 48 hours of onset, there is evidence that relatively complete recovery of GFR can be achieved within a week, while little or no further recovery occurs after 12 weeks. Complete or prolonged partial obstruction can lead to tubular atrophy and irreversible renal fibrosis. Hydronephrosis may be absent if obstruction is mild or acute or if the collecting system is encased by retroperitoneal tumor or fibrosis.

Frequency
United States
Considerable variability exists in reports about the incidence of hospital or community-acquired ARF. In one report, community-acquired ARF occurred in about 1% of all hospital admissions. Overall, ARF occurs in about 5% of all hospital admissions. However, differences exist in ARF occurring in the intensive care unit (about 15%) and in the coronary care unit (about 4%). In CKD, progressive azotemia leading to end-stage renal disease requiring dialysis or kidney transplantation occurs in a number of chronic diseases with frequencies for diabetes (36%), hypertension (24%), glomerulonephritis (15%), cystic kidney disease (4%), uncertain (5%), and all other known miscellaneous renal disorders (15%).

International
A report from Madrid evaluated 748 cases of ARF at 13 tertiary hospital centers. The most frequent causes were ATN (45%); prerenal (21%); acute or chronic renal failure, mostly due to ATN and prerenal disease (13%); urinary tract obstruction (10%); glomerulonephritis or vasculitis (4%); acute interstitial nephritis (2%); and atheroemboli (1%). Etiologies of CKD differ around the world. Diabetic nephropathy as a cause of CKD is on the rise in developed and developing countries.

Mortality/Morbidity
Prognosis in ARF generally is poor and depends on the severity of the underlying disease and the number of failed organs. While mortality rate in simple ARF without other underlying disease is 7-23%, the mortality in the patient in the intensive care unit on mechanical ventilation is as high as 80%.
The prognosis of patients with CKD depends on the etiology of the failure. Patients with diabetic kidney disease, hypertensive nephrosclerosis, and ischemic nephropathy (ie, large-vessel arterial occlusive disease) tend to have progressive azotemia resulting in end-stage renal disease. Different types of glomerulonephritis have major differences in prognosis, with some being quite benign and rarely progressing to end-stage renal disease, whereas others have rapid progression to end-stage renal disease within months. About 50% of patients with polycystic kidney disease progress to end-stage renal disease by the fifth or sixth decade of life.

Race
In the 2006 annual report of the United States Renal Data System (USRDS), more than 500,000 patients with end-stage renal disease were receiving dialysis or a kidney transplant in the United States. Racial distribution was reported as Asian/Pacific Islander (4.0%), black (33.0%), white (61.0%), American Indian (1.3%), and other/unknown (1.7%).

Sex
Of the patients reported in the 2006 annual report of the USRDS, male frequency is 56.0% and female frequency is 44.0%.
Age
Of the patients reported in the 2006 annual report of the USRDS, frequencies for patients aged 0-19 years is 1%; aged 20-44 years, 17.0%; aged 45-64 years, 41.0%; aged 65-74 years, 22.0%; and older than 75 years, 18.0%.

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Rheumatoid Arthritis

2008-06-17T12:01:00.001+03:00

Background
Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease characterized by synovitis and serositis (inflammation of the lining surfaces of the joints, pericardium, and pleura), rheumatoid nodules, and vasculitis. The hallmark feature of the disease is persistent symmetric polyarthritis (synovitis) that affects the hands and feet, although any joint lined by a synovial membrane may be involved. In addition to articular deterioration, systemic involvement may lead to weight loss, low-grade fever, and malaise. The severity of RA may fluctuate over time, but chronic RA most commonly results in the progressive development of various degrees of joint destruction, deformity, and a significant decline in functional status.
Juvenile rheumatoid arthritis (JRA) is the most common form of childhood arthritis. The cause remains unknown. For most patients, the immunogenic associations, clinical pattern, and functional outcome are different from adult onset RA.
The diagnostic criteria for JRA are onset occurring when younger than 16 years, persistent arthritis in one or more joints for at least 6 weeks, and exclusion of other types of childhood arthritis. The key points that characterize the diagnosis of JRA are as follows:
Arthritis must be present. Arthritis is defined as the presence of swelling, the presence of effusion, or the presence of 2 or more of the following signs: limited range of motion (ROM), tenderness, pain on motion, or joint warmth.
Arthritis must persist for at least 6 weeks.
Other causes of chronic arthritis in children must be ruled out.
No specific laboratory or other test can establish the diagnosis of JRA.

Pathophysiology
The diagnosis of RA must be considered in any patient with polyarticular inflammatory arthritis, especially if both the hands and feet are involved. The early phase of the disease is characterized by the following features:
Joint swelling that may affect joint margins
Joint tenderness upon palpation
Systemic malaise
Loss of energy
Severe morning stiffness that limits function and generally lasts more than an hour
A classic feature of the illness is the symmetry of involvement. If synovial-based inflammation persists over time, permanent damage to tendons, ligaments, and cartilage and subchondral bone destruction occur with resultant joint deformity and limited motion. Inflammation and deformity also are nearly always seen in the hands and feet. However, involvement of the knees, hips, and shoulders accounts for significant morbidity that leads to work disability in a large percentage of patients.
A major difference in the pathophysiology of RA versus osteoarthritis or mechanical joint problems is the presence of extensive synovial inflammation. The characteristic signs of inflammation were stated by Celsus as "rubor et tumor cum calore et dolore," meaning redness and swelling with heat and pain. Galen later added "et functio laesa" (disturbed function) to the characteristic signs of inflammation. Joint tenderness, swelling, stiffness, and pain on motion are the features of inflammation experienced by patients with RA.

Frequency
United States
The prevalence rate of RA is approximately 1% of the population (range 0.3-2.1%).
Race
RA is observed throughout the world and affects persons of all races.
Sex
Women are affected approximately 3 times more often than men. Sex differences diminish in older age groups.
Age
Although RA can occur at any age, the incidence increases with advancing age. The peak incidence of RA occurs in individuals aged 40-60 years.

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Osteoporosis

2008-06-07T19:54:00.001+03:00

Osteoporosis is a systemic skeletal disorder characterized by decreased bone mass and deterioration of bony microarchitecture. The result is fragile bones and an increased risk for fracture with even minimal trauma. Osteoporosis is a chronic condition of multifactorial etiology and is usually clinically silent until a fracture occurs. Osteoporosis is a significant health problem in the United States and around the world.
Pathophysiology: Osteoporosis results from a combination of genetic and environmental factors that affect both peak bone mass and the rate of bone loss. These factors include medications, diet, race, sex, lifestyle, and physical activity. Osteoporosis may be either primary or secondary. Primary osteoporosis is subdivided into types 1 and 2. Secondary osteoporosis is also called type 3.
Type 1, or postmenopausal, osteoporosis is thought to result from gonadal (ie, estrogen, testosterone) deficiency. Estrogen or testosterone deficiency, regardless of age of occurrence, results in accelerated bone loss. The exact mechanisms of this bone loss potentially are numerous, but, ultimately, an increased recruitment and responsiveness of osteoclast precursors and an increase in bone resorption, which outpaces bone formation, occurs. After menopause, women experience an accelerated bone loss of 1-5% per year for the first 5-7 years. The end result is a decrease in trabecular bone and an increased risk of Colles and vertebral fractures.
Evidence indicates that estrogen deficiency causes bone to become more sensitive to the effects of parathyroid hormone (PTH), leading to an increase in calcium release from bone, a decrease in renal calcium excretion, and increased production of 1,25-dihydroxyvitamin D (1,25[OH]2 D3). Increased production of 1,25(OH)2 D3, in turn, causes increased calcium absorption from the gut, increased calcium resorption from bone, and increased renal tubular calcium resorption. PTH secretion then decreases via a negative feedback effect, causing the opposite effects. Osteoclasts are also influenced by cytokines, such as tumor necrosis factor-alpha and interleukins 1 and 6, whose production by mononuclear cells may be increased in the presence of gonadal deficiency.
Type 2, or senile, osteoporosis occurs in women and men because of decreased formation of bone and decreased renal production of 1,25(OH)2 D3 occurring late in life. The consequence is a loss of cortical and trabecular bone and increased risk for fractures of the hip, long bones, and vertebrae.
Type 3 osteoporosis occurs secondary to medications, especially glucocorticoids, or other conditions that cause increased bone loss by various mechanisms.
Frequency:
In the US: Approximately 10 million people have osteoporosis. Another 14-18 million have osteopenia (low bone mass).
Internationally: According to the International Osteoporosis Foundation, osteoporosis affects approximately 1 in 3 women and 1 in 8 men worldwide.
Mortality/Morbidity:
In Europe, an estimated 1 in 8 persons older than 50 years experiences a spinal fracture, and 1 in 3 women and 1 in 9 men older than 80 years experiences a hip fracture due to osteoporosis.
Approximately 1.5 million fractures per year in the United States are attributed to osteoporosis, and more than 37,000 people die from subsequent fracture-related complications. Among women who sustain a hip fracture, 50% spend time in a nursing home while recovering, and 14% of all patients with hip fractures remain in nursing homes 1 year later.
Only one third of patients return to their prefracture level of function. Patients incur a diminished quality of life and decreased independence in daily living.
Race: Whites, especially of northern European descent, and Asians are at increased risk for osteoporosis.
Sex: In type 1 and type 2 osteoporosis, women are affected more often than men, with female-to-male ratios of 6:2 and 2:1, respectively. In type 3, both sexes are equally affected.
Age: The peak incidence of type 1 osteoporosis is in people aged 50-70 years, and the peak incidence for type 2 is in people aged 70 years or older. Type 3 can occur in persons of any age.

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Mitral Regurgitation

2008-06-07T08:00:00.000+03:00

Mitral regurgitation, in the acute and chronic decompensated states, is commonly encountered in the emergency department. An understanding of the underlying etiologies and pathophysiology of the condition is critical to direct appropriate treatment.
Pathophysiology
Mitral regurgitation can be divided into the following 3 stages: acute, chronic compensated, and chronic decompensated.
In the acute stage, which usually occurs with a spontaneous chordae tendineae rupture secondary to myocardial infarction, a sudden volume overload occurs on an unprepared left ventricle and left atrium. The volume overload on the left ventricle increases left ventricular stroke work. Increased left ventricular filling pressures, combined with the transfer of blood from the left ventricle to the left atrium during systole, results in elevated left atrial pressures. This increased pressure is transmitted to the lungs resulting in acute pulmonary edema and dyspnea.
If the patient tolerates the acute phase, the chronic compensated phase begins. The chronic compensated phase results in eccentric left ventricular hypertrophy. The combination of increased preload and hypertrophy produces increased end-diastolic volumes, which, over time, result in left ventricular muscle dysfunction. This muscle dysfunction impairs the emptying of the ventricle during systole. Therefore, regurgitant volume and left atrial pressures increase, leading to pulmonary congestion.

Frequency
United States
Previously, chronic rheumatic heart disease was the most common cause of acquired mitral valve disease in the Western world. More recently, however, mitral valve prolapse (MVP) has become the most common cause, being responsible for 45% of cases of mitral regurgitation. MVP has been estimated to be present in 4% of the population; however, significant regurgitation in this population only occurs in those with abnormalities of the valve.
International
In areas other than the Western world, rheumatic heart disease remains the leading cause of mitral regurgitation.
Mortality/Morbidity
The prognosis of patients with mitral regurgitation depends on the underlying etiologies and the state of the left ventricular function.
Acute pulmonary edema and cardiogenic shock often complicate the course of acute regurgitation. The operative mortality in these cases approaches 80%. A patient with ruptured chordae tendineae and minimal symptoms has a much better prognosis.
With chronic regurgitation, volume overload is tolerated very well for years before symptoms of failure develop. Left atrial enlargement predisposes patients to the onset of atrial fibrillation with the subsequent complication of embolization. In addition, these patients are susceptible to endocarditis. A study of the survival of patients with chronic regurgitation was performed using randomly selected patients. The study revealed that 80% of the patients were alive 5 years later, and 60% were alive after 10 years.
Most patients with MVP are asymptomatic. Prolapse in those older than 60 years is frequently associated with chest pain, arrhythmias, and heart failure. The prognosis of these patients is good; however, sudden death, endocarditis, and progressive regurgitation occur rarely.
When ischemic heart disease is the mechanism for regurgitation, the extent of anatomic disease and left ventricular performance are prognostic determinants. Complicating events include sudden death and myocardial infarction.

Sex
In those younger than 20 years, males are affected more often than females.
In those older than 20 years, no sexual predilection exists.
Males older than 50 years are affected more severely.

Age
Of those cases caused by prior rheumatic disease, the mean age is 36, plus or minus 6 years.
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Shock, Hypovolemic

2008-06-06T08:00:00.001+03:00

Hypovolemic shock refers to a medical or surgical condition in which rapid fluid loss results in multiple organ failure due to inadequate circulating volume and subsequent inadequate perfusion. Most often, hypovolemic shock is secondary to rapid blood loss (hemorrhagic shock).
Acute external blood loss secondary to penetrating trauma and severe GI bleeding disorders are 2 common causes of hemorrhagic shock. Hemorrhagic shock can also result from significant acute internal blood loss into the thoracic and abdominal cavities.
Two common causes of rapid internal blood loss are solid organ injury and rupture of an abdominal aortic aneurysm. Hypovolemic shock can result from significant fluid (other than blood) loss. Two examples of hypovolemic shock secondary to fluid loss include refractory gastroenteritis and extensive burns. The remainder of this article concentrates mainly on hypovolemic shock secondary to blood loss and the controversies surrounding the treatment of this condition. The reader is referred to other articles for discussions of the pathophysiology and treatment for hypovolemic shock resulting from losses of fluid other than blood.
The many life-threatening injuries experienced during the wars of the 1900s have significantly affected the development of the principles of hemorrhagic shock resuscitation. During World War I, W.B. Cannon recommended delaying fluid resuscitation until the cause of the hemorrhagic shock was repaired surgically. Crystalloids and blood were used extensively during World War II for the treatment of patients in unstable conditions. Experience from the Korean and Vietnam wars revealed that volume resuscitation and early surgical intervention were paramount for surviving traumatic injuries resulting in hemorrhagic shock. These and other principles helped in the development of present guidelines for the treatment of traumatic hemorrhagic shock. However, recent investigators have questioned these guidelines, and today, controversies exist concerning the optimal treatment of hemorrhagic shock.For more information, see Medscape's Trauma Resource Center.

Pathophysiology
The human body responds to acute hemorrhage by activating the following major physiologic systems: the hematologic, cardiovascular, renal, and neuroendocrine systems.
The hematologic system responds to an acute severe blood loss by activating the coagulation cascade and contracting the bleeding vessels (by means of local thromboxane A2 release). In addition, platelets are activated (also by means of local thromboxane A2 release) and form an immature clot on the bleeding source. The damaged vessel exposes collagen, which subsequently causes fibrin deposition and stabilization of the clot. Approximately 24 hours are needed for complete clot fibrination and mature formation.
The cardiovascular system initially responds to hypovolemic shock by increasing the heart rate, increasing myocardial contractility, and constricting peripheral blood vessels. This response occurs secondary to an increased release of norepinephrine and decreased baseline vagal tone (regulated by the baroreceptors in the carotid arch, aortic arch, left atrium, and pulmonary vessels). The cardiovascular system also responds by redistributing blood to the brain, heart, and kidneys and away from skin, muscle, and GI tract.
The renal system responds to hemorrhagic shock by stimulating an increase in renin secretion from the juxtaglomerular apparatus. Renin converts angiotensinogen to angiotensin I, which subsequently is converted to angiotensin II by the lungs and liver. Angiotensin II has 2 main effects, both of which help to reverse hemorrhagic shock, vasoconstriction of arteriolar smooth muscle, and stimulation of aldosterone secretion by the adrenal cortex. Aldosterone is responsible for active sodium reabsorption and subsequent water conservation.
The neuroendocrine system responds to hemorrhagic shock by causing an increase in circulating antidiuretic hormone (ADH). ADH is released from the posterior pituitary gland in response to a decrease in BP (as detected by baroreceptors) and a decrease in the sodium concentration (as detected by osmoreceptors). ADH indirectly leads to an increased reabsorption of water and salt (NaCl) by the distal tubule, the collecting ducts, and the loop of Henle.
The pathophysiology of hypovolemic shock is much more involved than what was just listed. To explore the pathophysiology in more detail, references for further reading are provided in the bibliography. These intricate mechanisms list above are effective in maintaining vital organ perfusion in severe blood loss. Without fluid and blood resuscitation and/or correction of the underlying pathology causing the hemorrhage, cardiac perfusion eventually diminishes, and multiple organ failure soon follows.

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Anaphylaxis

2008-06-05T08:00:00.000+03:00

Anaphylaxis refers to a severe allergic reaction in which prominent dermal and systemic signs and symptoms manifest. The full-blown syndrome includes urticaria (hives) and/or angioedema with hypotension and bronchospasm. The classic form, described in 1902, involves prior sensitization to an allergen with later re-exposure, producing symptoms via an immunologic mechanism. An anaphylactoid reaction produces a very similar clinical syndrome but is not immune-mediated. Treatment for both conditions is similar, and this article uses the term anaphylaxis to refer to both conditions unless otherwise specified.
Pathophysiology
Rapid onset of increased secretion from mucous membranes, increased bronchial smooth muscle tone, decreased vascular smooth muscle tone, and increased capillary permeability occur after exposure to an inciting substance. These effects are produced by the release of mediators, which include histamine, leukotriene C4, prostaglandin D2, and tryptase.
In the classic form, mediator release occurs when the antigen (allergen) binds to antigen-specific immunoglobulin E (IgE) attached to previously sensitized basophils and mast cells. The mediators are released almost immediately when the antigen binds. In an anaphylactoid reaction, exposure to an inciting substance causes direct release of mediators, a process that is not mediated by IgE. Increased mucous secretion and increased bronchial smooth muscle tone, as well as airway edema, contribute to the respiratory symptoms observed in anaphylaxis. Cardiovascular effects result from decreased vascular tone and capillary leakage. Histamine release in skin causes urticarial skin lesions.
The most common inciting agents in anaphylaxis are parenteral antibiotics (especially penicillins), IV contrast materials, Hymenoptera stings, and certain foods (most notably, peanuts). Oral medications and many other types of exposures also have been implicated. Anaphylaxis also may be idiopathic.
Frequency
United States
The true incidence of anaphylaxis is unknown, partly because of the lack of a precise definition of the syndrome. Some clinicians reserve the term for the full-blown syndrome, while others use it to describe milder cases. Fatal anaphylaxis is relatively rare; milder forms occur much more frequently. Some authors consider up to 15% of the US population "at risk" for anaphylaxis. The frequency of anaphylaxis is increasing and this has been attributed to the increased number of potential allergens to which people are exposed. Up to 500-1,000 fatal cases of anaphylaxis per year are estimated to occur in the US.
International
Reactions to insects and other venomous plants and animals are more prevalent in tropical areas because of the greater biodiversity in these areas.
Mortality/Morbidity
Approximately 1 in 5000 exposures to a parenteral dose of a penicillin or cephalosporin antibiotic causes anaphylaxis. More than 100 deaths per year are reported in the United States. Fewer than 100 fatal reactions to Hymenoptera stings are reported each year in the United States but this is considered to be an underestimate. One to 2% of people receiving IV radiocontrast experience some sort of reaction. The majority of these reactions are minor, and fatalities are rare. Low molecular weight contrast causes fewer and less severe reactions.
Race
Well-described racial differences in the incidence or severity of anaphylaxis do not exist. Cultural and socioeconomic differences may influence exposure rates.
Sex
No major differences have been reported in the incidence and prevalence of anaphylactic reactions between men and women.
Age
Anaphylaxis occurs in all age groups. While prior exposure is essential for the development of true anaphylaxis, reactions occur even when no documented prior exposure exists. Thus, patients may react to a first exposure to an antibiotic or insect sting. Adults are exposed to more potential allergens than are pediatric patients. The elderly have the greatest risk of mortality from anaphylaxis due to the presence of preexisting disease.

