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Saturday, 31 May 2008

Colon Cancer, Adenocarcinoma

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.

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Friday, 30 May 2008

Corpus Luteum Rupture

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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Thursday, 29 May 2008

Social Phobia and Selective Mutism

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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Wednesday, 28 May 2008

Achilles Tendon Rupture

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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Tuesday, 27 May 2008

Atrial Fibrillation

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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Monday, 26 May 2008

Suprapubic Aspiration

Suprapubic aspiration and catheterization is an easily performed emergency department procedure that is associated with minimal complications. Huze and Beeson1 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

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?

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

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).

Saturday, 24 May 2008

Headache, Migraine

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].
Thomas SH, Stone CK. Emergency department treatment of migraine, tension, and mixed-type headache. J Emerg Med. Sep-Oct 1994;12(5):657-64. [Medline].
Thomas SH, Stone CK, Ray VG, et al. Intravenous versus rectal prochlorperazine in the treatment of benign vascular or tension headache: a randomized, prospective, double-blind trial. Ann Emerg Med. Nov 1994;24(5):923-7. [Medline].
Headache, Migraine excerpt
Article Last Updated: Jan 3, 2008

Friday, 23 May 2008

Migraine Variants

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.

Grey Matter - from the writers of Grey's Anatomy