#Acute and Chronic Leukemia: What Are the Differences?

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Acute and Chronic Leukemia: What Are the Differences?

Resultado de imagem para leukemia


Leukemia is a cancer of the blood. It forms when blood cells in the bone marrow malfunction and form cancerous cells. The cancerous blood cells then overrun the normal blood cells. This interferes with the body’s ability to fight infections, control bleeding, and deliver oxygen to normal cells. The cancerous cells can also invade the spleen, liver, and other organs.


Chronic leukemia is a slow-growing leukemia. Acute leukemia is a fast-growing leukemia that progresses quickly without treatment.

Signs and symptoms

Signs and symptoms of chronic leukemia

Chronic leukemia develops slowly, and the early symptoms may be mild and go unnoticed. Acute leukemia develops quickly. This is because the cancerous cells multiply fast.

Chronic leukemia is most commonly diagnosed after a routine blood test. You may have low-level symptoms for years before it’s diagnosed. The symptoms may be vague and could occur due to many other medical conditions. The signs and symptoms may include:

general feelings of malaise, such as tiredness, bone and joint pain, or shortness of breath
weight loss
a loss of appetite
a fever
night sweats
bruising or bleeding, such as nosebleeds
enlarged lymph nodes that aren’t painful
pain or a full feeling in the upper-left abdomen, which is where the spleen is located
Signs and symptoms of acute leukemia

The common signs and symptoms of acute leukemia are:

low white blood cell counts
tiredness that doesn’t go away with rest
shortness of breath
pale skin
sweating at night
a slight fever
bruising easily
bone and joint aches
slow healing of cuts
tiny red dots under the skin

No one knows the cause of leukemia or why some people have chronic leukemia and others have an acute form of the condition. Both environmental and genetic factors are thought to be involved.

Leukemia may occur due to changes in the DNA of your cells. Chronic myeloid leukemia (CML) may also be associated with a gene mutation called the Philadelphia chromosome. This gene mutation isn’t inherited.

Some studies show that a combination of genetic and environmental factors are involved in childhood leukemia. Some children may not have inherited the particular version of genes that can get rid of harmful chemicals. Exposure to those chemicals might increase their risk for leukemia.

Risk factors

Possible risk factors for the different types of leukemia exist, but it’s possible to get leukemia even if you don’t have any of the known risk factors. Experts still don’t understand a lot about leukemia.

Some factors for developing chronic leukemia include:

being over age 60
being Caucasian
exposure to chemicals such as benzene or Agent Orange
exposure to high levels of radiation
Some risk factors for developing acute leukemia include:

smoking cigarettes
having chemotherapy and radiation therapy for other cancers
exposure to very high radiation levels
having genetic abnormalities, such as Down syndrome
having a sibling with acute lymphocytic leukemia (ALL)
Having one or more of these risk factors doesn’t mean that you’ll get leukemia.

How is leukemia diagnosed?

All types of leukemia are diagnosed by examining blood samples and bone marrow. A complete blood count will show the levels and types of:

white cells
leukemia cells
red cells
Bone marrow and other tests will give your doctor further information about your blood to confirm a diagnosis of leukemia. Your doctor may also look at a blood smear under a microscope to see the shape of the cells. Other tests may grow your blood cells to help your doctor identify changes to the chromosomes or genes.


Your treatment plan will depend on the type of leukemia you have and how advanced it is at the time of your diagnosis. You may want to get a second opinion before starting treatment. It’s important to understand what your treatment choices are and what you can expect.

Chronic leukemia

Chronic leukemia progresses slowly. You may not be diagnosed until symptoms, such as enlarged lymph nodes, appear. Chemotherapy, corticosteroids, and monoclonal antibodies may be used to control the cancer. Your doctor may use blood transfusions and platelet transfusions to treat the decrease in red blood cells and platelets. Radiation may help reduce the size of your lymph nodes.

If you have CML and also have the Philadelphia chromosome, your doctor may treat you with tyrosine kinase inhibitors (TKIs). TKIs block the protein produced by the Philadelphia chromosome. They may also use stem cell therapy to replace cancerous bone marrow with healthy bone marrow.