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Stevens-Johnson Syndrome

2008-06-04T08:00:00.001+03:00

Background
First described in 1922, Stevens-Johnson syndrome (SJS) is an immune-complex–mediated hypersensitivity complex that is a severe expression of erythema multiforme. It is known by some as erythema multiforme major, but disagreement exists in the literature. Most authors and experts consider SJS and toxic epidermal necrolysis (TEN) different manifestations of the same disease. For that reason, many refer to the entity as SJS/TEN. SJS typically involves the skin and the mucous membranes. While minor presentations may occur, significant involvement of oral, nasal, eye, vaginal, urethral, GI, and lower respiratory tract mucous membranes may develop in the course of the illness. GI and respiratory involvement may progress to necrosis. SJS is a serious systemic disorder with the potential for severe morbidity and even death. Missed diagnosis is common.
Although several classification schemes have been reported, the simplest breaks the disease down as follows:1
SJS - A "minor form of TEN," with less than 10% body surface area (BSA) detachment
Overlapping SJS/TEN - Detachment of 10-30% BSA
TEN - Detachment of more than 30% BSA

Pathophysiology
SJS is an immune-complex–mediated hypersensitivity disorder that may be caused by many drugs, viral infections, and malignancies. Cocaine recently has been added to the list of drugs capable of producing the syndrome. In up to half of cases, no specific etiology has been identified.
Pathologically, cell death results causing separation of the epidermis from the dermis. The death receptor, Fas, and its ligand, FasL, have been linked to the process. Some have also linked inflammatory cytokines to the pathogenesis.
Frequency
United States
Cases tend to have a propensity for the early spring and winter.
International
SJS occurs with a worldwide distribution similar in etiology and occurrence to that in the United States.
Mortality/Morbidity
Mortality is determined primarily by the extent of skin sloughing. When BSA sloughing is less than 10%, the mortality rate is approximately 1-5%. However, when more than 30% BSA sloughing is present, the mortality rate is between 25% and 35%.
See SCORTEN for a more complete discussion of severity of illness and mortality.
Lesions may continue to erupt in crops for as long as 2-3 weeks. Mucosal pseudomembrane formation may lead to mucosal scarring and loss of function of the involved organ system. Esophageal strictures may occur when extensive involvement of the esophagus exists. Mucosal shedding in the tracheobronchial tree may lead to respiratory failure.
Ocular sequelae may include corneal ulceration and anterior uveitis. Blindness may develop secondary to severe keratitis or panophthalmitis in 3-10% of patients. Vaginal stenosis and penile scarring have been reported. Renal complications are rare.

Race
A Caucasian predominance has been reported.
Sex
The male-to-female ratio is 2:1.
Age
Most patients are in the second to fourth decade of their lives; however, cases have been reported in children as young as 3 months.
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Dysmenorrhea

2008-06-03T08:00:00.001+03:00

Dysmenorrhea refers to the syndrome of painful menstruation. Primary dysmenorrhea occurs in the absence of pelvic pathology, whereas secondary dysmenorrhea results from identifiable organic diseases, most typically endometriosis, uterine fibroids, uterine adenomyosis, or chronic pelvic inflammatory disease. The prevalence of dysmenorrhea is estimated to be between 45 and 95% among reproductive-aged women. Although not life threatening, dysmenorrhea can be debilitating and psychologically taxing for many women and is one of the leading causes of absenteeism from work and school.

Pathophysiology
Historical attitudes toward menstrual pain were often dismissive. Pain was often attributed to women's emotional or psychological states, misconceptions about sex, and unhealthy maternal relations. Research has now established concrete physiologic explanations for dysmenorrhea, which discredit these prior theories.
Primary dysmenorrhea usually begins within the first 6-12 months after menarche once a regular ovulatory cycle has been established. During menstruation, sloughing endometrial cells release prostaglandins, which cause uterine ischemia through myometrial contraction and vasoconstriction. Elevated levels of prostaglandins have been measured in the menstrual fluid of women with severe dysmenorrhea. These levels are especially high during the first 2 days of menstruation. Vasopressin may also play a similar role.
Secondary dysmenorrhea may present at any time after menarche, but most commonly arises when a woman is in her 20s or 30s, after years of normal, relatively painless cycles. Elevated prostaglandins may also play a role in secondary dysmenorrhea, but, by definition, concomitant pelvic pathology must also be present. Common causes include endometriosis, leiomyomata (fibroids), adenomyosis, endometrial polyps, chronic pelvic inflammatory disease, and IUD use.

Frequency
United States
The prevalence of dysmenorrhea is estimated at 45-90%. This wide range can be explained by an assumed underreporting of symptoms. Many women self-medicate at home and never seek medical attention for their pain. As mentioned above, dysmenorrhea is responsible for significant absenteeism from work and school; 13-51% of women have been absent at least once, and 5-14% are repeatedly absent.
International
One longitudinal study from Sweden reported dysmenorrhea in 90% of women younger than 19 years and in 67% of women aged 24 years (French, 2005).
Mortality/Morbidity
Dysmenorrhea itself is not life threatening, but it can have a profoundly negative impact on a woman's day-to-day life. In addition to missing work or school, she may be unable to participate in sports or other activities, compounding the emotional distress brought on by the pain.

Race
No significant difference is apparent in the prevalence of dysmenorrhea among different populations.

Sex
Despite prevailing trends toward equality in the sexes, men are not yet known to experience dysmenorrhea.

Age
See Frequency above.

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Rh Incompatibility

2008-06-02T08:00:00.000+03:00

The Rh factor (ie, Rhesus factor) is a red blood cell surface antigen that was named after the monkeys in which it was first discovered. Rh incompatibility, also known as Rh disease, is a condition that occurs when a woman with Rh-negative blood type is exposed to Rh-positive blood cells, leading to the development of Rh antibodies.
Rh incompatibility can occur by 2 main mechanisms. The most common type occurs when an Rh-negative pregnant mother is exposed to Rh-positive fetal red blood cells secondary to fetomaternal hemorrhage during the course of pregnancy from spontaneous or induced abortion, trauma, invasive obstetric procedures, or normal delivery. Rh incompatibility can also occur when an Rh-negative female receives an Rh-positive blood transfusion. In part, this is the reason that blood banks prefer using blood type "O negative" or "type O, Rh negative," as the universal donor type in emergency situations when there is no time to type and crossmatch blood.
The most common cause of Rh incompatibility is exposure from an Rh-negative mother by Rh-positive fetal blood during pregnancy or delivery. As a consequence, blood from the fetal circulation may leak into the maternal circulation, and, after a significant exposure, sensitization occurs leading to maternal antibody production against the foreign Rh antigen.
Once produced, maternal Rh immunoglobulin G (IgG) antibodies may cross freely from the placenta to the fetal circulation, where they form antigen-antibody complexes with Rh-positive fetal erythrocytes and eventually are destroyed, resulting in a fetal alloimmune-induced hemolytic anemia. Although the Rh blood group systems consist of several antigens (eg, D, C, c, E, e), the D antigen is the most immunogenic; therefore, it most commonly is involved in Rh incompatibility.

Pathophysiology
The amount of fetal blood necessary to produce Rh incompatibility varies. In one study, less than 1 mL of Rh-positive blood was shown to sensitize volunteers with Rh-negative blood. Conversely, other studies have suggested that 30% of persons with Rh-negative blood never develop Rh incompatibility, even when challenged with large volumes of Rh-positive blood. Once sensitized, it takes approximately one month for Rh antibodies in the maternal circulation to equilibrate in the fetal circulation. In 90% of cases, sensitization occurs during delivery. Therefore, most firstborn infants with Rh-positive blood type are not affected because the short period from first exposure of Rh-positive fetal erythrocytes to the birth of the infant is insufficient to produce a significant maternal IgG antibody response.
The risk and severity of sensitization response increases with each subsequent pregnancy involving a fetus with Rh-positive blood. In women who are prone to Rh incompatibility, the second pregnancy with an Rh-positive fetus often produces a mildly anemic infant, whereas succeeding pregnancies produce more seriously affected infants who ultimately may die in utero from massive antibody-induced hemolytic anemia.
Risk of sensitization depends largely upon the following 3 factors:
Volume of transplacental hemorrhage
Extent of the maternal immune response
Concurrent presence of ABO incompatibility
The incidence of Rh incompatibility in the Rh-negative mother who is also ABO incompatible is reduced dramatically to 1-2% and is believed to occur because the mother's serum contains antibodies against the ABO blood group of the fetus. The few fetal red blood cells that are mixed with the maternal circulation are destroyed before Rh sensitization can proceed to a significant extent. Fortunately, ABO incompatibility usually does not cause serious sequela.
Rh incompatibility is only of medical concern for females who are pregnant or plan to have children in the future. Rh-positive antibodies circulating in the bloodstream of an Rh-negative woman otherwise have no adverse effects.

Frequency
United States
Only 15% of the population lack the Rh erythrocyte surface antigen and are considered Rh-negative. The vast majority (85%) of individuals are considered Rh positive. Rh sensitization occurs in approximately 1 per 1000 births to women who are Rh negative. The Southwest United States has an incidence approximately 1.5 times the national average, which likely is caused by immigration factors and limited access to medical care since blood typing is a routine part of prenatal care. Even so, only 17% of pregnant women with Rh-negative blood who are exposed to Rh-positive fetal blood cells ever develop Rh antibodies.

Mortality/Morbidity
During the course of Rh incompatibility, the fetus is primarily affected. The binding of maternal Rh antibodies produced after sensitization with fetal Rh-positive erythrocytes results in fetal autoimmune hemolysis. As a consequence, large amounts of bilirubin are produced from the breakdown of fetal hemoglobin and are transferred via the placenta to the mother where they are subsequently conjugated and excreted by the mother. However, once delivered, low levels of glucuronyl transferase in the infant preclude the conjugation of large amounts of bilirubin and may result in dangerously elevated levels of serum bilirubin and severe jaundice.
Mildly affected infants may have little or no anemia and may exhibit only hyperbilirubinemia secondary to the continuing hemolytic effect of Rh antibodies that have crossed the placenta.
Moderately affected infants may have a combination of anemia and hyperbilirubinemia/jaundice.
In severe cases of fetal hyperbilirubinemia, kernicterus develops. Kernicterus is a neurologic syndrome caused by deposition of bilirubin into central nervous system tissues. Kernicterus usually occurs several days after delivery and is characterized by loss of the Moro (ie, startle) reflex, posturing, poor feeding, inactivity, a bulging fontanelle, a high-pitched shrill cry, and seizures. Infants who survive kernicterus may go on to develop hypotonia, hearing loss, and mental retardation.
Another serious life-threatening condition observed in infants affected by Rh incompatibility is erythroblastosis fetalis, which is characterized by severe hemolytic anemia and jaundice. The most severe form of erythroblastosis fetalis is hydrops fetalis, which is characterized by high output cardiac failure, edema, ascites, pericardial effusion, and extramedullary hematopoiesis. Newborns with hydrops fetalis are extremely pale with hematocrits usually less than 5. Hydrops fetalis often results in death of the infant shortly before or after delivery and requires an emergent exchange transfusion by a neonatologist if there is to be any chance of infant survival.

Race
Approximately 15-20% of Caucasians, as opposed to 5-10% of African Americans, have the Rh-negative blood type.
Among individuals of Chinese and American Indian descent, the incidence of Rh-negative blood type is less than 5%.

CLINICAL

History of prior blood transfusion
Rh blood type of the mother
Rh blood type of the father (55% of Rh-positive men are genetically heterozygous for the Rh antigen and, therefore, produce Rh-negative offspring when mating with Rh-negative women 50% of the time.)
Previous pregnancies, including spontaneous and elective abortions
Previous administration of Rh IgG (RhoGAM)
Mechanism of injury in cases of maternal trauma during pregnancy
Presence of vaginal bleeding and/or amniotic discharge
Previous invasive obstetric procedures, such as amniocentesis, cordocentesis, chorionic villous sampling, or ectopic pregnancy
Note that a large fetal-maternal hemorrhage may occur without symptoms and with little or no evidence of trauma. Therefore, a high index of suspicion is warranted and a low threshold for treatment is indicated.

Physical
Evaluation of the vital signs and primary survey of the airway and cardiovascular system are indicated to ensure maternal stability.
A thorough pelvic examination is required.
In situations in which abdominal and/or pelvic trauma is a consideration, inspect for evidence of bruising that may suggest the possibility of significant fetomaternal hemorrhage.
When an infant with an Rh-negative mother is delivered in the emergency department, a thorough physical examination of the infant must be performed after initial stabilization, and a neonatologist must be consulted immediately.
Physical findings may vary from mild jaundice to extreme pallor and anemia with hydrops fetalis.

Causes
Factors that influence an Rh-negative pregnant female's chances of developing Rh incompatibility include the following:
Ectopic pregnancy
Placenta previa
Placental abruption
Abdominal/pelvic trauma
In utero fetal death
Any invasive obstetric procedure (eg, amniocentesis)
Lack of prenatal care
Spontaneous abortion

DIFFERENTIALS
Other Problems to be Considered
ABO incompatibility Autoimmune hemolytic anemia Microangiopathic hemolytic anemia Spherocytosis Hereditary enzyme deficiencies Alpha thalassemia Chronic fetomaternal hemorrhage Twin-twin transfusion Erythroblastosis fetalis Hydrops fetalis
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Alcoholism

2008-06-01T10:37:00.000+03:00

Alcoholism is common, serious, and expensive. Physicians encounter alcohol-related cirrhosis, cardiomyopathy, pancreatitis, and gastrointestinal bleeding, as well as intoxication and alcohol addiction, on a daily basis. Alcoholism is also associated with many cancers. Wernicke encephalopathy and Korsakoff psychosis are also important causes of chronic disability as well as dementia. Fetal alcohol syndrome is a leading cause of mental retardation. In addition, accidents (especially automobile), depression, dementia, suicide, and homicide are important consequences of alcoholism.
Alcohol-related diseases are discussed in separate articles. The focus of this article is screening, diagnosis, treatment, and new research findings on the natural history and heritability of alcoholism.

Pathophysiology
Alcohol affects virtually every organ system in the body and, in high doses, can cause coma and death. It affects several neurotransmitter systems in the brain, including opiates, GABA, glutamate, serotonin, and dopamine. Increased opiate levels help explain the euphoric effect of alcohol, while its effects on GABA cause anxiolytic and sedative effects.
Alcohol inhibits the receptor for glutamate. Long-term ingestion results in the synthesis of more glutamate receptors. When alcohol is withdrawn, the central nervous system experiences increased excitability. Persons who abuse alcohol over the long term are more prone to alcohol withdrawal syndrome than persons who have been drinking for only short periods. Brain excitability caused by long-term alcohol ingestion can lead to cell death and cerebellar degeneration, Wernicke-Korsakoff syndrome, tremors, alcoholic hallucinosis, delirium tremens, and withdrawal seizures. Opiate receptors are increased in the brains of recently abstinent alcoholic patients, and the number of receptors correlates with cravings for alcohol.
Frequency
United States
These statistics are based on the US National Longitudinal Alcohol Epidemiologic Study. Alcoholism is prevalent in 20% of adult hospital inpatients. One in 6 patients in community-based primary care practices had problem drinking. The following apply to the US adult population:
Current drinkers - 44%
Former drinkers - 22%
Lifetime abstainers - 34%
Abuse and dependency in the past year - 7.5-9.5%
Lifetime prevalence - 13.5-23.5%
Alcoholism is slightly more common in lower income and less educated groups. Vaillant studied the natural history of alcoholism and the differences between college-educated and inner-city alcoholic persons. He followed 2 cohorts (over 400 patients) of alcoholic patients over many years.1
According to Vaillant's research, inner-city men began problem drinking approximately 10 years earlier than college graduates (age 25-30 y vs age 40-45 y). Inner-city men were more likely to be abstinent from alcohol consumption than college graduates (30% vs 10%) but more likely to die from drinking (30% vs 15%). A large percentage of college graduates alternated between controlled drinking and alcohol abuse for many years. Returning to controlled drinking from alcohol abuse is uncommon, no more than 10%; however, this figure is likely to be high because it was obtained from self-reported data. Mortality in both groups was related strongly to smoking. Abstinence for less than 5-6 years did not predict continued abstinence (41% of men abstinent for 2 y relapsed).

International
The World Health Organization examined mental disorders in primary care offices and found that alcohol dependence or harmful use was present in 6% of patients. In Britain, 1 in 3 patients in community-based primary care practices had at-risk drinking behavior. Alcoholism is more common in France than it is in Italy, despite virtually identical per capita alcohol consumption.
Mortality/Morbidity
Alcohol use is the third leading cause of preventable death in the United States (after smoking and obesity). Annually, 85,000 deaths are attributable to alcohol at a cost of $185 billion.2, 3 Almost half of these deaths are attributable to alcohol-related injury.
Four percent of the global burden of disease is attributable to alcohol. This figure rises to 7% in North America, Europe, Japan, and Australia and to 12% in Eastern Europe and Central Asia. Worldwide, alcohol is responsible for a percentage of a number of conditions, as follows:
Cirrhosis - 32%
Motor vehicle accidents - 20%
Mouth and oropharyngeal cancers - 19%
Esophageal cancer - 29%
Liver cancer - 25%
Breast cancer - 7%
Homicide - 24%
Suicide - 11%
Hemorrhagic stroke - 10%
Below are the statistically significant relative risks from a study by the American Cancer Society for men and women who consume 4 or more drinks daily. A drink is defined as one 12-oz beer, one 4- to 5-oz glass of wine, or one mixed drink containing 1.5 oz of spirits (80 proof). The relative risk for the noted maladies with consumption of 4 or more drinks daily is as follows:
Cirrhosis - For men, 7.5; for women, 4.8
Injuries - For men, 1.3
Ear, nose, and throat cancer; esophagus cancer; liver cancer - For men, 2.8; for women, 3
Moderate alcohol consumption (1-2 drinks/d) reduces the risk of cardiovascular disease in men and women by approximately 30%.4, 5, 6 The effect of heavy alcohol consumption on the risk of cardiovascular disease varies in different studies. The person's drinking pattern appears to have an effect on cardiovascular disease. Drinking with meals may reduce the risk, while binge drinking increases risk (even in otherwise moderate drinkers).
Moderate alcohol consumption appears to increase the risk of breast cancer in women. Total mortality is reduced with moderate alcohol consumption but not with heavy alcohol consumption; the cardiovascular benefit is offset by cirrhosis, cancer, and injuries. The amount of alcohol associated with the lowest mortality appears to be 2 drinks per day in men and 1 drink or fewer per day in women. Moderate alcohol consumption reduces the risk of developing diabetes, but heavy alcohol consumption may increase the risk. The cardiovascular benefit becomes important in men older than 40 years and in women older than 50 years. The risk of hypertension is increased with 3 or more drinks daily.
No benefits are noted in people at low risk for coronary disease (men <40 name="refsrc7">7 This effect was exacerbated by binge drinking.
Of men aged 18-25 years, 60% binge drink. (Binge drinking is defined as 5 alcoholic drinks for men [4 for women] in a row.) Binge drinking significantly increases the risk of injury and contracting sexually transmitted diseases. Women who binge drink at this age are at higher risk of becoming pregnant and potentially harming an unborn child. (Any amount of alcohol consumption during pregnancy is risky.)
More than three quarters of all foster children in the United States are children of alcohol- or drug-dependent parents. From 60-70% of reported domestic violence incidents involve alcohol. Half of all violent crime is alcohol or drug related.
Overall, morbidity and mortality are related strongly to smoking, and people who drink heavily are less likely to quit smoking. Additionally, persons who begin smoking early are more likely to develop problems with alcohol.
With regard to pregnancy, fetal alcohol syndrome is the leading known cause of mental retardation (1 in 1000 births). More than 2000 infants annually are born with this condition in the United States. Alcohol-related birth defects and neurodevelopmental problems are estimated to be 3 times higher. Even small amounts of alcohol consumption may be risky in pregnancy. A 2001 study by Sood et al reported that children aged 6-7 years whose mothers consumed alcohol even in small amounts had more behavioral problems.8 In a study from 2003, Baer et al showed that moderate alcohol consumption while pregnant resulted in a higher incidence of offspring problem drinking at age 21 years, even after controlling for family history and other environmental factors.9 All women who are pregnant or planning to become pregnant should avoid alcohol.

Race
The 2 largest studies, the US National Comorbidity Survey and the Epidemiologic Catchment Area Survey, both showed a lower prevalence of alcoholism in African Americans than in white Americans. The prevalence was equal or higher in Hispanic Americans compared with white Americans.
Studies of Native Americans and Asian Americans are smaller. These studies indicate the prevalence of alcoholism is higher in Native Americans and lower in Asian Americans when compared with white Americans.
Sex
Alcoholism is at least twice as prevalent in men as it is in women. In the National Comorbidity Survey, it was 2.5 times more prevalent in men than in women. The lifetime prevalence was 20% in men and 8% in women. For alcohol abuse or dependence in the past year, the rates were 10% for men and 4% for women.
Women do not metabolize alcohol as efficiently as men. Hazardous drinking (not alcoholism) is greater than 1 drink daily for women and greater than 2 drinks daily for men.
Problem drinking in women is much less common than it is in men, and the typical onset of problem drinking in females occurs later than in males. However, progression is more rapid, and females usually enter treatment earlier than males. Women more commonly combine alcohol with prescription drugs of abuse than do males. Women living with substance-abusing men are at high risk.
Alcohol problems are less likely to be recognized in women, and women with alcohol problems are less likely to be treated. This may be because women are less likely than men to have job, financial, or legal troubles as a result of drinking.
Age
The prevalence of alcoholism declines with increasing age. The prevalence in elderly populations is unclear but is probably approximately 3%. A study of the US Medicare population found that alcohol-related hospitalizations were as common as hospitalizations for myocardial infarction.
Among older patients with alcoholism, from one third to one half develop alcoholism after age 60 years. This group is harder to recognize. A recent population-based study found that problem drinking (>3 drinks/d) was observed in 9% of older men and in 2% of older women. Alcohol levels are higher in elderly patients for a given amount of alcohol consumed than in younger patients.

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Colon Cancer, Adenocarcinoma

2008-05-31T10:35:00.000+03:00

Colorectal cancer is the third most common cancer in both men and women in the United States. Risk factors include age, a diet rich in fat and cholesterol, inflammatory bowel disease (especially ulcerative colitis), and genetic predisposition, including hereditary polyposis and nonpolyposis syndromes.
If detected early, colorectal cancer is curable by surgery. Adjuvant chemotherapy can prolong survival in disease that has reached the lymph nodes. Both systemic and locoregional chemotherapy (eg, intrahepatic intraarterial chemotherapy for liver metastases) have a role in patients with metastatic colon cancer. Radiotherapy is used in cases of rectal cancer to reduce the risk of local recurrence.
Long-term survival correlates with stage of disease in colorectal cancer. Progress has been made in understanding the molecular basis of colorectal cancer predisposition and progression. Efforts are underway to develop better screening strategies, chemopreventive approaches, and novel therapies to improve patient survival rates and to minimize toxicity. Despite all efforts, colorectal cancer remains the third leading cause of death from cancer in the United States.
Recent advances have included the development of orally available forms of 5-fluorouracil (5-FU) and the demonstration that anti-vascular endothelial growth factor (VEGF) therapy with bevacizumab prolongs survival in advanced colorectal cancer when combined with irinotecan, 5-FU, and leucovorin.
Pathophysiology
The vast majority of colorectal cancers are adenocarcinomas, which arise from preexisting adenomatous polyps that develop in the normal colonic mucosa. This adenoma-carcinoma sequence is a well-characterized clinical and histopathologic series of events with which discrete molecular genetic alterations have been associated.
Pioneering work by Bert Vogelstein and colleagues over the last 20 years has identified a number of critically important genetic alterations that contribute, through their multiplicity over many years, to the eventual development of colorectal cancer. The earliest event appears to involve the APC (adenomatous polyposis coli) gene, which is mutated in individuals affected by familial adenomatous polyposis (FAP). The protein encoded by the APC gene targets the degradation of beta-catenin, a protein component of a transcriptional complex that activates growth-promoting oncogenes, such as cyclin D1 or c-myc. APC mutations are very common in sporadic colorectal cancer, and beta-catenin mutations have also been identified.
DNA methylation changes are a relatively early event and have been detected at the polyp stage. Colorectal cancers and polyps have an imbalance in genomic DNA methylation, with global hypomethylation and regional hypermethylation. Hypomethylation can lead to oncogene activation, whereas hypermethylation can lead to silencing of tumor suppressor genes. ras gene mutations are observed commonly in larger polyps but not smaller polyps, suggesting a role for this oncogene in polyp growth.
Chromosome arm 18q deletions are a later event associated with cancer development. These deletions likely involve the targets DPC4 (a gene deleted in pancreatic cancer and involved in the transforming growth factor [TGF]-beta growth-inhibitory signaling pathway) and DCC (a gene frequently deleted in colon cancer). Chromosome arm 17p losses and tumor suppressor p53 mutations are common late events in colon cancer. Bcl2 overexpression leading to inhibition of cell death signaling has been observed as a relatively early event in colorectal cancer development. 18q deletions detected in Dukes stage B colon cancers have been associated with an increased risk of recurrence following surgery, and studies are in progress to determine whether patients with 18q deletions might benefit from more aggressive adjuvant chemotherapy.
Another predisposing condition is hereditary nonpolyposis colon cancer, in which affected individuals inherit a mutation in one of several genes involved in DNA mismatch repair, including MSH2, MLH1, and PMS2. ras gene mutations have been detected in the stool of patients with colorectal cancer and may in the future be useful in early diagnosis.
Although the use of nonsteroidal anti-inflammatory agents, such as sulindac, have been shown to affect the number of polyps, this has not translated to a clinical impact on cancer prevention.
Frequency
United States
The American Cancer Society estimates that about 104,950 new cases of colon cancer and 40,340 new cases of rectal cancer will be reported in 2005 in the United States. Combined, the 2 cancer types will cause about 56,290 deaths.
International
According to the World Health Organization's April 2003 report on global cancer rates more than 940,000 new cases of colorectal cancer and nearly 500,000 deaths are reported worldwide each year.
Mortality/Morbidity
The overall 5-year survival rate from colon cancer is approximately 60%, and nearly 60,000 people die of the disease each year in the United States. The 5-year survival rate is different for each stage (see Staging); the staging classification for colon cancer can predict prognosis well. For Dukes stage A tumors involving only the mucosa, the 5-year survival rate exceeds 90%, whereas for metastatic colon cancer, the 5-year survival rate is about 5%. For Dukes stage B colon cancers, the 5-year survival rate is greater than 70% and can be greater than 80% if the tumor does not penetrate the muscularis mucosa. Once the tumor has spread to the lymph nodes (ie, Dukes stage C), the 5-year survival rate usually is less than 60%.
Race
Recent data demonstrate a decrease in incidence rates of colorectal carcinoma in whites since the mid 1980s, particularly for the distal colon and rectum. Proximal colon carcinoma rates in blacks are considerably higher than in whites and continue to increase, whereas rates in whites show signs of decline.
Sex
The frequency of colon cancer is essentially the same among men and women.
Age
Age is a well-known risk factor for colon cancer, and risk begins to rise in people older than 40 years. Age is a risk factor because a number of rare genetic alterations are believed to occur within the somatic cells of the colonic epithelium over years, ultimately leading to the development of colon cancer in older individuals. Individuals affected by one of the well-known familial predispositions to colon cancer are much more likely to develop cancer at a young age. For example, individuals with familial adenomatous polyposis have a 100% chance of developing colon cancer unless their colon is removed surgically, usually when they are aged 20-30 years.
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CLINICAL
Section 3 of 10
Authors and Editors
Introduction
Clinical
Differentials
Workup
Treatment
Medication
Follow-up
Miscellaneous
References
History
Colon cancer often is found by screening and may be completely asymptomatic. Approximately 50% of patients present with abdominal pain, 35% with altered bowel habits, 30% with occult bleeding, and 15% with intestinal obstruction. Right-sided colon cancers tend to be larger and more likely to bleed, whereas left-sided tumors tend to be smaller and more likely to be obstructing. Obtain a family history of colon cancer, familial polyposis, or ulcerative colitis. Consider the possibility of cancer of the colon in patients with a fever of unknown origin and in patients with polymyositis.
Physical
The physical examination findings may be completely normal, especially in early stage colorectal cancer, or general or specific findings due to progression of the disease may be present. These may include weight loss, cachexia, abdominal discomfort or tenderness, liver mass, abdominal distention, ascites, rectal mass, rectal bleeding, or occult blood on rectal examination.
Causes
A number of risk factors have been associated with colon cancer. Colonic polyps, which occur with increasing age, represent a risk for colon cancer development. A study considering the clinical evidence for the adenoma-carcinoma sequence recently concluded that adenomas probably are precursors of carcinomas, but the ultimate effect of removing polyps on reducing cancer incidence in the population remains unknown.
Genetics is a very important risk factor for development of colorectal cancer. Familial polyposis, in which patients inherit a mutant copy of the APC tumor suppressor gene, is rare but confers very high risk. Familial nonpolyposis colon cancer, which accounts for 1-5% of colon cancers, develops because of inherited mutations in DNA mismatch repair genes.
Alcohol consumption is a risk factor for gastrointestinal cancer, including colon cancer. Increasing age and a lower intake of total folate have been associated with mutations of the Ki-ras oncogene, which are found commonly in colorectal cancer. Diet, and in particular fat content of diet, has been associated with increased risk of colon cancer. Animal studies have found that dietary beef induces and dietary rye bran prevents formation of intestinal polyps. Several studies have suggested that red meat and processed meats, through the action of heme, predispose to colon cancer by enhancing formation of N-nitrosocompounds, which result in DNA damage. One study suggested that obesity, rather than fat intake per se, predisposed to colon cancers induced in animals by exposure to the carcinogen azoxymethane.
The evidence is weak that soy food or isoflavones in the diet protect a person from colon cancer. Exercise is believed to reduce the risk of colon cancer. The risk of colon cancer may be decreased among women who recently used postmenopausal hormone replacement therapy. Women who are postmenopausal and who have never used hormone replacement therapy have a higher risk of colon, but not rectal, cancer than do women who are premenopausal and of the same age, sociocultural class, and dietary habits. Apparently, no association exists between frequency of bowel movement or laxative use and risk of colon cancer. Some data associate calcium intake and risk of colon cancer. A statistically significant association exists between Helicobacter exposure and colonic polyps.
Tobacco smoking is associated with a higher risk of colon cancer, which appears to be mediated by induction of 5-lipoxygenase–associated angiogenic pathways.

Corpus Luteum Rupture

2008-05-30T10:31:00.001+03:00

Ruptured corpus luteum is a common phenomenon with presentation ranging from no symptoms to symptoms mimicking an acute abdomen. Sequelae vary. Resolution may be spontaneous (most often); intraperitoneal hemorrhage and death may occur. Although most patients require only observation, some need laparoscopy or laparotomy to achieve hemostasis.
Pathophysiology
Each month, a mature ovarian follicle ruptures, releasing an ovum so the process of fertilization can begin. Occasionally, this rupture site may bleed, causing abdominal pain and signs of hemorrhage. The etiology of this increased bleeding is unknown, although abdominal trauma and anticoagulation treatments may increase the risk.
Frequency
United States
Occurrence is unknown but is likely quite frequent and without symptoms.
International
Occurrence is unknown but is likely quite frequent and without symptoms.
Mortality/Morbidity
Although circulatory collapse, hemorrhagic shock, disseminated intravascular coagulation (DIC), and death have been reported, these are rare. Most cases are self-limiting, with abdominal pain relieved with analgesics.
Race
No differences in frequency are reported by race or socioeconomic standing.
Sex
Ruptured corpus luteum occurs only in females.
Age
The condition most commonly occurs in women aged 18-35 years (peak reproductive years).

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Social Phobia and Selective Mutism

2008-05-29T10:17:00.001+03:00

Social phobia (social anxiety disorder) is the third most common mental health disorder after major depression and substance abuse, affecting approximately 10 million Americans, including children and adults. This disorder is defined by marked and persistent fear of social or performance situations in which embarrassment may occur; exposure to the social or performance situation almost always causes an anxiety reaction such as a situationally bound or situationally predisposed panic attack.
The anxiety reaction is not due to psychosis; individuals are able to recognize their fears as excessive and unreasonable. However, the ability to fully comprehend that the reaction is out of proportion to the precipitant may be less complete in children and may depend on their cognitive-developmental level of functioning.
The person's level of functioning (eg, ability to complete required educational, social, or family tasks) is significantly impaired, and the person may experience significant emotional distress (eg, dread, avoidance) as a response to social or performance situations. By definition, social phobia must persist for at least 6 months (in persons <18 y), must not be due to the direct physiological effects of a substance (eg, caffeine) or a general medical condition, and must not be better accounted for by another mental health disorder.
Often, social phobia can coexist with, or be the precursor to, agoraphobia. Agoraphobia is a specific phobia in which the individual fears being in crowded places. People with agoraphobia often become homebound.
Selective mutism is a disorder primarily affecting children, with some adolescents and adults who continue to experience an inability to speak in public. This inability is generally most disabling at school, as the child cannot be assertive and speak when called on by teachers. In adults, functional impairment occurs when public speaking or lecturing are required in one's vocation.
Formerly, selective mutism was called elective mutism in the Diagnostic and Statistical Manual of Mental Health Disorders, Third Edition (DSM-III), which was reflective of a previous view that the child intentionally refused to speak with others who are outside of the immediate family group. Often, the child with selective mutism designates a friend or close family member to serve as an interpreter of communication and whispers in that person's ear, so that communication occurs with the designated person as intermediary.
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Pathophysiology
Serotonin pathways may be involved in the mediation of the anxious and obsessive qualities of both social phobia and selective mutism. This theory is reinforced by animal models of phobic behavior and by response to commonly prescribed medications such as selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, sertraline, or older heterocyclic-type antidepressants, such as Anafranil (clomipramine).
Frequency
United States
Social phobia is the third most common mental health disorder after depression. Lifetime prevalence ranges from 3-13%. Selective mutism is seen in fewer than 1% of children observed in mental health settings.
Mortality/Morbidity
No mortality occurs except with associated major depression resulting in suicide or reaction to medication treatment (sudden cardiac death with imipramine or clonidine) or adverse reaction such as newly onset suicidality to SSRIs or other antidepressants. A high morbidity rate is observed, with many missed school or workdays; the child often develops associated school refusal because of the anxiety associated with being asked to speak in class.
Age
Onset of social phobia may occur as early as school age but generally occurs by mid adolescence following a childhood history of social inhibition or excessive shyness. Often, onset is abrupt, occurring after a stressor or humiliating social experience.
Onset of selective mutism is typically when a child first attends school (either kindergarten or preschool) and, like social phobia, is often associated with an initial negative school experience, such as a stressor or humiliating social experience.

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Achilles Tendon Rupture

2008-05-28T10:14:00.001+03:00

Ruptures of the Achilles tendon most commonly occur spontaneously in healthy, young, active individuals who are aged 30-50 years and have no antecedent history of calf or heel pain. Unlike tears or ruptures at the musculotendinous junction of the Achilles tendon (tennis leg), Achilles tendon ruptures are located within the tendon substance itself, approximately 1-2 inches proximal to its insertion into the calcaneus. Poor conditioning, advanced age, and overexertion are risk factors for this injury. However, the common precipitating event is a sudden eccentric force applied to a dorsiflexed foot. Ruptures of the Achilles tendon also may occur as the result of direct trauma or as the end result following Achilles peritenonitis with or without tendinosis.
Achilles tendon pathology, other than rupture, can be classified into a spectrum of injuries including peritenonitis, tendinosis, and peritenonitis with tendinosis. Patients with peritenonitis experience localized burning pain along the tendon during or following activities; as the disease progresses, onset of pain may occur earlier during activities, with decreased activity level, or even at rest. Tendinosis usually is comprised of an asymptomatic, noninflammatory, degenerative disease process (mucoid degeneration); patients with tendinosis may complain of a sensation of fullness or a nodule in the back of the leg. Peritenonitis with tendinosis is comprised of activity-related pain, diffuse swelling of the tendon sheath, and presence of nodules. Treatment of these entities is not discussed in this article.
Frequency
United States
The true prevalence of Achilles tendon rupture is unknown, although it occurs more commonly in men who are in their third to fifth decade of life and who participate in recreational activities.

Functional Anatomy
The Achilles tendon, coined after the mythologic Greek god, is the largest and strongest tendon in the human body. The Achilles tendon is formed from the tendinous contributions of the gastrocnemius and soleus muscles coalescing approximately 15 cm proximal to its insertion. Along its course in the posterior aspect of the leg, the tendon spirals 30-150° until it inserts into the calcaneal tuberosity. The gliding ability of the Achilles tendon is aided by a thin sheath of paratenon rather than a true synovial sheath. The sheath of paratenon is composed of a visceral layer and a parietal layer.
The blood supply of the Achilles tendon arises from its osseous insertion, its musculotendinous junction, and multiple infiltrating mesosternal vessels, which cross the layers of the anterior paratenon. Various injection and nuclear medicine studies have demonstrated a paucity of mesosternal and intratendinous vessels 2-6 cm proximal to the heel insertion (ie, the watershed area). Due to the relative lack of blood supply in this area, the tendon is less resilient to repetitive microtrauma and has a higher tendency for irritation, degeneration, and rupture.
Sport Specific Biomechanics
The entire gastrocnemius-soleus musculotendinous unit spans the knee, tibiotalar (ankle), and talocalcaneal (subtalar) joints. Contracture of this complex flexes the knee, plantar flexes the ankle, and supinates the subtalar joint. The function of the gastrocnemius-soleus musculotendinous unit is necessary in running, jumping, toe standing, and stair-climbing activities because it forcefully plantar flexes the ankle. During running, forces 10 times the body weight have been measured within the tendon substance.

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Atrial Fibrillation

2008-05-27T09:25:00.001+03:00

Background:
Atrial fibrillation (AF) is a common arrhythmia (see Image 1) and is a significant public health problem in the United States, affecting 2.2 million Americans and almost 5% of the population older than 69 years and 8% of the population older than 80 years. Thus, the prevalence of AF increases with advancing age. Data from the Framingham heart study show that AF is associated with a 1.5- to 1.9-fold higher risk of death, which may be due to thromboembolic stroke. While patients can be asymptomatic, many experience a wide variety of symptoms, including palpitations, dyspnea, fatigue, dizziness, angina, and congestive heart failure (CHF). In addition, the arrhythmia can be associated with hemodynamic dysfunction, tachycardia-induced cardiomyopathy, and systemic embolism.
Overall, approximately 15-25% of all strokes in the United States (75,000/y) can be attributed to AF. Known risk factors include male sex, valvular heart disease (rheumatic valvular disease), CHF, hypertension, and diabetes. Additional risk factors, such as advanced age and prior history of stroke, diabetes, and hypertension, place patients with preexisting AF at even higher risk for further comorbidities such as stroke. Patients with nonvalvular AF and risk factors have a 5-fold increased risk for stroke. Patients with rheumatic heart disease and AF have an even higher risk for stroke (17-fold). At least 4 large clinical trials have clearly demonstrated that anticoagulation with warfarin decreases the risk of stroke by 50-80%.
Given the frequency of these comorbidities, management can result in significant medical costs. Therapeutic goals include rate control, maintenance of sinus rhythm, and prevention of thromboembolism. Additionally, current practice and economic pressures force many physicians to reconsider outpatient treatment options.
Pathophysiology: Several classification schemas have been proposed for the study of AF, but none fully accounts for all aspects of AF. A number of different labels and nomenclature have been used to describe patterns of AF, including acute, chronic, paroxysmal, intermittent, and permanent. The vagaries of each of these definitions make comparing the results of studies assessing the magnitude and treatment of AF difficult.
Recently published guidelines from expert committees of the American College of Cardiology/American Heart Association and European Society of Cardiology on the treatment of patients with AF suggest that AF be classified into 3 patterns. These include a first detectable episode, irrespective of whether it is symptomatic or self-limited. Recurrent AF is considered to be present when a patient has 2 or more episodes of AF. If AF terminates spontaneously, then recurrent AF is designated as paroxysmal; if this arrhythmia becomes sustained, then AF is considered persistent (irrespective of whether AF is terminated with pharmacologic therapy or electrical cardioversion).
Persistent AF may be either the first presentation of AF or the result of recurrent episodes of paroxysmal AF. Patients with persistent AF also include patients with long-standing AF in whom cardioversion has not been indicated or attempted, often leading to permanent AF. Permanent AF is recognized as the accepted rhythm, and the only treatment goals are rate control and anticoagulation.
This classification schema pertains to cases that are not related to a reversible cause of AF (eg, thyrotoxicosis, electrolyte abnormalities, acute ethanol intoxication). The occurrence of AF secondary to acute myocardial infarction, cardiac surgery, pericarditis, pulmonary embolism, or acute pulmonary disease is considered separately because in these situations, AF is less likely to recur once the precipitating condition has been resolved and adequately treated.
Some patients with paroxysmal AF, typically younger patients, have been found to have distinct electrically active foci within their pulmonary veins. These patients generally have many atrial premature beats noted on Holter monitoring. Isolation or elimination of these foci can lead to elimination of the trigger for paroxysms of AF.
Patients can also have AF as a secondary arrhythmia associated with cardiac disease that affects the atria (eg, CHF, hypertensive heart disease, rheumatic heart disease, coronary artery disease [CAD]). These patients tend to be older, and AF is more likely to be chronic. Paroxysmal AF may progress to chronic AF, and aggressive attempts to restore and maintain sinus rhythm may prevent comorbidities associated with AF.
Persistent AF with an uncontrolled, rapid ventricular heart rate response can cause a dilated cardiomyopathy and can lead to electrical remodeling in the atria (atrial cardiomyopathy). Therapy, such as drugs or atrioventricular (AV) nodal ablation and permanent pacemaker implantation, to control the ventricular rate can improve left ventricular (LV) function and improve quality-of-life scores.
New developments aimed at curing AF are being actively explored. By reducing the critical mass required to sustain AF with either surgical or catheter-based compartmentalization of the atria (ie, MAZE procedure), fibrillatory wavelets collide with fixed anatomic obstacles, such as suture lines or complete lines of ablation, thus eliminating or reducing the chance of chronic AF. Some patients with focal origins of their AF also may be candidates for catheter ablation. Still, much remains to be accomplished before either of these procedures is appropriate for primary treatment.
Frequency:
In the US: AF affects 2.2 million Americans. It can occur in the absence of comorbidities, as it does in 10-15% of individuals (lone AF); however, AF is associated more frequently with hypertension; organic heart disease; CHF; ischemic heart disease; and valvular, dilated, hypertrophic, restrictive, and congenital cardiomyopathies. Paroxysmal AF is commonly associated with cardiac surgery, pulmonary disease, thyrotoxicosis, acute ethanol intoxication, and electrolyte imbalance. Given the almost epidemic proportions of patients with AF, clinicians must be aware of the multiple mechanisms and presentations and then correct the underlying etiology, if possible. For example, a logical decision may be to correct an overactive thyroid gland before attempting cardioversion.
Mortality/Morbidity: AF is associated with increased morbidity. The static nature of blood flow during AF can lead to the development of thrombus, most commonly in the left atrial appendage. Dislodgement of clot can lead to embolic phenomena, including stroke. Thus, anticoagulation remains the primary focus in appropriate patient populations. A target international normalized ratio of 2-3 limits the risks of hemorrhage while providing protection against the formation of thrombus.
Age:
AF is strongly age-dependent, affecting 4% of individuals older than 60 years and 8% of persons older than 80 years. The rate of ischemic stroke among elderly patients not treated with warfarin averages approximately 5% per year.