Acute leukemia

People with acute leukemia will generally begin treatment quickly following a diagnosis. This is because the cancer can progress quickly. Treatment may include chemotherapy, targeted therapy, or stem cell therapy, depending on the type of acute leukemia you have.

The treatment for acute leukemia is generally very intense in the beginning. The main goal of treatment is to kill the leukemia cells. Hospitalization is sometimes necessary. The treatment often causes side effects.

Your doctor will do regular blood and bone marrow tests to determine how well your treatment is killing the leukemia cells. They may try various mixtures of drugs to see what works best.

Once your blood has returned to normal, your leukemia will be in remission. Your doctor will continue to test you in case the cancerous cells return.

What is the outlook?

Each type of leukemia is different and will require different treatment. The outlook is also unique to the type of leukemia you have and how advanced it is when you begin treatment. Other factors that will affect your outlook are:

your age
your general health
how much the leukemia has spread in your body
how well you respond to treatment
Survival rates for leukemia have greatly improved in the last 50 years. New drugs and new types of treatments continue to be developed.

Your doctor will give you your outlook based on leukemia research findings from the past years. These statistics are based on people who had your type of leukemia, but each person is different. Try not to focus too much on these types of statistics if you receive a diagnosis of leukemia. Your outlook will depend on your age, your overall health, and the stage of your leukemia. The following were the five-year survival rates for people with different types of leukemia in the United States from 2005 to 2011:

CML: 63.2 percent
CLL: 84.8 percent
ALL: 70.1 percent overall and 91.2 percent for those under 15
AML, or acute myeloid leukemia: 26 percent overall and 66.5 percent for those under 15
The outlook for people with any type of leukemia will continue to improve as the research advances. Researchers in many ongoing clinical trials are testing new treatments for each type of leukemia.


No early screening tests for leukemia are available. If you have risk factors and symptoms, ask your doctor about blood tests.

It’s important to keep copies of your treatments, the dates, and the drugs that were used. These will help you and your future doctors if your cancer comes back.

Experts haven’t found ways to prevent leukemia. Being proactive and telling your doctor if you notice any symptoms of leukemia may improve your chances of recovery.



#Chronic Alcohol Abuse: Complications and Consequences

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Image from Wikimedia Commons | Ed Uthman, MD.
The above image demonstrates hepatocellular carcinoma (HCC) on top, with a fibrous reaction sandwiched between that and cirrhotic liver on the bottom. Patients with viral hepatitis who abuse alcohol significantly increase their risk for cirrhosis and ensuing HCC.
Alcoholism is a common substance-abuse disorder that leads to significant medical complications. Alcohol affects virtually every organ system, and alcoholics are at increased risk for cirrhosis, gastrointestinal (GI) bleeding, pancreatitis, cardiomyopathy, trauma, mental health disorders, and a wide variety of cancers. Patients frequently have very poor insight into their addiction—a state commonly referred to as denial—and must be made aware of the numerous devastating short- and long-term complications of alcohol abuse.

Liver Disease and Associated Complications
Alcohol abuse is the second most common cause of cirrhosis in the United States, after hepatitis C. [1] Damage to the liver parenchyma from alcohol leads to progressive fibrosis, producing a nodular contour to the liver (white arrows). The subsequent increased resistance to portal blood flow induces portal hypertension, which may cause splenomegaly (yellow arrow), transudative ascites (red arrow), and varices. The computed tomography (CT) image shown here demonstrates very prominent esophageal varices (green arrow). Specialized multiphasic, contrast-enhanced CT and magnetic resonance (MR) protocols can be used in patients suspected of liver disease. [2]

A 60-year-old woman presents for a new patient evaluation. She has been suffering from depression after the loss of her husband a year ago. She admits to drinking approximately 60 g of alcohol daily. She has recently undergone an abdominal CT scan, seen here, in the course of a visit to the emergency department (ED) for pain.
On review of her CT scan, which of the following changes do you suspect to be present secondary to her alcohol use?
None; study is normal
Alcoholic hepatic steatosis
Alcoholic hepatitis
Alcoholic cirrhosis