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Suprapubic Aspiration

2008-05-26T19:04:00.001+03:00

Suprapubic aspiration and catheterization is an easily performed emergency department procedure that is associated with minimal complications. Huze and Beeson 1 first published this practice in 1956 as an alternative to more traditional methods of obtaining urine for analysis and culture. Their findings suggested that suprapubic catheterization and aspiration was superior to clean-catch or transurethral (via catheterization) collection of bladder urine for bacteriologic study. Since then, the indications for suprapubic catheterization and aspiration have expanded to acute and chronic conditions.

Indication:

Urinary retention (eg, prostate hypertrophy or cancer, gynecologic malignancy, spinal cord injury)
Urinalysis or urine culture in neonates or children younger than 2 years
Phimosis
Chronic infection of the urethra or periurethral glands
Urethral stricture
Urethral trauma

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Gastrointestinal Duplications

2008-05-26T19:02:00.001+03:00

Gastrointestinal duplications are rare congenital malformations that may vary greatly in presentation, size, location, and symptoms.
Problem
In 1733, Calder published the first report of an intestinal duplication. In 1937, Ladd introduced the term duplication of the alimentary tract. This condition consists of a group of congenital anomalies with the following 3 characteristics:
A well-developed coat of smooth muscle is present.
The epithelial lining represents some portion of the alimentary tract.
Duplications are frequently intimately attached to some portion of the gastrointestinal tract.

Frequency
Gastrointestinal duplications are observed in 1 of every 4500 autopsies, predominantly in white males. The small intestine is the most frequent site involved, whereas gastric, duodenal, rectal, and thoracoabdominal involvement is relatively rare. Synchronous gastrointestinal duplications occur in as many as 15% of patients.
Cervical duplications: Cervical esophageal duplication cysts are the most unusual gastrointestinal duplication, with fewer than 10 cases reported.
Thoracic and thoracoabdominal duplications: These make up 4% of all gastrointestinal duplications.
Gastric duplications: These duplications account for 7% of all gastrointestinal duplications.
Pyloric duplications: These are extremely rare. However, they are reported in the literature.1
Duodenal duplications: These account for 5% of all gastrointestinal duplications.
Small-intestine duplications: The small intestine is the most frequent site of gastrointestinal duplications, accounting for 44% of cases.
Colonic duplications: They may be cystic or tubular; colonic duplications represent 15% percent of duplications.
Rectal duplications: These represent up to 5% of gastrointestinal duplications.

Etiology
The true etiology of gastrointestinal tract duplications is not known. Several theories have been postulated. The idea that the initial developmental abnormality occurs in the gastrulation stage and results in a split notochord has been proposed. During early embryogenesis, the notochord is open, and the endoderm of the yolk sac and the ectoderm of the notochord are fused; a tube called the neuroenteric canal connects the yolk sac and the amnion. As part of the development of the split notochord, an endodermal-ectodermal adhesion between the cord has been proposed to result in the persistence of an endomesenchymal tract between the yolk sac and the amnion. The endomesenchymal tract formed is responsible for the anomalies of the entire gastrointestinal system. However, not all duplications are compatible with this theory, and other etiologies have been proposed.
Some duplications of the foregut and hindgut may occur as a result of "partial twinning." These duplications may be associated with other paired structures, such as those found in the genital and urinary tract. Other duplications, especially those of the ileum, may occur as a result of persistent embryological diverticula. Some portions of the intestinal tract have a solid stage during development; therefore, duplications of these structures may result from "aberrant luminal recanalization." Finally, intrauterine environmental factors, such as trauma or hypoxia during a vascular accident, may cause duplications at any level of the gastrointestinal tract.

Clinical
Presentation depends on the size and location of the duplication.
Cervical duplications: Patients with cervical duplications present with respiratory distress that may be life-threatening and requires rapid diagnosis and treatment.
Thoracic and thoracoabdominal duplications: Respiratory distress caused by airway compression may be noted in younger children; however, in older patients, heartburn or melena has been reported, which is probably caused by the presence of gastric mucosa in one third of patients with thoracic and thoracoabdominal duplications.
Gastric duplications: Patients usually present when younger than 1 year with vomiting, poor feeding, failure to gain weight, and a palpable mass upon physical examination. Hypertrophic pyloric stenosis is often a misdiagnosis in such infants. The mucosal lining of the cysts is often gastric and can lead to melena or hematemesis.
Duodenal duplications: Fifteen percent of these duplications contain ectopic gastric mucosa, which predisposes the patient to ulceration. Peptic ulceration may lead to painless gastrointestinal hemorrhage that can progress to perforation. Duplications may extend into the liver or even transdiaphragmatically. These are generally diagnosed after onset of high intestinal obstruction or hemorrhage that may commonly be accompanied by icterus or pancreatitis.
Small-intestine duplications: Clinical presentation depends on the type, size, location, and mucosal lining of the duplication. Small cystic duplications can be anchor points for intussusception or can result in volvulus, whereas long tubular duplications with proximal communication drain poorly, and retention of intestinal contents can obstruct adjacent intestine. Distal communication is more common and is more difficult to diagnose than proximal communication. Gastric mucosa in a duplication can lead to ulceration and perforation. The diagnosis is often not established before surgery.
Colonic duplications
Cystic colonic duplications are either asymptomatic or present as abdominal masses that may be accompanied by pain. Bleeding may be observed despite the lower prevalence of ectopic gastric mucosa in colon duplications. Newborns may present with volvulus or acute intestinal obstruction.
Tubular colonic duplications are usually asymptomatic, but severe esthetic problems are observed with the duplicated genitalia.
Rectal duplications: Presenting signs of colonic or presacral duplications may include constipation, rectal bleeding, hematochezia, rectal prolapse, hemorrhoids, fistula-in-ano, and perirectal abscess.

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What is Ashman Phenomenon?

2008-05-26T10:00:00.004+03:00

Ashman phenomenon is an aberrant ventricular conduction due to a change in QRS cycle length. In 1947, Gouaux and Ashman reported that in atrial fibrillation, when a relatively long cycle was followed by a relatively short cycle, the beat with a short cycle often has right bundle-branch block (RBBB) morphology. This causes diagnostic confusion with premature ventricular complexes (PVCs). If a sudden lengthening of the QRS cycle occurs, the subsequent impulse with a normal or shorter cycle length may be conducted with aberrancy.
Pathophysiology
Ashman phenomenon is an intraventricular conduction abnormality caused by a change in the heart rate. This is dependent on the effects of rate on the electrophysiological properties of the heart and can be modulated by metabolic and electrolyte abnormalities and the effects of drugs.
The aberrant conduction depends on the relative refractory period of the conduction tissues. The refractory period depends on the heart rate. Action potential duration (ie, refractory period) changes with the R-R interval of the preceding cycle; shorter duration of action potential is associated with a short R-R interval and prolonged duration of action potential is associated with a long R-R interval. A longer cycle lengthens the ensuing refractory period, and, if a shorter cycle follows, the beat ending it is likely to be conducted with aberrancy.
Aberrant conduction results when a supraventricular impulse reaches the His-Purkinje system while one of its branches is still in the relative or absolute refractory period. This results in slow or blocked conduction through this bundle branch and delayed depolarization through the ventricular muscles, causing a bundle-branch block configuration (ie, wide QRS complex) on the surface ECG, in the absence of bundle-branch pathology. A RBBB pattern is more common than a left bundle-branch block (LBBB) pattern because of the longer refractory period of the right bundle branch.
Several studies have questioned the sensitivity and specificity of the long-short cycle sequence. Aberrant conduction with a short-long cycle sequence has also been documented.
Frequency
United States
No geographic variations occur. Ashman phenomenon is related to the underlying pathology and is a common ECG finding in clinical practice.

History
The diagnosis of Ashman phenomenon is made using ECG evaluation findings. Patients may be asymptomatic or may have symptoms of the underlying cardiac condition.
Ashman phenomenon, per se, causes no symptoms. Symptoms, if present, are related to the premature complexes and are not related to whether the complexes are conducted aberrantly.

Physical
No specific physical examination findings are described for Ashman phenomenon.
Pulse findings may include an irregular pulse, tachycardia, and/or pulse deficit in atrial fibrillation.

Causes
Conditions causing an altered duration of the refractory period of the bundle branch or the ventricular tissue cause Ashman phenomenon. These conditions are commonly observed in (1) atrial fibrillation, (2) atrial tachycardia, and (3) atrial ectopy.

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Paroxysmal Supraventricular Tachycardia

2008-05-26T09:20:00.001+03:00

Supraventricular tachycardia (SVT), a common clinical condition, is any tachyarrhythmia that requires only atrial and/or atrioventricular (AV) nodal tissue for its initiation and maintenance. It is usually a narrow-complex tachycardia that has a regular, rapid rhythm; exceptions include atrial fibrillation (AF) and multifocal atrial tachycardia (MAT). Aberrant conduction during SVT results in a wide-complex tachycardia. SVT occurs in persons of all age groups, and treatment can be challenging.
Paroxysmal supraventricular tachycardia (PSVT) is episodic, with an abrupt onset and termination. Manifestations of SVT are quite variable; patients may be asymptomatic or they may present with minor palpitations or more severe symptoms. Results from electrophysiology studies have helped determine that the pathophysiology of SVT involves abnormalities in impulse formation and conduction pathways. The most common mechanism identified is reentry (Denes, 1973; Rosen, 1974; Akhtar, 1984; Waldo, 1993). This article focuses on SVT, including the pathophysiology, clinical presentation, diagnosis, management, and treatment options of this condition.
Pathophysiology
The development of intracardiac electrophysiology studies has dramatically changed the classification of SVT. Intracardiac recordings have identified the various mechanisms of SVT. Depending on the site of origin of the dysrhythmia, SVTs may be classified as an atrial or AV tachyarrhythmia (Klein, 1987; Basta, 1997).
Atrial tachyarrhythmias include (1) sinus tachycardia, (2) inappropriate sinus tachycardia (IST), (3) sinus nodal reentrant tachycardia (SNRT), (4) atrial tachycardia, (5) MAT, (6) atrial flutter, and (7) AF.
AV tachyarrhythmias include (1) AV nodal reentrant tachycardia (AVNRT), (2) AV reentrant tachycardia (AVRT), (3), junctional ectopic tachycardia (JET), and (4) nonparoxysmal junctional tachycardia (NPJT).
Atrial tachyarrhythmias
Sinus tachycardia
Sinus tachycardia is an accelerated sinus rate that is a physiologic response to a stressor. It is characterized by a heart rate faster than 100 beats per minute (bpm) and generally involves a regular rhythm (see Image 1). Underlying physiological stresses such as hypoxia, hypovolemia, fever, anxiety, pain, hyperthyroidism, and exercise usually induce sinus tachycardia (Tintinalli, 2000; Ganz, 2002). Treatment involves addressing the basic underlying stressor. Certain drugs, such as stimulants (eg, nicotine, caffeine), medications (eg, atropine, salbutamol), recreational drugs (eg, cocaine, amphetamines, ecstasy), and hydralazine, can also induce sinus tachycardia.
Inappropriate sinus tachycardia
IST is an accelerated baseline sinus rate in the absence of a physiological stressor. In this situation, healthy adults may have an elevated resting heart rate and an exaggerated heart rate response to even minimal exercise. This tachyarrhythmia is observed most commonly in young women without structural heart disease (Bellet, 1963; Krahn, 1995; Xie, 1998). The underlying mechanism of IST may be hypersensitivity of the sinus node to autonomic input or an abnormality within the sinus node, its autonomic input, or both (Bellet, 1963; Krahn, 1995; Xie, 1998).
Sinus nodal reentrant tachycardia
SNRT is frequently confused with IST. SNRT is due to a reentry circuit, either in or near the sinus node. Therefore, it has an abrupt onset and offset. The heart rate is usually 100-150 bpm, and ECG tracings usually demonstrate normal sinus P-wave morphology (Bellet, 1963; Krahn, 1995; Xie, 1998).
Atrial tachycardia
Atrial tachycardia is an arrhythmia originating in the atrial myocardium. Enhanced automaticity, triggered activity, or reentry may result in this rare tachycardia (Wellens, 1978; Farre, 1981; Brugada, 1984; Lesh, 1994; Xie, 1998). The heart rate is regular and is usually 120-250 bpm. The P-wave morphology is different from the sinus P waves and is dependent on the site of origin of the tachycardia (see Image 2). Because the arrhythmia does not involve the AV node, nodal blocking agents such as adenosine and verapamil are usually unsuccessful in terminating this arrhythmia. Atrial tachycardia has also been associated with digoxin toxicity via the triggered mechanism (Wellens, 1978; Farre, 1981; Brugada, 1984; Lesh, 1994; Xie, 1998).
Multifocal atrial tachycardia
MAT is a tachyarrhythmia that arises within the atrial tissue; it is composed of 3 or more P-wave morphologies and heart rates. This arrhythmia is fairly uncommon and is typically observed in elderly patients with pulmonary disease. The heart rate is greater than 100 bpm, and ECG findings typically include an irregular rhythm, which may be misinterpreted as AF (see Image 3). Treatment involves correcting the underlying disease process (Phillips, 1969; Habibzadeh, 1980; Scher, 1989). Magnesium and verapamil may sometimes be effective.
Atrial flutter
Atrial flutter is a tachyarrhythmia arising above the AV node with an atrial rate of 250-350 bpm. The mechanism behind atrial flutter is generally reentrant in nature. Typically, counterclockwise atrial flutter is due to a macroreentrant right atrial circuit. It is commonly observed in patients with ischemic heart disease, myocardial infarction, cardiomyopathy, myocarditis, pulmonary embolus, toxic ingestion (eg, alcohol), or chest trauma. It may be a transitional rhythm and can progress to AF. ECG findings of typical atrial flutter include negative sawtooth flutter waves in leads II, III, and aVF. AV conduction is most commonly 2:1, which yields a ventricular rate of approximately 150 bpm (see Image 4) (Akhtar, 1984; Tintinalli, 2000; Josephson, 2001).
Atrial fibrillation
AF is an extremely common arrhythmia arising from chaotic atrial depolarization. The atrial rate is usually 300-600 bpm, while the ventricular rate may be 170 bpm or more. ECG findings characteristically include an irregular rhythm with fibrillatory atrial activity (see Image 5). This arrhythmia is associated with rheumatic heart disease, hypertension, ischemic heart disease, pericarditis, thyrotoxicosis, alcohol intoxication, mitral valve prolapse and other disorders of the mitral valve, and digitalis toxicity (Akhtar, 1984; Tintinalli, 2000; Josephson, 2001). When AF occurs in young or middle-aged patients in the absence of structural heart disease or any apparent cause, it is called lone or idiopathic AF.
AV tachyarrhythmias
AV nodal reentrant tachycardia
The most common cause of PSVT is AVNRT. AVNRT is diagnosed in 50-60% of patients who present with regular narrow QRS tachyarrhythmia (Josephson, 1977; Akhtar, 1984; Jazayeri, 1992; Akhtar, 1993). The heart rate is 120-250 bpm and is typically quite regular (see Images 6-7). AVNRT may occur in healthy, young individuals, and it occurs most commonly in women (Jazayeri, 1992). Most patients do not have structural heart disease. However, occasionally these individuals may have an underlying heart condition such as rheumatic heart disease, pericarditis, myocardial infarction, mitral valve prolapse, or preexcitation syndrome (Josephson, 1977; Akhtar, 1984; Jazayeri, 1992; Akhtar, 1993).
An understanding of the electrophysiology of AV nodal tissue is very important in order to comprehend the mechanism of AVNRT. In most people, the AV node has a single conducting pathway that conducts impulses in an anterograde manner to depolarize the bundle of His. In certain cases, AV nodal tissue may have 2 conducting pathways with different electrophysiological properties (see Image 8). One pathway (alpha) is a relatively slow conducting pathway with a short refractory period, while the second pathway (beta) is a rapid conducting pathway with a long refractory period. The coexistence of these functionally different pathways serves as the substrate for reentrant tachycardia (Josephson, 1977; Akhtar, 1984; Akhtar, 1993; Ganz, 1995). Electrophysiologic studies have demonstrated dual AV nodal pathways in 40% of patients.
Onset of AVNRT is triggered by a premature atrial impulse. A premature atrial impulse may reach the AV node when the fast pathway (beta) is still refractory from the previous impulse but the slow pathway (alpha) may be able to conduct. The premature impulse then conducts through the slow pathway (alpha) in an anterograde manner; the (beta) pathway continues to recover because of its longer refractory period. After the impulse conducts in an anterograde manner through the slow (alpha) pathway, it may find the fast (beta) pathway recovered; the impulse then conducts in a retrograde manner via the fast (beta) pathway. If the slow pathway (alpha) has repolarized by the time the impulse completes the retrograde conduction, the impulse can then reenter the slow (alpha) pathway and initiate AVNRT (see Image 8).
Importantly, note that AVNRT does not involve the ventricles as part of the reentry circuit; the necessity of perinodal atrial tissue to the circuit is controversial. Because the impulse typically conducts in an anterograde manner through the slow pathway and in a retrograde manner through the fast pathway, the PR interval is longer than the RP interval. Thus, in patients with typical AVNRT, the P wave is usually located at the terminal portion of the QRS complex (Josephson, 1977; Akhtar, 1984; Akhtar, 1993; Ganz, 1995; Josephson, 2001). In patients with atypical AVNRT, anterograde conduction is via the fast pathway, while retrograde conduction is via the slow pathway. For these atypical patients, the RP interval is longer than the PR interval (Josephson, 1977; Wu, 1977; Akhtar, 1984; Jazayeri, 1992; Akhtar, 1993; Ganz, 1995; Josephson, 1997; Josephson, 2001).
AV reentrant tachycardia
AVRT is the second most common form of PSVT. The incidence rate of AVRT in the general population is 0.1-0.3%. AVRT is more common in males than in females (male-to-female ratio of 2:1), and patients with AVRT commonly present at a younger age than patients with AVNRT. AVRT is associated with the Ebstein anomaly, although most patients with AVRT do not have evidence of structural heart disease. AVRT occurs in the presence of accessory pathways, or bypass tracts. Accessory pathways are errant strands of myocardium that bridge the mitral or tricuspid valves (Josephson, 1977; Murdock, 1991; Ganz, 1995; Xie, 1998).
AVRT is the result of 2 or more conducting pathways: the AV node and 1 or more bypass tracts. In a normal heart, only a single route of conduction is present. Conduction begins at the sinus node, progresses to the AV node, and then to the bundle of His and the bundle branches. However, in AVRT, 1 or more accessory pathways connect the atria and the ventricles. The accessory pathways may conduct impulses in an anterograde manner, a retrograde manner, or both (Wolff, 1930; Coumel, 1967; Josephson, 1977; Gallagher, 1978; Murdock, 1991; Oren, 1993; Ganz, 1995; Xie, 1998). When impulses travel down the accessory pathway in an anterograde manner, ventricular preexcitation results. This produces a short PR interval and a delta wave as is observed in persons with Wolff-Parkinson-White (WPW) syndrome (see Image 9) (Wolff, 1930).
Importantly, note that not all accessory pathways conduct in an anterograde manner. Concealed accessory pathways are not evident during sinus rhythm, and they are only capable of retrograde conduction. A reentry circuit is most commonly established by impulses traveling in an anterograde manner through the AV node and in a retrograde manner through the accessory pathway; this is called orthodromic AVRT. A reentry circuit may also be established by a premature impulse traveling in an anterograde manner through a manifest accessory pathway and in a retrograde manner through the AV node; this is called antidromic AVRT (see Image 10) (Bardy, 1984; Obel, 1997). While the orthodromic AVRT is typically a narrow-complex tachycardia (see Image 11), antidromic AVRT inscribes a bizarre, wide-complex tachycardia (see Image 12) (Bardy, 1984; Atie, 1990; Obel, 1997).
Patients with WPW syndrome can develop AF and atrial flutter (see Image 13). The rapid nondecremental conduction via the accessory pathways can result in extremely rapid rates, which can degenerate to ventricular fibrillation and cause sudden death. Patients with preexcitation syndromes with AF must not be administered an AV nodal blocking agent; these agents can further increase conduction via the accessory pathway, which increases the risk of ventricular fibrillation and death (Campbell, 1977; Sung, 1977; Klein, 1979; Bardy, 1984; Vidaillet, 1987; Montoya, 1991; Obel, 1998).
Junctional ectopic tachycardia and nonparoxysmal junctional tachycardia
JET and NPJT are rare and presumably arise because of increased automaticity, triggered activity, or both. They are usually observed following valvular surgery, after myocardial infarction, during active rheumatic carditis, or with digoxin toxicity. These tachycardias are also observed in children following congenital heart surgery. ECG findings include a regular narrow QRS complex, although P waves may not be visible. Patients with AV dissociation have also been described (Ganz, 1995; Pieper, 1995; Trohman, 2000).

Headache, Migraine

2008-05-24T08:00:00.002+03:00

Background
Migraine headaches are recurrent headaches that may be unilateral or bilateral. Migraine headaches may occur with or without a prodrome. The aura of a migraine may consist of neurologic symptoms, such as dizziness, tinnitus, scotomas, photophobia, or visual scintillations (eg, bright zigzag lines). The International Headache Society (IHS) redefined and classified headaches to formulate the current categorization, which has been maintained in the second edition. The headache previously described as classic migraine is now known as migraine with aura, and that described as common migraine is now termed migraine without aura. Migraines without aura are the most common, accounting for more than 80% of all migraines.
In April 2000, the US Headache Consortium, a multispecialty group that includes the American College of Emergency Physicians, released evidence-based guidelines for the diagnosis, treatment, and prevention of migraine headaches. Guidelines are also available from the American Academy of Neurology, the National Headache Foundation, and the Canadian Association of Emergency Physicians.

Pathophysiology
The pathophysiology of migraine headaches is not clearly understood. Growing evidence supports the role of neurogenic peptides, such as serotonin and dopamine, in the brain. These vasoactive neuropeptides stimulate an inflammatory cascade with the release of endothelial cells, mast cells, and platelets. This inflammation causes vasodilation and a perivascular reaction. The serotonin receptor (5-HT) is believed to be the most important receptor in the headache pathway.
Some of the symptoms associated with migraine headaches, such as nausea (80%), vomiting (50%), yawning, irritability, hypotension, and hyperactivity, can be associated with dopamine receptor activation. Dopamine receptor hypersensitivity has been shown experimentally with dopamine agonists such as apomorphine, bromocriptine, and pergolide. Dopamine antagonists, such as metoclopramide (Reglan), haloperidol (Haldol), and prochlorperazine (Compazine), have been shown clinically to treat migraine headaches effectively.

Frequency
United States
An estimated 10-20% of the US population suffers from migraine headaches. Frequency of headaches varies greatly by individual. An estimated 6% of men and 15-17% of women in the United States have migraine. Migraine is the second most common type of headache syndrome in the United States. Tension headaches are the most common.
Sex
Migraines most commonly are found in women, with a 3:1 female-to-male ratio. In childhood, however, migraines are more common in boys than in girls.
Age
The first attack often is in childhood, and incidence increases in adolescence. More than 80% of patients who develop migraines will have a first attack by age 30. Migraines continue through the patient's 30s and 40s. They may begin or occur at any age but are rare after age 50. With increased age, attacks usually decrease in severity and frequency. Age older than 55 years is a strong predictor for intracranial pathology.

History
Moderately severe to severe headache with or without a prodrome
Aura (20%) - A variety of preceding events that begins and ends days to hours prior to the headache itself. Visual aura symptoms are most common. Nonspecific prodrome may precede migraine without an aura.
Scotoma (blind spots)
Fortification (zig-zag patterns)
Scintilla (flashing lights)
Unilateral paresthesia/weakness
Hallucinations
Hemianopsia
Headache
Unilateral, also known as hemicrania (30-40% are bilateral)
Throbbing or pulsatile (More than 50% of people who suffer from migraines report nonthrobbing pain at some time during the attack.)
Lasts 4-72 hours
Systemic manifestations
Nausea (80-90%)
Vomiting (40-60%)
Photophobia (80%)
Phonophobia (75-80%)
Lightheadedness (70%)
The patient might prefer to be in a quiet and darkened room.
History factors suggesting a more serious underlying cause of headache
The first or worst headache of the patient's life, especially if the headache onset was rapid
A change in frequency, severity, or clinical features of the attack from what usually is experienced
New progressive headache that persists for days
Precipitation of headache with Valsalva maneuvers (ie, coughing, sneezing, bearing down)

Physical
Usually, patients have no specific physical findings other than the physical manifestations of the associated systemic symptoms listed above (photophobia, phonophobia); abnormality on physical examination may suggest another cause of headache.
The physician must perform a thorough screening neurologic examination.
Physical examination findings suggesting a more serious cause of headache include the following:
Systemic symptoms (eg, myalgia, fever, malaise, weight loss, scalp tenderness, jaw claudication)
Focal neurologic abnormalities or confusion, seizures, or any impairment of level of consciousness
Focal neurologic findings that occur with the headache and persist temporarily after the pain resolves suggest a migraine variant. In hemiplegic migraine, the patient may have unilateral paralysis or weakness. Aphasia, syncope, and balance problems may be seen in basilar migraines. In ophthalmoplegic migraine, the patient may present with a third nerve palsy, with ocular muscle paralysis, including or sparing the pupillary response, as well as ptosis. Ophthalmic migraines cause a visual disturbance (usually lateral field deficit). This diagnosis is more common in children, with the abnormal motor findings lasting hours to days after the headache.

Causes
Exact etiology is unknown.
Family history of migraine headaches (70-80%)
Medications (ie, birth control pills, vasodilators)
Fatigue or emotional stress
Specific foods or alcohol
Exertion

DIFFERENTIALS
Other Problems to be Considered
Brain tumor (increased intracranial pressure) Opiate dependance/opiate withdrawal headache Pseudotumor cerebri Vascular pathology (eg, aneurysm)
WORKUP

Lab Studies
Laboratory and radiographic evaluation excludes other potential diagnoses in the differential.

Imaging Studies
CT scan of the head is indicated to rule out intracranial mass or hemorrhage in selected or atypical cases. A negative CT scan may miss some small subarachnoid hemorrhages, tumors, and strokes, particularly those in the posterior fossa. A CT scan without intravenous contrast also may miss some aneurysms. MRI and magnetic resonance angiography are more sensitive. Neuroimaging is rarely productive in patients who have a normal neurologic examination. Neuroimaging is not warranted in patients with a diagnosis of migraine who present with a typical event. They are useful if neurologic examination findings are abnormal, the migraine occurs for the first time after age 40 years, the frequency or intensity is increasing, and the accompanying symptoms of the attack change.

Procedures
Lumbar puncture (LP): In selected patients with appropriately concerning histories, an LP should be performed to rule out infection or small subarachnoid hemorrhage not visible on CT scan of the head.

TREATMENT
Prehospital Care
Patients should be transported in a way that minimizes visual and auditory stimulation. Most patients should not receive opiate analgesics until a thorough neurologic examination can be completed by the responsible physician.
Emergency Department Care
While the emergency physician must be able to identify patients with serious headache etiology, note that more than 90% of patients in the ED have migraine, tension, or mixed-type benign headache. Therefore, providing symptomatic relief should be a priority.
Migraine-specific medications and analgesia are the keys of ED care.
Rest in a darkened, quiet room is helpful.
Some patients find cool compresses to painful areas helpful.

Consultations
Neurologic consultation may be required in complex cases, though referral to a primary care provider often is sufficient.

MEDICATION
The goals of pharmacotherapy are to prevent attacks or alter the migraine attack once it is underway. Specifically, this is done by reducing the severity and the duration of the attack. Preventive therapy encompasses these same objectives and decreases the frequency of attacks, improves responsiveness to treatment, and improves function while decreasing disability.
An estimated half of migraine patients stop seeking care for their headaches, partly because they are dissatisfied with therapy.
Drug Category: Analgesics
Initial therapy for patients with infrequent migraines can be simple analgesics.
Drug Name
Acetaminophen and codeine (Tylenol #3)
Description
Drug combination indicated for treatment of mild to moderately severe headache.Note: Some patients may respond to maximal acetaminophen alone, without codeine.
Adult Dose
30-60 mg/dose based on codeine content PO q4-6h or 1-2 tab q4h; not to exceed 12 tab/d (4 g acetaminophen/d)
Pediatric Dose
0.5-1 mg/kg/dose based on codeine content PO q4-6h; 10-15 mg/kg/dose based on acetaminophen content; not to exceed 2.6 g/d of acetaminophen
Contraindications
Documented hypersensitivity
Interactions
CNS depressants or tricyclic antidepressants increase toxicity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in patients dependent on opiates because this substitution may result in acute opiate-withdrawal symptoms; caution in severe renal or hepatic dysfunction
Drug Name
Acetaminophen (Tylenol, Aspirin Free Anacin, Panadol)
Description
DOC for treatment of pain in patients with documented hypersensitivity to aspirin or NSAIDs, in those with upper GI disease, or in those taking oral anticoagulants.
Adult Dose
325-650 mg PO q4-6h or 1000 mg tid/qid; not to exceed 4 g/d
Pediatric Dose
<12>12 years: 325-650 mg PO q4h; not to exceed 5 doses in 24 h
Contraindications
Documented hypersensitivity; G-6-PD deficiency
Interactions
Rifampin can reduce analgesic effects; barbiturates, carbamazepine, hydantoins, and isoniazid may increase hepatotoxicity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Hepatotoxicity possible in chronic alcoholism following various dose levels; severe or recurrent pain or high or continued fever may indicate serious illness; acetaminophen contained in many OTC products, and combined use with these products may result in cumulative acetaminophen doses exceeding recommended maximum dose
Drug Name
Aspirin (Anacin, Ascriptin, Bayer Aspirin)
Description
May alleviate migraine attacks by inhibiting prostaglandin synthesis. Mild migraines usually respond well to this medication.
Adult Dose
325-650 mg PO q4-6h prn; not to exceed 4 g/d
Pediatric Dose
10-15 mg/kg/dose PO q4-6h; not to exceed 60-80 mg/kg/d
Contraindications
Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; bleeding disorders; asthmaBecause of association with Reye syndrome, do not use in children (<16>2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusD - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
May cause transient decrease in renal function and aggravate chronic kidney disease; avoid use in patients with severe anemia, in those with history of blood coagulation defects, or in those taking anticoagulants
Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs)
These agents may alleviate migraine pain by inhibiting prostaglandin synthesis, reducing serotonin release, and blocking platelet aggregation. Although the effects of NSAIDs in the treatment of migraine pain tend to be patient specific, ibuprofen usually is the DOC for the initial therapy. Other options include naproxen, ketoprofen, and ketorolac.
Drug Name
Naproxen (Anaprox, Naprelan, Naprosyn)
Description
Used for relief of mild to moderately severe headaches. Inhibits inflammatory reactions and pain by decreasing activity of enzyme cyclooxygenase, thus inhibiting prostaglandin synthesis.
Adult Dose
500 mg PO followed by 250 mg q6-8h; not to exceed 1.25 g/d
Pediatric Dose
<2>2 years: 2.5 mg/kg/dose PO; not to exceed 10 mg/kg/d
Contraindications
Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency
Interactions
Aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity; may decrease effects of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT in patients taking anticoagulants (monitor PT closely and instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; may increase phenytoin levels
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusD - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and may require discontinuation of drug
Drug Name
Ketoprofen (Oruvail, Orudis, Actron)
Description
Used for relief of mild to moderately severe headaches and inflammation.Administer small dosages initially to patients with small body size, elderly patients, and patients with renal or liver disease.Doses >75 mg does not increase therapeutic effects. Administer high doses with caution, and closely observe the patient for response.
Adult Dose
25-50 mg PO q6-8h prn; not to exceed 300 mg/d
Pediatric Dose
<3>12 years: Administer as in adults
Contraindications
Documented hypersensitivity
Interactions
Aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity; may decrease effects of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT in patients taking anticoagulants (monitor PT closely and instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; may increase phenytoin levels
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusD - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in coagulation abnormalities or during anticoagulant therapy
Drug Name
Ketorolac (Toradol)
Description
Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclooxygenase, which results in decreased formation of prostaglandin precursors.PO form available, but no advantage vs other less expensive PO NSAIDs.
Adult Dose
30 mg IV single dose (most common route used in ED)>65 years, renal impairment, or body weight <50>2 years: 0.25-1 mg/kg PO/IV/IM/PR q4-6h prn
Contraindications
Documented hypersensitivity; children younger than 2 y (incidences of death due to respiratory depression)
Interactions
May have additive effects with other CNS depressants or anticonvulsants; with epinephrine may cause hypotension
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in cardiovascular disease, impaired liver function, seizures, sleep apnea, and asthma
Drug Name
Metoclopramide (Reglan)
Description
Indicated for migraine-associated nausea. Works by blocking dopamine receptors in the chemoreceptor trigger zone of the CNS. Can be used as an alternative to prochlorperazine. Studies have shown that prochlorperazine is better.
Adult Dose
5-10 mg PO or 5-20 mg IV/IM tid
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; pheochromocytoma or GI hemorrhage, obstruction or perforation; history of seizure disorders
Interactions
Anticholinergic agents may antagonize effects of metoclopramide; opiate analgesics may increase metoclopramide toxicity in CNS
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in history of mental illness and Parkinson disease
Drug Name
Droperidol (Inapsine)
Description
Neuroleptic agent that may reduce emesis by blocking dopamine stimulation of chemoreceptor trigger zone.
Adult Dose
2.5-10 mg IV/IM q3-4h prn (2.5 mg for headache)
Pediatric Dose
<2>12 years: Administer as in adults
Contraindications
Documented hypersensitivity; prolonged QT interval
Interactions
May increase toxicity of CNS depressants
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Hypovolemic patients may experience hypotension; droperidol may decrease pulmonary arterial pressure; tardive dyskinesia in patients receiving droperidol is 40%; elderly persons may experience high rate of extrapyramidal reactions; life-threatening arrhythmias may occur in patients receiving this medication (for droperidol, the black box warning: potentially fatal QT prolongation; many institutions recommend an ECG or rhythm strip to look for QT prolongation before administering)
Drug Category: Ergot alkaloids and derivatives
These are direct vasoconstrictors of smooth muscle in cranial blood vessels. Their activity depends on the CNS vascular tone at the time of administration.
Drug Name
Ergotamine tartrate (Cafergot, Cafatine, Cafetrate)
Description
Has alpha-adrenergic antagonist and serotonin antagonist effects. Causes constriction of peripheral and cranial blood vessels.
Adult Dose
2 tab PO at onset of attack, 1 tab q30min prn; not to exceed 6 tab per attack or 10 tab/wk1 tab SL at first sign of attack and 1 tab q30min; not to exceed 3 tab/d or 5 tab/wk1 supp PR at first sign of attack with second dose after 1 h prn; not to exceed 2 supp/attack or 5 supp/wk
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; hepatic or renal disease; peptic ulcer disease; sepsis; peripheral vascular disease
Interactions
Increases effects of heparin; increases toxicity of nitroglycerin, propranolol, erythromycin, and clarithromycin
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Avoid using prolonged regimens because of danger of causing gangrene or dependency
Drug Name
Dihydroergotamine (D.H.E. 45, Migranal Nasal Spray)
Description
More effective when given early in migraine attack. Has alpha-adrenergic antagonist and serotonin antagonist effects.
Adult Dose
1 mg IM at first sign of headache, repeat q1h; not to exceed 3 mg total dose2 mg IV maximum dose for faster effects; most commonly given at 0.5-1 mg IV with antiemetic; not to exceed 6 mg/wkIntranasal: 1 spray into each nostril and repeat prn within 15 min; not to exceed 6 sprays/d or 8 sprays/wk
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; sumatriptan or zolmitriptan within last 24 h; MAOIs in last 2 wk
Interactions
Increases effects of heparin; increases toxicity of nitroglycerin, propranolol, erythromycin, and clarithromycin
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Caution in angina, hypertension, impaired renal or hepatic function, or peripheral vascular disease
Drug Category: 5- HT1 Serotonin receptor agonist
The stimulation of 5-HT1 receptors produce a direct vasoconstrictive effect.
Drug Name
Sumatriptan (Imitrex)
Description
Selective agonist for serotonin 5-HT1 receptors in cranial arteries. Suppresses inflammation associated with migraine headaches.
Adult Dose
25 mg PO; if satisfactory response not observed in 2 h, additional dose of up to 100 mg may be administered; additional doses at intervals of 2 h prn; not to exceed 300 mg/d6 mg SC; if satisfactory response not observed in 1 h, an additional 6 mg SC may be administered; not to exceed 2 injections/dIntranasal: Single dose of 5, 10, or 20 mg may be administered in 1 nostril; give 10-mg dose by administering single 5-mg dose in each nostril; if satisfactory response not observed in 2 h, additional dose may be administered; not to exceed 40 mg/d
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; ischemic heart disease; uncontrolled hypertension; coadministration or within 2 wk of MAOIs
Interactions
Toxicity may increase when used within 24 h of ergotamines or other 5-HT agonists; coadministration with SSRIs may cause weakness, hyperreflexia, or incoordination; CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir, erythromycin) may increase plasma concentration and subsequent toxicity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Flushing and chest pain are common;hypertensive crisis, coronary artery vasospasm, cardiac arrest, peripheral ischemia, and bloody diarrhea may occur rarelyPatients with known or suspected coronary artery disease may have increased risk of myocardial ischemia, infarction, or other cardiac or cerebrovascular events (5-HT1 agonists may cause coronary vasospasm)
Drug Name
Zolmitriptan (Zomig, Zomig-ZMT)
Description
Selective agonist for serotonin 5-HT1 receptors in cranial arteries. Suppresses inflammation associated with migraine headaches.
Adult Dose
2.5 mg or 5 mg PO; repeat dose after 2 h prn; not to exceed 10 mg/d
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; ischemic heart disease; uncontrolled hypertension; another serotonin agonist or ergotamine within last 24 h; MAOI within last 2 wk
Interactions
Toxicity may increase when used within 24 h of ergotamines or other 5-HT agonists; coadministration with SSRIs may cause weakness, hyperreflexia, or incoordination; CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir, erythromycin) may increase plasma concentration and subsequent toxicity
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Flushing and chest pain are common; hypertensive crisis, coronary artery vasospasm, cardiac arrest, peripheral ischemia, bloody diarrhea, and death may occurDecrease dose of almotriptan and do not exceed 12.5 mg/d in renal or hepatic impairment
Drug Name
Frovatriptan (Frova)
Description
Used to treat acute migraine. Selective 5-HT1B/1D receptor agonist with long half-life of 24 h and low headache recurrence rate within 24-hour period of taking the drug. Results in cranial vessel constriction, inhibition of neuropeptide release, and reduced pain transmission in trigeminal pathways. Has unique characteristics and benefits in the acute treatment of migraine.
Adult Dose
2.5 mg PO once at onset of migraine attack
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; hemiplegic or basilar migraine; ischemic heart disease; uncontrolled hypertension
Interactions
Toxicity may increase when used within 24 h of ergotamines or other 5-HT agonists; coadministration with SSRIs may cause weakness, hyperreflexia, or incoordination
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Hypertensive crisis, coronary artery vasospasm, cardiac arrest, peripheral ischemia, bloody diarrhea, and death may occur
Drug Name
Eletriptan (Relpax)
Description
Selective serotonin agonist. Specifically acts at 5-hydroxytryptamine 1B/1D/1F (5-HT1B/1D/1F) receptors on intracranial blood vessels and sensory nerve endings to relieve pain associated with acute migraine.
Adult Dose
20-40 mg/dose PO at onset of migraine; if initial dose ineffective, may repeat dose once after 2 h; not to exceed 80 mg/d
Pediatric Dose
<18>65 y; administration within 72 h of potent CYP450 3A4 inhibitors
Interactions
Potent CYP450 3A4 inhibitors (eg, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) may increase toxicity; concurrent administration with ergot-containing drugs may increase vasospastic reactions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Patients with known or suspected coronary artery disease may have increased risk of myocardial ischemia, infarction, or other cardiac or cerebrovascular events (5-HT1 agonists may cause coronary vasospasm)
Drug Name
Almotriptan (Axert)
Description
Used to treat acute migraine. Selective 5-HT1B/1D receptor agonist. Results in cranial vessel constriction, inhibition of neuropeptide release, and reduced pain transmission in trigeminal pathways.
Adult Dose
6.25-12.5 mg PO at onset of migraine; may repeat once, not to exceed 25 mg/d
Pediatric Dose
<18>18 years: Administer as in adults
Contraindications
Documented hypersensitivity; hemiplegic or basilar migraine; ischemic heart disease; uncontrolled hypertension
Interactions
Toxicity may increase when used within 24 h of ergotamines or other 5-HT agonists; coadministration with SSRIs may cause weakness, hyperreflexia, or incoordination; CYP450-3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir, erythromycin) may increase plasma concentration and subsequent toxicity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Decrease dose and do not exceed 12.5 mg/d in renal or hepatic impairment
Drug Name
Rizatriptan (Maxalt, Maxalt-MLT)
Description
Selective agonist for serotonin 5-HT1 receptors in cranial arteries and suppresses the inflammation associated with migraine headaches.
Adult Dose
5-10 mg PO q2h prn for headache; not to exceed 30 mg/d
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity
Interactions
Toxicity increases when administered concomitantly with ergot-containing drugs, selective serotonin reuptake inhibitors, and MAOIs
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Hypertensive crisis, coronary artery vasospasm, cardiac arrest, peripheral ischemia, bloody diarrhea, and death may occur when administering this medication
Drug Category: Combination antimigraine drugs
These agents are useful in aborting migraine attacks.
Drug Name
Isometheptene dichloralphenazone acetaminophen (Midrin)
Description
Has sympathomimetic properties. Dilates cranial and cerebral arterioles, causing reduction in stimuli that lead to vascular headaches.
Adult Dose
2 cap PO at once followed by 1 cap q1h until satisfactory response obtained; not to exceed 5 cap/12 h
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; glaucoma; hypertension; organic heart disease; severe renal disease; hepatic disease; MAOI within last 2 wk
Interactions
Concurrent MAOIs may result in severe headache, hypertension, and hyperpyrexia, which, in turn, may result in hypertensive crisis
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in hypertension, peripheral vascular disease, and recent cardiovascular injuries
Drug Category: Barbiturates
These agents are used in combination with aspirin and acetaminophen for pain relief and to induce sleep. Caffeine is also used to increase GI absorption. However, butalbital and narcotics are associated with rebound headaches. Increasing the use of combination preparations may fail to provide pain relief and worsen headache symptoms.
Drug Name
Acetaminophen/butalbital/caffeine (Fioricet)
Description
Drug combination used to relieve tension headaches. Barbiturate component has generalized depressant effect on CNS.
Adult Dose
1-2 tab or cap PO q4h; not to exceed 6 tab or cap/d
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity
Interactions
Effects decreased by phenothiazines, quinidine, tricyclic antidepressants, theophylline, haloperidol, chloramphenicol, ethosuximide, corticosteroids, warfarin, doxycycline, and beta-blockers; effects increased by CNS depressants, methylphenidate, valproic acid, propoxyphene, and benzodiazepines
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Risk of rebound headache and overuse; caution in patients with history of substance abuse
Drug Name
Aspirin/butalbital/caffeine (Fiorinal)
Description
Drug combination used to relieve tension headaches. Barbiturate component has generalized depressant effect on CNS.
Adult Dose
1-2 tab or cap PO q4h; not to exceed 6 tab or cap/d
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; children or adolescents experiencing flulike symptoms or chickenpox
Interactions
Effects decreased by phenothiazines, quinidine, tricyclic antidepressants, theophylline, haloperidol, chloramphenicol, ethosuximide, corticosteroids, warfarin, doxycycline, and beta-blockers; effects increased by CNS depressants, methylphenidate, valproic acid, propoxyphene, and benzodiazepines
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Risk of rebound headache and overuse; caution in patients with history of substance abuse