Image courtesy of Lars Grimm, MD.
Answer: B. Alcoholic hepatic steatosis.
Ingestion of more than 60 g of alcohol daily causes morphologic changes to the liver. The first such change is fatty replacement of the liver, or hepatic steatosis. Alcoholic fatty liver is believed to be due to an increase in fatty acids and glycerol 3-phosphate. [3] With regard to diagnostic imaging, the liver will appear to be lower in attenuation (ie, darker) than the spleen on CT scans (see the previous slide), to be more echogenic (ie, brighter) (red arrow) than the kidney (blue arrow) on ultrasonography (US), and to lose signal on out-of-phase sequences on magnetic resonance imaging (MRI). MRI, in particular, is an excellent means of also evaluating for subsequent complications such as portal hypertension, ascites, and HCC. [4] Hepatic steatosis is reversible, but if ingestion of alcohol is not decreased, alcoholic hepatitis will develop, followed by alcoholic cirrhosis.

The images seen here demonstrate prominent esophageal varices visible on upper GI endoscopy, with some punctate areas of active hemorrhage (arrows).
Varices develop secondary to cirrhosis, which changes the pressure and flow gradients of the vasculature. The classic locations for cirrhotic varices are the esophagus, rectum, stomach, and abdominal wall. [5] As varices grow in size, the risk of rupture and hemorrhage increases dramatically. The cherry red spots in the above images are suggestive of recent or impending hemorrhage (with variceal bleeding in the esophagus potentially proving fatal). Patients who have bled from esophageal varices have a 70% chance of rebleeding.

Esophageal Damage
A 50-year-old man who has a long-standing history of alcohol abuse with known esophageal varices (red arrow) diagnosed on recent esophagography presents to the ED with hematemesis. His friend reports that the man was drinking heavily earlier in the day and started vomiting about 1 hour ago. The patient’s initial vital signs show a heart rate of 90 beats/min, a blood pressure of 115/73 mm Hg, and a normal respiratory rate. While sitting in the waiting room, he has filled two cups with reddish fluid.
After intravenous (IV) administration of fluids has been initiated, which of the following is the most appropriate next step in management?
Watchful waiting
Repeat esophagography
CT scan of the chest, abdomen, and pelvis
GI consult for endoscopy
Interventional radiology consult for angiography

Answer: D. GI consult for endoscopy.
The patient presents with a history that suggests either a bleeding esophageal varix or a Mallory-Weiss tear, both of which can be diagnosed and managed by means of endoscopy. Mallory-Weiss tears are longitudinal mucosal lacerations at the gastroesophageal junction or gastric cardia that develop from a sudden rise in intragastric pressure. The classic scenario is that of a patient with protracted vomiting after alcoholic binge drinking who then develops hematemesis. Although some patients can be managed conservatively, hemodynamic instability and shock may develop in as many as 10% of cases. Endoscopy can usually identify the mucosal defect, especially if there is active bleeding (shown), and treatment can be directly initiated. Evidence suggests that rebleeding rates are significantly lower with Doppler probe–guided hemostasis than with standard, visually guided hemostasis. [6] In some cases, surgery or angiotherapy is required to stop the bleeding. [7]

Hepatocellular Carcinoma
The CT scan seen here demonstrates a large multifocal HCC (arrows) in an 80-year-old man.
HCC is one of the most common causes of cancer-related death worldwide. Life expectancy after diagnosis is generally in the range of 6-20 months. Roughly 30% of HCCs are due to excessive alcohol use; such abuse results in the development of reactive oxygen species, which leads to DNA damage. [8] In patients with 10 years of chronic alcohol use, the HCC risk is increased fivefold. HCC usually takes many years to develop after the initial insult, but when it is discovered, it is multifocal within the liver 75% of the time. Curative therapy is possible, but success is rare, being achieved in fewer than 5% of patients. However, multiple new treatment options are now available for patients with unresectable HCC, including transarterial chemoembolization, drug-eluting embolization, and radioembolization. [9] Unfortunately, no consistently effective and cost-efficient screening programs are available.