FOLLOW-UP
Further Outpatient Care
Avoid precipitants of attacks, if possible.
Follow-up with primary care physician and neurologist after first or subsequent attacks.

In/Out Patient Meds
Multitude of drugs used for migraine prophylaxis
Beta-blockers: Atenolol, propranolol, timolol
Antidepressants: Amitriptyline (Elavil), nortriptyline (Pamelor)
Ergot derivatives: Methysergide (Sansert)
Antihistamines: Cyproheptadine (Periactin)
Anticonvulsants: Valproic acid (Depakene, Depakote)
Abortive therapies
Alpha2-adrenergic receptor agonists (Clonidine)
Calcium channel blockers: Nimodipine, nifedipine, verapamil
NSAIDs

Patient Education
For excellent patient education resources, see eMedicine's Headache Center. Also, visit eMedicine's patient education articles Causes and Treatments of Migraine and Related Headaches, Migraine Headache, Alternative and Complementary Approaches to Migraine and Cluster Headaches, Migraine Headache FAQs, and Understanding Migraine and Cluster Headache Medications.
For more information, see Medscape's Headache Resource Center.

MISCELLANEOUS
Medical/Legal Pitfalls
Must rule out other potentially life-threatening forms of headache (eg, subarachnoid hemorrhage, meningitis).

REFERENCES
Bussone G, Grazzi L, D'Amico D, et al. Acute treatment of migraine attacks: efficacy and safety of a nonsteroidal anti-inflammatory drug, diclofenac-potassium, in comparison to oral sumatriptan and placebo. The Diclofenac- K/Sumatriptan Migraine Study Group. Cephalalgia. May 1999;19(4):232-40. [Medline].
Cady R. Migraine. In: Five Minute Clinical Consult. 1997:676-77.
Caesar R. Acute headache management: the challenge of deciphering etiologies to guide assessment and treatment. Emerg Med Rep. 1995;16(13):117-28.
Capobianco DJ, Cheshire WP, Campbell JK. An overview of the diagnosis and pharmacologic treatment of migraine. Mayo Clin Proc. Nov 1996;71(11):1055-66. [Medline].
Diener HC, Kaube H, Limmroth V. A practical guide to the management and prevention of migraine. Drugs. Nov 1998;56(5):811-24. [Medline].
Ducharme J. Canadian Association of Emergency Physicians Guidelines for the acute management of migraine headache. J Emerg Med. Jan-Feb 1999;17(1):137-44. [Medline].
Evans RW. Diagnostic testing for the evaluation of headaches. Neurol Clin. Feb 1996;14(1):1-26. [Medline].
Members of the task force; Evers S, Afra J, Frese A, Goadsby PJ, Linde M. EFNS guideline on the drug treatment of migraine - report of an EFNS task force. Eur J Neurol. Jun 2006;13(6):560-72. [Medline].
Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24 Suppl 1:9-160. [Medline].
Henry GL. Headache. In: Emergency Medicine Concepts and Clinical Practice. 3rd ed. 1992:1751-66.
Hoffman GL. Headache and facial pain. In: Emergency Medicine. 4th ed. 1996:chap192/1008-14.
Lance JW. Current concepts of migraine pathogenesis. Neurology. Jun 1993;43(6 Suppl 3):S11-5. [Medline].
Matchar DB, Young WB, Rosenberg JA, et al. Evidence-based guidelines for migraine headache in the primary care setting: Pharmacological management of acute attacks. American Academy of Neurology. Available at http://www.aan.com/. Accessed October 31, 2007.
Ramirez-Lassepas M, Espinosa CE, Cicero JJ, et al. Predictors of intracranial pathologic findings in patients who seek emergency care because of headache. Arch Neurol. Dec 1997;54(12):1506-9. [Medline].
Saper JR. Diagnosis and symptomatic treatment of migraine. Headache. 1997;37 Suppl 1:S1-14. [Medline].
Sheftell FD, Tepper SJ. New paradigms in the recognition and acute treatment of migraine. Headache. Jan 2002;42(1):58-69. [Medline].
Silberstein SD. Evaluation and emergency treatment of headache. Headache. Sep 1992;32(8):396-407. [Medline].
Solomon GD, Cady RK, Klapper JA, Ryan RE Jr. Standards of care for treating headache in primary care practice. National Headache Foundation. Cleve Clin J Med. Jul-Aug 1997;64(7):373-83. [Medline].
Stewart WF, Lipton RB, Celentano DD, et al. Prevalence of migraine headache in the United States. Relation to age, income, race, and other sociodemographic factors. JAMA. Jan 1 1992;267(1):64-9. [Medline].
Stewart WF, Shechter A, Rasmussen BK. Migraine prevalence. A review of population-based studies. Neurology. Jun 1994;44(6 Suppl 4):S17-23. [Medline].
Tfelt-Hansen P. Efficacy and adverse events of subcutaneous, oral, and intranasal sumatriptan used for migraine treatment: a systematic review based on number needed to treat. Cephalalgia. Oct 1998;18(8):532-8. [Medline].
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Headache, Migraine excerpt
Article Last Updated: Jan 3, 2008

Migraine Variants

2008-05-23T08:00:00.001+03:00

Migraine is a paroxysmal headache disorder affecting more than 13% of the general population in the United States. Migraine is a syndrome and not a disease; it is characterized by paroxysmal headache associated with others signs and symptoms. About 80% of migraineurs have migraine without aura, while migraine with typical aura accounts for 15-20% of cases. Isolated migraine aura without headache (acephalic migraine) may be encountered in 5% of patients.
Migraine variant (MV) or migraine equivalent is the term applied to migraine, which exhibits itself in a form other than head pain. MV is characterized by paroxysmal episodes of prolonged visual auras; atypical sensory, motor, or visual aura; confusion; dysarthria; focal neurologic deficits; or gastrointestinal manifestations or other constitutional symptoms with or without a headache.
The diagnosis of MV is determined by history of paroxysmal signs and symptoms with or without cephalgia, a prior history of migraine with aura, in the absence of other medical disorders that may contribute to the symptoms. Many of these patients usually have a family history of migraine.
MVs are less recognized and poorly understood. They are less common than typical migraine without and with aura, and they usually affect children and young adults.
MVs should be differentiated from trigeminal cephalic neuralgias and other primary headaches such as stabbing and thunderclap headaches, cough headaches, or hypnic headaches. MVs should also be differentiated from exertional headaches, a group of headache syndromes associated with physical activity such as running, coughing, sneezing, or sexual intercourse.
Many MVs have been defined by the International Classification of Headache Disorders (ICHD-II) 2004 classification. These include hemiplegic migraines, basilar migraine, childhood periodic syndromes, retinal migraine, complicated migraines, and ophthalmoplegic migraine. Vertiginous migraine, acute confusional migraine of childhood, and nocturnal migraine, although well recognized entities, remain unclassified by the IHCD-II.
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Pathophysiology
Although activation and sensitization of the trigeminovascular in migraine is believed to generate and maintain migraine pain, cortical spreading depression (CSD) is recognized as the phenomenon underlying migraine aura. CSD is believed to begin in the occipital region and to gradually spread rostrally. This phenomenon is accompanied by a transient oligemia, followed by hyperemia in other parts of the cortex. Various molecular and cellular mechanisms may lead to the increased susceptibility of CSD in migraineurs, which could potentially play an important role in the pathophysiology of MVs. Researchers have suggested that a vasogenic leakage from leptomeningeal vessels, with activation of the trigeminovascular system, probably contribute to the prolonged aura in patients with hemiplegic migraine.
Migraine with prolonged aura
The typical duration of a migraine aura, predominantly visual, is up to 30 minutes. In rare cases, the aura could be prolonged, lasting up to 60 minutes, raising concerns of possible stroke.
Migraine aura without headache or acephalic migraine
Around 3-5% of migraineurs experience an aura without headache. This presentation is more common in older patients who have had a history of migraine with aura during early age. Symptoms may include scintillating scotomata, formed stereotyped visual hallucinations in a single visual field or bilaterally, micropsia, and tunnel vision. Other auras include paroxysmal vertigo, hemisensory dysesthesias, and rarely auditory hallucinations. Acephalic migraine should be differentiated from transient ischemic attack, occipital lobe seizures, or temporal lobe seizures.
Hemiplegic migraine
Hemiplegic migraine is a very rare but well described form of MV. It was initially described in 1910 as a type of migraine consisting of recurrent headaches associated with temporary unilateral hemiparesis or hemiplegia, at times accompanied by ipsilateral numbness or tingling, with or without a speech disturbance. The focal neurologic deficit may precede or accompany the headache, which is usually less dramatic than motor deficit. Other migraine symptoms may variably be present. Patients may also experience disturbance of consciousness, and rarely coma. The neurologic deficit is transient and usually clears in minutes to hours, or resolves with the beginning of the headache phase.
Two forms of hemiplegic migraine are known: familial and sporadic. Both familial hemiplegic migraine (FHM) and sporadic hemiplegic migraine (SHM) are phenotypically similar subtypes of migraine with aura, differentiated only by the unilateral motor symptoms.
Familial hemiplegic migraine
FHM is an autosomal dominant disorder. FHM is a channelopathy; most of the affected families bear mutations in the CACNA1A gene (a defect linked to abnormal voltage-dependent P/Q-type calcium channel alpha-1A) on 19p13. Mutations in ATP1A2 (R548H) on 1q23 (Mendelian Inheritance in Man #182340) and other genes have been identified.
Alternating hemiplegic migraine (primarily in childhood)
Alternating hemiplegia of childhood (AHC) is a chronic progressive disorder, associated with high prevalence of neurologic deficit. It is distinguished from familial hemiplegic migraine by its infantile onset and by its characteristic associated symptoms. The onset of the disorder is before age 18 months. It is characterized by vomiting, headache, alternating hemiplegia, loss of consciousness, paroxysmal ocular palsies, choreoathetosis, autonomic dysfunction, and mental retardation. Single-photon emission computed tomography (SPECT) studies have shown progressive decrease of cerebral perfusion in cases of alternating hemiplegic migraine.
Sporadic hemiplegic migraine
SHM is defined as migraine attacks associated with motor weakness in the absence of family history of similar attacks. Cases of SHM have also been linked to the CACNA1A gene.
Diagnosis of FHM is usually confirmed with repeated stereotyped reversible episodes, particularly in the presence of positive family history of similar attacks. The absence of first- and or second-degree relatives with similar disorder raises suspicion of SHM. Differential diagnosis includes focal seizures with postictal paralysis, mitochondrial cytopathies, intracranial hemorrhage, mass, infection, or cerebral infarction.
Basilar-type migraine
Basilar migraine (BM), also known as Bickerstaff syndrome, consists of headache accompanied by dizziness, ataxia, tinnitus, decreased hearing, nausea and vomiting, dysarthria, diplopia, loss of balance, bilateral paresthesias or paresis, altered consciousness, syncope, and sometimes loss of consciousness. BM is observed most frequently in adolescent girls and young women. Localized vertebrobasilar vasoconstriction leading to transient posterior circulation ischemia may contribute to the symptomatology of the disorder. A novel mutation in the ATP1A2 gene, similar to FHM, has been reported in members of one family with BM. Differential diagnosis includes various causes of syncopal, inner ear disease, intoxication, and posterior fossa pathologies.
Childhood periodic syndromes that are commonly precursors of migraine
Childhood periodic syndromes are characterized by multiple cyclic attacks of pain or vomiting with our without migraine headaches. They are common in children and adolescents.
Cyclic vomiting syndrome
Cyclic vomiting of childhood is characterized by recurrent attacks of violent or prolonged vomiting without headache, which may last for hours. Attacks may be precipitated by infection, menstruation, or physical or emotional stress. During the attacks, patients characteristically show other symptoms of migraine such as nausea, lethargy, yawning, and drowsiness. Cyclic vomiting is thought to result from abnormal activity in the area postrema. Additionally, gastroparesis, which occurs during migraine, has been implicated as an etiologic factor for cyclic vomiting and abdominal migraine.
Abdominal migraine
Abdominal migraine most typically occurs in children, although it has been reported in adults. Patients usually complain of paroxysmal midabdominal pain lasting form 1-72 hours, associated with nausea and vomiting, flushing, or pallor. Like cyclic vomiting, attacks may be associated with other migraine prodromes such as fatigue and drowsiness. Aura and headaches are frequently absent or minimal. Patients may develop migraine late in their life, and family history of migraine is common. Gastroenterologic evaluation and workup is unremarkable.
Benign paroxysmal vertigo of childhood
Benign paroxysmal vertigo of childhood (BPVC) is another MV characterized by brief episodes of vertigo and disequilibrium lasting for hours, without headache, aura, hearing loss, or tinnitus. It affects children aged 1-4 years. Children usually complain of a spinning sensation during the attack. Typical migraine is common later in life, and a family history of migraine is helpful in confirming the diagnosis.
Retinal migraine
Retinal migraine (ophthalmic, ocular) is not an uncommon cause of transient monocular blindness in young adults. It is manifested by recurrent attacks of unilateral visual disturbance or blindness lasting from minutes to 1 hour, associated with minimal or no headache. This phenomenon is frightening to patients, who usually seek medical help to exclude amaurosis fugax due to ischemia of the retinal arteries. Patients describe a gradual visual disturbance in a mosaic pattern of scotomata that gradually enlarge, producing total unilateral visual loss. Postural changes, exercise, and oral contraceptive agents may precipitate attacks. The condition is thought to result from transient vasospasm of the choroidal or retinal arteries. A personal or family history of migraine confirms the diagnosis. The condition needs to be differentiated from ocular or vascular causes of transient monocular blindness, mainly carotid artery disease.
Complicated migraine
Complications of migraine include chronic migraine, status migrainosus, persistent aura without infarction, migrainous infarction, and migraine-triggered seizure. Complicated migraines are rare, accounting for less than 1% of total patients with migraine. Chronic migraine and status migrainosus are not considered MVs and therefore are not included in this article.
Persistent aura
A typical migraine aura usually lasts 20-60 minutes. When the aura of migraine is prolonged, lasting for hours or days, complicated migraine including ischemic strokes need to be excluded. Prolonged aura lasting beyond 60 minutes, in the absent of radiographic evidence of cerebral infarction, is referred to as migraine with persistent aura.
Migraine infarctions
The relationship between migraine, mostly migraine with aura, and ischemic stroke has been well recognized. Migraine, generally a benign condition, has been recognized as an independent risk factor for ischemic stroke. Additionally, migraine, predominantly migraine with aura, is associated with the presence of silent infarctions or white matter changes on brain MRI. When a cerebral infarction occurs during a typical migraine aura attack, the term migrainous infarction is used. The mechanism of migrainous infarction is complex. Whether the relationship between migraine and stroke is the consequence of other underlying etiologies or the presence of similar ischemic risk factors, or whether migraine is associated with conditions that could potentially cause stroke, is yet to be determined.
Migraine-triggered seizures (migralepsy)
Migraine and epilepsy are highly comorbid conditions probably sharing the same pathophysiology, but the nature of their association is unclear. Migralepsy is the term used when a seizure occurs during or within 1 hour of a typical migraine aura attack. Reversible brain MRI abnormalities have been reported in a patient with migraine-triggered seizure, possibly due to supratentorial focal cerebral edema. Electroencephalogram (EEG) findings are usually normal interictal, although various abnormalities, mainly diffuse slowing, have been reported in migraineurs.
Ophthalmoplegic migraine
This is a very rare condition in children, characterized by a migrainelike attack, followed within days by periorbital pain and diplopia secondary to cranial neuropathies. The oculomotor nerve is most commonly involved, with pupillary abnormality and ptosis, followed by the abducens, and rarely the trochlear nerve. The attack usually lasts from days to months and resolves spontaneously. A number of adult cases have been reported. Although previously considered an MV, the condition has been classified as neuralgia by the IHCD-II. The condition is thought to be due to recurrent demyelinating cranial neuropathies. Differential diagnosis includes conditions involving the parasellar, orbital, and posterior fossa leading to headache and ophthalmoplegia.
Acute confusional migraine (primarily in childhood)
Acute confusional migraine is a rare MV, almost exclusively seen in young children, manifested by episodes of confusion, disorientation, and vomiting, with or without headaches. The attacks are usually relieved by sleep. The condition should be differentiated from seizures, and various causes of confusion, including toxic, metabolic, mitochondrial, or infectious encephalopathies.
Vertiginous migraine
Growing evidence suggests that recurrent episodes of vertigo are related to migraine. Vertigo, a common complaint among migraineurs, has been reported in one third of cases. Recurrent episodes of vertigo lasting between 5 minutes and 1 hour, with or without nausea, vomiting, photophobia, or headache, in the setting of a previous personal history or a positive family history of migraine supports the diagnosis of vestibular or vertiginous migraine. The pathophysiology of migraine-related vertigo is not fully understood. Differential diagnosis includes vertebrobasilar insufficiency and paroxysmal vestibular syndromes.
Nocturnal migraine
Although not a true MV, nocturnal migraine is unique because of its occurrence during the middle of the night or early morning hours. Its nocturnal occurrence is thought to be related to circadian activation of certain neurotransmitters during sleep, which are known to trigger a migraine attack.
Frequency
United States
Migraine affects nearly 13% of the adult US population, with a postpubertal female-to-male ratio of 4:1. The frequency of the less common MVs varies with type and age. The prevalence of hemiplegic migraine is 0.03%; both familial and sporadic forms are equally frequent. The prevalence of the distinct alternating hemiplegic migraine of infancy is unknown. Similarly, the frequency of ophthalmoplegic, retinal, and confusional migraine is unknown.
Sex
Sex prevalence may be observed in some types of MVs. Basilar migraine and migraine aura without headaches are more common in women than in men. Similarly, hemiplegic migraine is more common in women, with a sex ratio (male-to-female) of 1:3.
Basilar migraine in adults is more common in women than in men.
Benign coital headache has a male-to-female ratio of 4:1.

Age
Specific MVs are observed at a higher incidence in different age groups. Ophthalmoplegic migraine, childhood periodic vomiting, and abdominal migraine are almost exclusively of childhood onset, affecting children younger than 10 years. In contrary, basilar and retinal migraines are more frequent in adolescents and young adults, while migraine aura without headache is mainly encountered in adults with long-standing history of migraine aura in early life. Hemiplegic migraine in its familial and sporadic forms has been reported in all age groups, while alternating hemiplegia of childhood is exclusive to children younger than 18 months.

CLINICAL

History
A detailed headache history is necessary to establish the diagnosis of MVs. As many as 20% of patients with MV may experience prodromal symptoms without subsequent headaches. Such paroxysmal symptoms, with the recurrent attacks of transient neurologic symptoms, whether a headache is absent or present, with a positive family history of migraine, and with a normal neurologic examination interictally are confirmatory.
History of recurrent transient hemiplegia or hemiparesis that occurs during an attack of migraine headache suggests hemiplegic migraine. The hemiparesis may resolve prior to the headache or may persist for days to week.
Migraine aura without headaches is suspected in patients with history of recurrent attacks of unilateral transient monocular blindness in patients with otherwise absent risk factors for other causes of carotid disease and a personal or family history of migraine.
Patients with basilar migraine usually present with symptoms of vertebrobasilar insufficiency, which may precede a headache. The most common symptoms are dizziness and vertigo. Other symptoms, including visual disturbance (usually bilateral), dysarthria, acroparesthesias, tinnitus, confusion, or diplopia, may occur.
Ophthalmoplegic migraine present with diplopia and periorbital pain with or without headache. Other symptoms include alteration of consciousness, acute confusion, recurrent vomiting, or seizures.
Retinal migraine: A history of recurrent attacks of transient monocular visual disturbance or blindness with or without a headache, in the absence of other neurological symptoms is suggestive of retinal migraine.
Cyclic vomiting should be suspected in children presenting with recurrent attacks of vomiting without headache, especially when a family history of migraine is present.
A history of recurrent episodes of vertigo accompanied by other migrainous symptoms such as photophobia, headache, nausea, or vomiting is suggestive of vestibular migraine, predominantly in patients with a personal or family history of migraine.

Physical
The neurologic examination in between attack is nonfocal. Ictally, hemiparesis, ophthalmoplegia, or altered consciousness may be observed. Abnormalities of oculomotor nerve with pupillary involvement are seen in ophthalmoplegic migraine, followed by the abducens, and less commonly trochlear nerve palsy. Children with abdominal migraine or cyclic vomiting may show subtle clumsiness, attention deficit, or development delay. In migrainous infarction, some form of neurologic deficit with abnormal neuroimaging is present. Rarely, when patients with retinal migraine are evaluated and examined during an attack of visual loss, optic pallor or narrowing of the retinal vessels can be seen.

DIFFERENTIALS
Section 4 of 9
Other Problems to be Considered
Cerebral autosomal dominant arteriopathy and subcortical infarcts and leukoencephalopathy (CADASIL) Episodic ataxia Gastrointestinal motility disorders Miller-Fisher syndrome Volvulus
WORKUP

Imaging Studies
Patients with MV usually undergo unnecessary extensive and invasive diagnostic and laboratory evaluations before the diagnosis is made. A careful history of multiple attacks with complete recovery, with a symptom-free period in between attacks, and a family history of migraine or similar disorder is usually helpful in confirming the diagnosis.
Neuroimaging (CT, MRI) is indicated when the patient presents with a first attack of focal neurologic deficits or altered mental status, or when focal findings persist between attacks. Neuroimaging studies are frequently obtained to exclude other acute causes of the symptoms and to exclude migrainous infarction in patients with persistent aura.
Imaging with MRI of the brain and MRA of the circle of Willis is indicated in ophthalmoplegic migraine to exclude posterior fossa or orbital pathologies associated with ophthalmoplegia. Abnormal enhancement on MRI and enlargement of the cisternal portion of the oculomotor nerve, have been reported. Further assessment may include a CT angiogram or lumbar puncture.
The yield for diagnostic testing in basilar migraine is low. Transient abnormalities on CT scan and MRI have been reported during or immediately following attacks. SPECT studies suggest decreased regional cerebral blood flow in the posterior circulation in basilar migraine during attacks, but transcranial Doppler studies have not revealed changes in blood flow velocities.
Invasive testing in children with periodic syndromes with a strong family history of migraine is unnecessary. A high-resolution MRI and magnetic resonance angiography (MRA) are indicated in suspicious cases in the absence of supportive family history.
In retinal migraine, ruling out eye disease or vascular causes, especially when risk factors for arteriosclerosis exist, is important. Carotids Duplex sonography, transcranial Doppler study, MRA, or CT angiography examinations of the brain are helpful. Fluorescein or cerebral angiographies are rarely necessary. Hypercoagulability workup and sedimentation rate may be useful in excluding other coagulation disorders associated with retinal vasculopathy.

Other Tests
EEG is unnecessary in MVs, except in conditions where seizure disorders need to be excluded, such as migraine-triggered seizure, and in patients with recurrent episodes of confusion. EEG generally does not offer additional information in migraineurs. In general, nonspecific interictal EEG abnormalities, including epileptiform activity, are reported in higher frequencies in migraineurs during or immediately after an episode, with slowing in focal or generalized patterns, and occipital spike-wave complexes.
Continuous ambulatory or video EEG may be useful in patients with episodic confusion or recurrent focal neurologic deficits to exclude partial seizures or nonconvulsive status epilepticus.
Genetic testing is now available for familial hemiplegic migraine using polymerase chain reaction to detect point mutations in the CACNA1A and ATP1A2 genes using and DNA sequencing is now available. Genetic testing may also be performed for other conditions associated with migraine such as CADASIL, an autosomal dominant disorder in which patients may present with migraine, multiple subcortical strokes, and dementia in early adulthood.
In children with cyclic vomiting, a serum lactate level is helpful in excluding mitochondrial disorders. Other tests including, upper and lower gastrointestinal series and vagal autonomic function testing, are rarely indicated.
More recently, functional neuroimaging studies during and immediately after an attack of migraine have demonstrated abnormalities of perfusion and have helped in understanding the pathophysiology of auras. Similarly, SPECT might show hypoperfusion during the aura phase.

Medical Care
The first step in treatment is to establish the diagnosis. Once the syndromes are recognized, MVs respond to typical migraine preventive medications.
Treatment is divided into eliminating particular triggers, acute management of the specific attack, and long-term preventive approach. Patients should follow risk factor modifications including smoking cessation, and they should avoid the use of hormonal replacement therapy and birth control pills, all of which could potentially increase the risk of hypercoagulability migraineurs.
In hemiplegic migraine, acute treatment options include antiemetics, nonsteroidal anti-inflammatory drugs, and nonnarcotic pain relievers. Triptans and ergotamine preparations are contraindicated because of their potential vasoconstrictive effects. Prophylactic treatment is generally warranted because of the severity of the attacks. No data are available to support the use of any particular antimigraine agent. Beta-blockers, low-dose tricyclics, anticonvulsants, and calcium channel blockers can be administered. Acetazolamide has been frequently prescribed to patients with hemiplegic migraine, but its benefit in decreasing the frequency or severity of the attacks is questionable. No data support the use of antiplatelet therapy to decrease the risk of stroke.
In ophthalmoplegic migraine, prednisone has been used with mixed results. The data on the benefit of prophylactic therapy with beta-blockers, such as propranolol, are anecdotal.
In retinal migraine, vasoconstrictive agents such as triptans and ergots should be avoided. The use of prophylactic therapy is also anecdotal; when considered, calcium channel blockers are preferred.
In migraine-triggered seizures, antiepileptic agents are drugs of choice because of their dual benefit in migraine prevention and seizure control
In childhood periodic vomiting syndrome, early use of intravenous fluids containing adequate glucose (to prevent a catabolic state) and analgesics may abort the attack. Some patients respond to the triptans or ergotamine classes of medication. Antiemetic drugs are usually not effective, but ondansetron may be more efficacious given its central mechanism of action. Preventive medications such as cyproheptadine and tricyclic antidepressants are preferred in children.
Abdominal migraine symptoms are usually relieved with sleep. Antiemetics may help aborting an acute attack. For chronic prevention, low doses of tricyclic antidepressants and flunarizine, a calcium channel blocker, are effective. Other migraine prevention medications are occasionally of some benefit.
Triptans, ergots, and dihydroergotamine are contraindicated in patients with migrainous infarction. These patients may respond to nonsteroidal anti-inflammatory drugs (NSAIDs), antiemetics, and non-narcotic pain relievers. Prophylactic therapy is recommended, with tricyclics, beta-blockers, calcium channel blockers, or antiepileptic drugs. Long-term antiplatelet therapy is indicated in patients with migrainous infarction.
Patients with vertiginous migraine rarely respond to migraine prophylactic therapy. Anecdotal data are available on the benefit of verapamil, a calcium channel blocker, and amitriptyline, a tricyclic antidepressant, because of their anticholinergic properties, which may help control the vertigo.

Consultations
Consultation with a neuro-ophthalmologist is warranted in patients who present with persistent visual aura, retinal migraine, or recurrent ophthalmoplegia. Children with cyclic vomiting syndrome rarely require an evaluation by a gastroenterologist to exclude other gastrointestinal disorders. An evaluation by an audiologist may be necessary to exclude other vestibulopathies in patients with vertiginous migraine.

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Carbonic anhydrase inhibitors (diuretic)
Carbonic anhydrase (CA) is an enzyme found in many tissues. It catalyzes a reversible reaction whereby carbon dioxide becomes hydrated and carbonic acid dehydrated. These changes may result in a decrease in cerebrospinal fluid by the choroid plexus.
Drug Name
Acetazolamide (Diamox)
Description
For familial hemiplegic migraine. This recommended medication not typically used in migraine, but in hemiplegic MV. Available in 125 mg and 250 mg tab.
Adult Dose
8-30 mg/kg IV/IM divided qid; optimal adult dose 250-1000 mg/dose
Pediatric Dose
5-25 mg/kg IV/IM divided qid
Contraindications
Documented hypersensitivity; hepatic disease; severe renal disease; adrenocortical insufficiency; severe pulmonary obstruction; coadministration with aspirin
Interactions
Can decrease therapeutic levels of lithium and alter excretion of drugs (eg, amphetamines, quinidine, phenobarbital, salicylates) by alkalinizing urine
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Patients with impaired hepatic function may go into coma; may cause substantial increase in blood glucose in some diabetic patients
Drug Category: Antiemetics
These agents typically are used in migraine and MVs, especially when nausea and vomiting are prominent.
Drug Name
Ondansetron (Zofran)
Description
Selective 5-HT3-receptor antagonist that blocks serotonin both peripherally and centrally.
Adult Dose
8 mg PO bid
Pediatric Dose
4-12 years: 4 mg PO tid>12 years: Administer as in adults
Contraindications
Documented hypersensitivity
Interactions
Although potential for cytochrome P-450 inducers (eg, barbiturates, rifampin, carbamazepine, phenytoin) to change half-life and clearance, dosage adjustment not usually required
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
To be administered for prevention of nausea and vomiting, not for rescue of nausea and vomiting
Drug Name
Promethazine (Phenergan)
Description
Used to control symptoms of nausea and vomiting.
Adult Dose
12.5-25 mg PO/IV/IM/PR q6h
Pediatric Dose
<2>2 years: 12.5-25 mg PO/PR q6h prn
Contraindications
Documented hypersensitivity; asthma; children younger than 2 y (incidences of death due to respiratory depression)
Interactions
May have additive effects when used concurrently with other CNS depressants or anticonvulsants; coadministration with epinephrine may cause hypotension
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in cardiovascular disease, impaired liver function, seizures, sleep apnea, asthma, bone marrow depression, compromised respiratory function, stenosing peptic ulcer, seizure disorders, pediatric patients > 2 y
Drug Category: Calcium channel blockers
These agents inhibit calcium ions from entering slow channels, select voltage-sensitive areas, or vascular smooth muscle.
Drug Name
Verapamil (Calan, Calan SR, Covera-HS, Verelan)
Description
Relaxes smooth muscles and increases oxygen delivery during vasospasms. Used for migraine prophylaxis.
Adult Dose
80 mg PO 3-4 times/d
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; severe CHF; sick sinus syndrome or second- or third-degree AV block; hypotension (<90>40 kg: 10 mg PO qd
Contraindications
Documented hypersensitivity; depression; extrapyramidal symptoms
Interactions
Avoid with beta-blockers
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
May cause drowsiness
Drug Category: Antihistamines
These agents prevent histamine response in sensory nerve endings and blood vessels. They are more effective in preventing histamine response than in reversing it.
Drug Name
Cyproheptadine (Periactin)
Description
Occasionally useful for migraine prophylaxis. An antihistamine that has been used for migraine prevention in children more than in adults. Usually well tolerated. Mechanism of action not clarified and hypotheses include antihistaminic and anti-5-HT 2 effects.
Adult Dose
4 mg PO bid/tid; not to exceed 20 mg/d
Pediatric Dose
<2>14 years: Administer as in adults
Contraindications
Documented hypersensitivity; narrow-angle glaucoma; stenosing peptic ulcer; symptomatic prostatic hypertrophy; bladder neck obstruction; pyloroduodenal obstruction; lower respiratory tract symptoms
Interactions
Potentiates effects of CNS depressants; MAOIs may prolong and intensify anticholinergic and sedative effects of antihistamines
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in patients with a predisposition to urinary retention, history of bronchial asthma, increased intraocular pressure, hyperthyroidism, cardiovascular disease, or hypertension; may thicken bronchial secretions caused by anticholinergic properties and may inhibit expectoration and sinus drainage
Drug Category: Tricyclic antidepressants
These agents are used for migraine prophylaxis that is effective independent of antidepressant effect. Mechanism of action is unknown. These agents inhibit activity of such diverse agents as histamine, 5-HT, and acetylcholine.
Drug Name
Amitriptyline (Elavil)
Description
Tricyclic antidepressant used traditionally for migraine prophylaxis. Antimigraine effect is independent from antidepressant effects. Mechanism of action is not clear, but possibly is due to enhanced central serotoninergic and noradrenergic. Cannot be formally recommended for individuals <12>12 years: 10-25 mg PO; titrate up slowly
Contraindications
Documented hypersensitivity; use of MAOIs within 14 d of initiating therapy; history of seizures, cardiac arrhythmias, glaucoma, or urinary retention
Interactions
Phenobarbital may decrease effects; coadministration with CYP2D6 enzyme system inhibitors (eg, cimetidine, quinidine) may increase amitriptyline levels; amitriptyline inhibits hypotensive effects of guanethidine; may interact with thyroid medications, alcohol, CNS depressants, barbiturates, and disulfiram
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in cardiac conduction disturbances and history of hyperthyroidism, renal or hepatic impairment; avoid using in elderly persons
Drug Category: Anticonvulsants
Anticonvulsants, particularly those that interact with the GABAergic system, seem to have a positive effect in reducing migraine attacks. Valproate and gabapentin are most commonly used in this manner.
Drug Name
Topiramate (Topamax)
Description
Indicated for migraine headache prophylaxis. Precise mechanism unknown, but the following properties may contribute to its efficacy: (1) electrophysiological and biochemical evidence showing blockage of voltage-dependent sodium channels, (2) augments the activity of the neurotransmitter GABA at some GABA-A receptor subtypes, (3) antagonizes AMPA/kainate subtype of the glutamate receptor, and (4) inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.
Adult Dose
100 mg/d PO divided bid
Pediatric Dose
<2>2 years: 50 mg/d PO divided bid
Contraindications
Documented hypersensitivity
Interactions
Phenytoin, carbamazepine, and valproic acid can significantly decrease topiramate levels; reduces digoxin and norethindrone levels, when administered concomitantly; concomitant use with carbonic anhydrase inhibitors may increase risk of renal stone formation and should be avoided; extreme caution when administering concurrently with CNS depressants since may have an additive effect in CNS depression as well as other cognitive or neuropsychiatric adverse events
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Risk of developing a kidney stone formation is increased 2-4 times that of untreated population; risk may be reduced by increasing fluid intake; caution in renal or hepatic impairment; patients taking topiramate should seek immediate medical attention if they experience blurred vision or periorbital pain; continued usage after symptoms develop can lead to glaucoma; primary treatment is discontinuation of topiramate; if left untreated, serious sequelae, including permanent vision loss, may occurOligohidrosis and hyperthermia have been reported predominantly in children during vigorous exercise or exposure to warm environmental temperatures (ensure proper hydration prior and during activity and warm temperatures); may cause hyperchloremic, nonanion gap metabolic acidosis or acute or chronic metabolic acidosis resulting in hyperventilation and nonspecific symptoms, such as fatigue and anorexia, or more severe adverse effects including cardiac arrhythmias or stupor; chronic, untreated metabolic acidosis may increase nephrolithiasis or nephrocalcinosis risk, osteomalacia (ie, rickets in pediatric patients), or osteoporosis with an increased risk for bone fractures; chronic metabolic acidosis in pediatric patients may also reduce growth rates; measure baseline and periodic serum bicarbonate
Drug Name
Valproic acid (Depakote, Depakene)
Description
Delayed-release or extended-release dosage forms are used for prophylaxis of migraine headaches. Although mechanism of action is not established, activity may be related to increased brain levels of GABA, or enhanced GABA action.
Adult Dose
Delayed-release: 250 mg PO bid initially; may titrate upward, not to exceed 1000 mg/d divided bidExtended-release: 500 mg PO qd initially; may increase dose, not to exceed 1000 mg/d
Pediatric Dose
<10>10 years: 250 mg PO bid; 1000 mg/d maximum
Contraindications
Documented hypersensitivity; hepatic disease/dysfunction; hyperammonemic encephalopathy and urea cycle disorders
Interactions
Coadministration with cimetidine, salicylates, felbamate, and erythromycin may increase toxicity; rifampin may significantly reduce valproate levels; in pediatric patients, protein binding and metabolism of valproate decrease when taken concomitantly with salicylates; coadministration with carbamazepine may result in variable changes of carbamazepine concentrations with possible loss of seizure control; valproate may increase diazepam and ethosuximide toxicity (monitor closely); valproate may increase phenobarbital and phenytoin levels while either one may decrease valproate levels; valproate may displace warfarin from protein-binding sites (monitor coagulation tests); may increase zidovudine levels in HIV-seropositive patients
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Thrombocytopenia and abnormal coagulation parameters have occurred; risk of thrombocytopenia increases significantly at total trough valproate plasma concentrations >110 mcg/mL in females and >135 mcg/mL in males; at periodic intervals and prior to surgery, determine platelet counts and bleeding time before initiating therapy; reduce dose or discontinue therapy if hemorrhage, bruising, or a hemostasis/coagulation disorder occur; hyperammonemia may occur, resulting in hepatotoxicity; monitor patients closely for appearance of malaise, weakness, facial edema, anorexia, jaundice, and vomiting; may cause drowsiness

In/Out Patient Meds
Acetazolamide
Ondansetron

Patient Education
Benign coital headache: If coital headaches have been a problem for a significant period of time, the patient or couple may need psychological counseling.

TREATING PATIENTS WITH COMPLICATED ADHD

2008-05-22T16:22:00.001+03:00

INTRODUCTION
According to parental surveys, nearly 8% of children in the United States have been diagnosed with attention-deficit/hyperactivity disorder (ADHD) at some point during their childhood. Slightly over half of these children have taken medications for the condition, with boys outnumbering girls at a ratio of more than 2:1. Approximately one third of children with ADHD outgrow the disorder; an estimated 4.4% of adults have ADHD. Significant morbidity and mortality is associated with ADHD in children with the condition, which leads to an increased likelihood of failure in school and an increased chance of use or abuse of illicit substances. The symptoms of ADHD are also associated with numerous other undesirable social and injury-related statistics, such as an increased number of speeding tickets, more vehicular crashes, more license suspensions, and fewer friends.

Countless theories abound regarding the pathogenesis of ADHD, ranging from an association with the genetics of dopamine-mediated neural pathways to the supposition of a cause and effect relationship with extensive television viewing. Family, twin, and adoption data support the theory that ADHD is heritable, with more than twenty different genes having been studied to date. Current pharmacologic treatment strategies, however, base their therapeutic principles on empirical studies of the cerebral spinal fluid (CSF) in affected individuals. Such studies have demonstrated depletions of dopamine and norepinephrine in the nucleus accumbens and locus coeruleus, respectively. Mild cases of ADHD may respond to environmental restructuring and behavioral therapy. Very young children are often treated with these nonpharmacologic therapies before the demands of school become more strenuous.

Stimulants are the first line of treatment and are considered the most effective therapy.1 Stimulant drugs currently in use (eg, methylphenidate [MPH], amphetamine [AMP]) act within the dopaminergic system. The results of the Multimodal Treatment Study of ADHD have suggested a linear relationship between stimulant dose and clinical response, though each patient has his or her own dose-response curve. Additionally, longer-acting formulations of stimulants are now available, such as dextromethylphenidate. These newer, longer-acting stimulants are associated with less diversion for abuse, greater persistence, and reduced stimulant switching.2 Atomoxetine, a norepinephrine reuptake inhibitor, has proven effectiveness and has replaced pemoline for treatment of refractory symptoms. Bupropion or a tricyclic antidepressant can also be added to further treat refractory symptoms in ADHD.3

While evidence that polypharmacy generally offers an advantage over stimulants alone is not available, patients with comorbidities may be helped by the addition of other classes of medication.

ADHD COMPLICATED BY PSYCHIATRIC COMORBIDITIES
ADHD is commonly complicated by several different psychiatric conditions. The discussion to follow reviews 3 psychiatric comorbidities that are common in patients with ADHD and the evidence-based treatments for these conditions when they appear concomitantly with ADHD.

ADHD and aggression
ADHD may be accompanied by aggressive behavior that ranges from stealing or fighting to severe aggressive outbursts. In these cases, ADHD can commonly be associated with anxiety, depression, or both. Aggression is of obvious concern to caregivers and anyone else exposed to the behavior. Aggressive behaviors should be quantified using one of many available rating scales that include instruments for both caregivers and clinicians. Specific different diagnoses may accompany the aggression, such as oppositional defiant disorder or intermittent explosive disorder. Irrespective of the exact categorization of the behavior and diagnosis, the aggressive behavior can be targeted and reduced.

Treatment begins with standard ADHD treatments. Pharmacologically, this means starting with MPH or AMP. After initiation of standard therapy, the aggression should be reassessed. If treatment elicits improvement of the ADHD symptoms but the aggression is unsatisfactorily improved, a behavioral intervention should be carried out next. This intervention should target the aggressive behavior and contributing factors, such as family or social contacts.

If attenuation of the aggression is unsuccessful after the initiation of standard pharmacologic therapy for ADHD and behavioral interventions, or if the aggression is considered a danger to the patient or others, an atypical antipsychotic should be added to the initial stimulant. Of the atypical antipsychotics, risperidone has been studied most often in randomized controlled trials, but any atypical antipsychotic may be tried. The patient and his or her family should be counseled on the risks associated with atypical antipsychotic treatment, such as extrapyramidal symptoms and gastrointestinal adverse effects.4 If the aggression still does not abate with the addition of atypical antipsychotics, a trial of divalproex sodium or lithium is recommended. Some evidence also suggests efficacy of clonidine in treatment of comorbid aggression with ADHD.5

ADHD and anxiety
Comorbidity rates for ADHD and anxiety are estimated at 20-45%. Levy postulates that comorbidity of ADHD and anxiety is related to a deficit in the synaptic gating mechanism between the prefrontal cortex, hippocampus, and amygdala.6 At the level of the nucleus accumbens, this synapse is impaired by decreased prefrontal cortex inhibition, which allows anxiety-related processes greater impact as a result of greater influence by the amygdala. This damaged “gating of anxiety” at the accumbens allows increased amygdala-based fear or anxiety to manifest in some children with ADHD.6

Atomoxetine was initially developed for depression but was observed to be effective in treating ADHD and, as some literature suggests, in treating anxiety. Its adverse effect profile is very similar to that of the stimulants, with the notable exceptions that atomoxetine does not worsen anxiety or reduce growth rates. It is recommended as an alternative initial therapy to address ADHD, especially when associated with anxiety. This recommendation complements previously recommended treatments, specifically therapy that starts with stimulants and adds selective serotonin reuptake inhibitors (SSRIs) for refractory anxiety.

In effect, the treatment of coexisting ADHD and anxiety has 3 optional initial treatment strategies: atomoxetine, stimulants such as MPH or AMP, and nonpharmacologic alternatives. If atomoxetine is used as a first trial with subsequent failure to improve symptoms, stimulants should be tried next. On the other hand, if stimulants are the first class of medications initiated, and the symptoms of ADHD improve but the symptoms of anxiety worsen or do not improve for the patient, an SSRI should be added. If neither ADHD nor anxiety responds to stimulants, atomoxetine should be tried.7 Indeed, these coexisting but separate disorders are just that and must often be treated separately.

ADHD and depression
In treating the patient with both ADHD and major depressive disorder (MDD), whichever disorder is the most severe and impairing should be treated first. Treatment of one of these coexisting disorders often results in improvement in or abatement of symptoms of the other.

The Children’s Medication Algorithm Project consensus conference held in June of 2007 updated recommendations for approaching the patient with coexisting MDD and ADHD. The conference reinforced the notion that the disorder with the most severe symptoms should be treated first. If monotherapy improves symptoms in one category but not the other, the next step in each separate algorithm should be followed.8 For example, if the treatment of MDD results in improvement of depression but not of the symptoms of ADHD, stimulant therapy may be added to antidepressant therapy. If, on the other hand, ADHD treatment is initiated first with stimulants or atomoxetine, and depression does not improve, cognitive behavioral therapy, SSRIs, or both may be added to stimulant treatment.9

The 2 conditions are assessed separately between regimen changes, and treatment is augmented or altered, as needed. For depression, this may mean starting with monotherapy with an SSRI, cognitive behavioral therapy (CBT), or both, followed by a change in SSRI monotherapy, if needed. If only a partial response is elicited, this treatment can be augmented with lithium, bupropion, or mirtazapine. An alternative to augmenting the SSRI is to discontinue the SSRI and instead treat with monotherapy of a drug from a different class (eg, venlafaxine, bupropion, mirtazapine, duloxetine). Evidence-based psychotherapy can be used at any time during treatment; CBT and interpersonal therapy have also demonstrated efficacy in clinical trials.

ADHD and other comorbidities
Several other comorbidities can occur with ADHD. Among these are learning disorders, substance abuse, Tourette syndrome or other tic disorders, sleep and arousal problems, and bipolar disorder.

ADHD and learning disorders
Children with ADHD repeat grades more often, have lower grades, are more often placed in special classes, and need more tutoring than children without ADHD. Conservative estimates of the prevalence of learning disorders among children with ADHD are about 20-25%.10 One randomized placebo-controlled trial suggested that children with learning disabilities tended to respond more poorly to treatment with MPH than did children without learning disabilities (55% vs 75 %). This was mainly because children with mathematics disabilities were particularly unresponsive.11

ADHD and substance abuse
Retrospective and prospective data demonstrate that children with ADHD are at increased risk for substance abuse. Current data suggest that these children become involved with cigarettes, alcohol, and then drugs. In addition, persons with ADHD, regardless of comorbidity, tend to remain addicted longer than peers without ADHD. However, research shows that children who are treated with stimulants for ADHD have lower rates of substance use disorders than those who are untreated.

ADHD and tourette syndrome or other tic disorders
Children with tic disorders frequently have comorbid ADHD. MPH or AMP is an appropriate first-line agent, as most patients do not experience increased tics with these medications. If tics worsen, whichever stimulant was not used initially should be tried sequentially. The addition of an alpha agonist is the next line of treatment. If response is insufficient, an atypical antipsychotic should be tried in its place. Finally, haloperidol or pimozide is added to the stimulant of choice.12

ADHD and sleep or arousal problems
Parental-report studies demonstrate sleep problems in children with ADHD, though numerous objective studies have not indicated consistent concomitant differences in sleep architecture. Many sleep disturbances, such as restless sleep, night awakening, and difficulty with sleep latency, can be attributed to either medication effects or common psychiatric comorbidities. Many other sleep disorders, such as sleep-disordered breathing, restless legs syndrome, periodic limb movement disorder, delayed sleep phase syndrome, and narcolepsy, may also present concomitantly with the symptoms of ADHD. Evidence has linked the same neurotransmitters that regulate sleep and attention or arousal with ADHD; abnormalities in noradrenergic and dopaminergic systems may be found in both ADHD and sleep disorders.13

ADHD and bipolar disorder
Since many features of ADHD and bipolar disorder overlap (eg, distractibility, inattention, impulsivity, hyperactivity), the rate of comorbidity of these two conditions may be overestimated. The misdiagnosis of bipolar disorder as ADHD can lead to inappropriate treatment resulting in mania or rapid cycling.14 In one study, however, in pediatric patients with both established ADHD and bipolar disorder, after the patients’ manic symptoms were controlled with valproic acid, a randomized placebo-controlled trial of AMP was undertaken. The trial demonstrated the combination of these two medications as both safe and effective treatment. Valproic acid alone did not effectively treat the symptoms of ADHD in these patients with concurrent bipolar disorder.15

CONCLUSION
ADHD is a common disorder in childhood, with a significant percentage of patients continuing to experience the symptoms of their ADHD into adulthood. The symptoms of ADHD often coexist with other psychiatric disorders, such as aggression, depression, and anxiety. Evidence-based treatments for these comorbidities are available, including both pharmacologic and nonpharmacologic therapy. In most cases, and especially when the patient has comorbid depression, treatment of the most debilitating condition should begin first. Symptoms should be reassessed at periodic intervals and after each regimen change.

the diagnosis of Traveler's Fever

2008-05-14T12:01:00.000+03:00

This case is an example of malaria caused by Plasmodium falciparum. In the context of the patient's recent travel to Nigeria and presentation with fever, malaria was strongly suspected. The patient's blood smear was notable for 15% parasitemia, most likely P falciparum (as evidenced by the circles within some of the red blood cells [RBCs] in the smear seen in Figure 2). The other laboratory findings, such as the thrombocytopenia and elevated bilirubin, correlated with the disease burden. The elevated creatinine value was also noted, as this finding is sometimes seen in more aggressive cases of the disease; however, this usually resolves with time.

Worldwide, there are about 300-500 million new cases of malaria annually. Malaria is the most deadly vector-borne illness in the world, causing 3.5-5 million deaths annually. On average, 40% of the 50 million people who travel from industrialized to developing countries each year report some illness associated with their travel. Approximately 1,200 cases of malaria are reported each year in the United States among travelers; therefore, it is important to consider malaria as a possible cause of fever in the returning traveler.

Malaria results from an infection caused by any of the following 4 protozoa of the genus Plasmodium: falciparum, vivax, ovale and malariae. Transmission of the parasite occurs via the bite of the Anopheles mosquito. Once the protozoa are injected into the bloodstream, they enter the hepatic cells and reproduce; eventually, the hepatic cells erupt and release more protozoa into the host's circulation. These parasites then remain in the bloodstream, periodically invading erythrocytes, causing hemolysis, and infecting new RBCs.

The incubation period tends to be 9-18 days for P falciparum, P vivax and P ovale, but P malariae has an incubation period of 18-40 days. The most common parasites seen in the US are P falciparum, which is often found in travelers returning from Sub-Saharan Africa, and P vivax, which is found in those returning from Asia, Eastern Europe, and Latin America. The clinical presentation also varies between these 2 parasites: P falciparum often causes symptoms within the first month following the travel period, and it can be fatal; of patients infected with P vivax, 50% have symptoms within 1 month after travel, and approximately 2% of patients may have symptoms 1 year after exposure. The majority of patients infected with either parasite are usually symptomatic within the first 3 months after they return to the US.

The clinical presentation of malaria can vary widely and depends on the species of Plasmodium involved. Common symptoms include fever, malaise, myalgias, and headache, which may be accompanied by cough, abdominal pain, or diarrhea. Since these symptoms are non-specific, malaria should be considered in all febrile travelers, regardless of their clinical presentation. In fact, approximately 78-100% of patients presenting with malaria are febrile when they are first examined. The classically described fever patterns are rarely observed; however, when these fevers do occur at 48- to 72-hour intervals, this finding is virtually pathognomonic for P vivax, P ovale, and P malariae infections. This cyclical pattern of symptoms coincides with the regular interval of erythrocyte hemolysis. On examination, splenomegaly is found in 24-48% of patients, and patients may complain of abdominal pain. Severe malaria, usually caused by P falciparum, causes several manifestations, including prostration, impaired consciousness or coma, respiratory distress caused by pulmonary edema and acute respiratory distress syndrome (ARDS), seizures, circulatory collapse, abnormal bleeding (including disseminated intravascular coagulopathy), splenic rupture, jaundice, severe anemia, acute renal failure, and acidosis. The level of parasitemia often exceeds 5%.

The diagnosis of malaria is made by examination of both thin and thick blood smears. These smears are used to quantify the level of parasitemia, which is used to guide treatment. If the first smear is negative, it should be repeated at 12- to 24-hour intervals for 48-72 hours. If the diagnosis is clinically suspected and a sufficient laboratory diagnosis is not possible, empirical treatment for P falciparum should be started because the disease can be fatal if left untreated. Other laboratory findings, such as normocytic anemia, thrombocytopenia, low WBC count, elevated lactate dehydrogenase, and elevated bilirubin, are nonspecific, but they may provide clues to the diagnosis.

The treatment options for malaria vary according to the region where the traveler was likely to have acquired the infection. This is based on the local prevalence and antimalarial drug susceptibility of particular Plasmodium species. Chloroquine is the treatment of choice for those patients infected with P vivax, P ovale, and P malariae. Patients infected with either P vivax or P ovale must also take primaquine, as these species may lie dormant within the liver and are not eradicated by chloroquine alone. Failure to treat P vivax and P ovale with both agents frequently leads to recrudescence of the disease. If P falciparum has been eliminated as the causative agent, patients may be treated in the ambulatory setting. If P falciparum is suspected, treatment should be initiated as soon as possible, as severe illness or death can occur in as little as 1-2 days after presentation. The CDC recommends hospitalization in order to ensure that patients are able to tolerate oral therapy and have an appropriate response to treatment. For those patients returning from areas where Plasmodium species have known chloroquine resistance, such as Southern Asia, Sub-Saharan Africa, and Oceania, there are 3 available treatment options: (1) oral quinine along with tetracycline, doxycycline, or clindamycin; (2) atovaquone-proguanil; or (3) mefloquine along with doxycycline. Depending on the severity of the disease and the region where the parasite was acquired, different lengths of treatment are recommended; these vary from 3 to 7 days of quinine therapy and 7 days of antibiotics. For those patients with severe malaria, an initial course of doxycycline with quinidine, an intravenous isomer of quinine, is recommended until the parasite burden is <1%, at which point oral therapy should be initiated. Unfortunately, quinine and quinidine have several side effects, and patients must be closely monitored for cardiac dysrhythmias caused by prolongation of the QTc, profound asymptomatic hypoglycemia, and respiratory distress.

In this case, the diagnosis of malaria resulting from P falciparum infection was promptly made based on the patient's travel history and the severity of his symptoms. He was admitted to the pediatric intensive care unit for close observation because of the potentially dangerous side effects of treatment. The patient received a bolus of intravenous quinidine and clindamycin. His parasitemia was <0.5% on the second day of treatment, and the patient was switched to oral quinine therapy and clindamycin. His platelet and creatinine levels improved on hospital day 5, and he was discharged to home on oral therapy for a total of 7 days.

A Traveler’s Fever

2008-05-13T11:53:00.000+03:00

A 17-year-old man presents to the emergency department (ED) complaining of a headache that has lasted for the past 2 days. The patient states that he returned to the United States 2 days ago after spending 3 weeks in Nigeria. According to the patient, he felt well when he initially arrived in the United States, but he developed a severe headache soon after. The headache is constant and throbbing, is lasting throughout the day, and is relieved with ibuprofen. He complains of subjective fevers and intermittent sweats, especially at night, but he has not taken his temperature.

Today, while preparing to board a plane, he developed a worsening headache, bilious emesis, palpitations, and sweats. He decided to delay his trip and is now presenting to the local ED for further evaluation. The patient denies having any trauma, seizures, abdominal pain, stiff neck, or photophobia. He has no significant past medical history, and his only medication use is the ibuprofen that he has taken over the past 2 days.

On physical examination, his temperature is 103.0° F (39.4° C), his pulse is 83 bpm, his blood pressure is 120/70 mm Hg, his respiratory rate is 16 breaths/min, and his oxygen saturation is 96% while breathing room air. The patient is generally well-appearing, alert, and oriented. The examination of the head, eyes, and pupils is unremarkable. The neck is supple, without any lymphadenopathy. On auscultation, the lungs are clear; additionally, the patient's heart has a regular rate and rhythm, without any murmurs. The examination of the abdomen reveals normal bowel sounds, with mild tenderness to palpation in the right and left upper quadrants. The spleen is noted to be 3 cm below the costal margin. The neurologic examination is unremarkable.

The patient is treated with intravenous fluids. An electrocardiogram (ECG) shows a normal sinus rhythm, with a QTc of 390 msec. Serum laboratory tests are done, and they are significant for the following values: creatinine, 1.2 mg/dL (106.08 µmol/L); magnesium, 1.2 mg/dL (0.49 mmol/L); alanine aminotransferase (ALT), 110 U/L (normal range 0-35 U/L); aspartate aminotransferase (AST), 159 U/L (normal range 0-35 U/L); total bilirubin, 2.7 mg/dL (46.17 μmol/L) (normal range <1.20 mg/dL); direct bilirubin, 0.9 mg/dL (15.39 μmol/L) (normal range <0.20 mg/dL); and alkaline phosphatase, 152 U/L (normal range 30-130 U/L). A complete blood count (CBC) reveals a white blood cell (WBC) count of 5.7 × 103/µL (5.7 × 109/L), a hematocrit of 44 % (0.44), and platelets of 34 × 103/µL (34 × 109/L). A blood smear is obtained

What is the Diagnosis??? Check tomorrow for the answer and you might as well want to leave your answer..