Esophageal Cancer
The gross pathology image above demonstrates non-neoplastic esophagus on the far right, non-neoplastic rugal folds of the stomach on the far left, and an esophageal cancer with associated Barret metaplasia (circled).
Like tobacco use, the use of alcohol is one of the leading causes of esophageal cancer in the United States. [10] Among patients who drink more than 30 g of ethanol daily, the risk ratio for squamous cell carcinoma is 4.61 in comparison with abstainers; there is no increased risk for adenocarcinoma. Interestingly, some variations in the alcohol dehydrogenase gene, which facilitates the enzymatic breakdown of alcohol, may be protective. [11]
Dysphagia with solids and eventually with liquids is the most common presenting symptom of esophageal cancer. Endoscopy allows direct visualization and tissue biopsy. Direct surgical excision is the best option for curative therapy; nonoperative treatment is reserved for palliation of dysphagia. The overall 5-year survival rate for all stages of esophageal cancer is approximately 25%; the survival rate for late-stage cancer is less than 5%. [12,13] Esophageal cancer represents 1% of all new cancer diagnoses but 2.6% of all cancer deaths, according to the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. [14]

The above brain CT scan demonstrates two areas of intracerebral hemorrhage in the right lentiform nucleus.
Stroke is the fifth leading cause of death in the United States, as well as a major source of disability in adults. [15,16] Although low to moderate alcohol use is associated with a reduced risk of stroke, heavy alcohol use, either chronic or irregular, significantly increases the risk of both ischemic and hemorrhagic stroke. [17,18] In addition to the increased risk of head trauma in alcohol abusers, alcohol has an anticoagulant effect. Although this effect may be protective at lower levels of alcohol consumption, it is thought to be partly responsible for the increased risk of hemorrhagic stroke at higher levels of consumption.

Alcohol abuse is the second most common cause of acute pancreatitis, after gallstones; with regard to alcohol-associated hepatic or pancreatic complications, the most common discharge diagnosis is alcoholic pancreatitis. [19] Pancreatitis may develop either from an isolated episode of binge drinking or from habitual abuse. Injury to the pancreatic acinar cells creates an inflammatory cascade, leading to significant damage to the pancreas. A number of classic physical examination findings have been described in acute pancreatitis, including the Cullen sign, which is periumbilical discoloration from hemoperitoneum (shown), and the Grey-Turner sign, which is discoloration of the flanks from retroperitoneal hemorrhage. The most serious complications are pancreatic necrosis, pseudocyst, and infection of inflammatory fluid collections.

The CT scan seen here demonstrates extensive calcification of the pancreas (red arrow) and a large pancreatic pseudocyst (black arrow).
In chronic pancreatitis, progressive pancreatic damage results in damage to exocrine and endocrine function. Alcoholism is associated with 70% of cases of chronic pancreatitis. The most common manifestation is chronic calcifying pancreatitis, in which precipitation of proteinaceous material in the pancreatic ducts forms plugs that calcify. Acute or chronic pancreatitis flares are common and may not be associated with significant elevation in pancreatic enzymes. The main symptom of chronic pancreatitis is pain, but the exact mechanism behind the pain is poorly understood, and there are multiple neurobiologic theories. [20] Pseudocyst formation is the most common complication and may lead to an intestinal obstruction, an abscess, a pseudoaneurysm, or a fistula. The 10-year mortality rate in patients with chronic pancreatitis is 30%. [21]

Pancreatic Cancer
A 70-year-old man with a long-standing history of alcohol abuse presents with painless jaundice, malaise, and weight loss. You order a CT scan of the abdomen, which reveals a mass in the head of the pancreas (red arrow), presumably representing a pancreatic adenocarcinoma. The patient asks you if the cancer is treatable.
Which of the following is the most important factor influencing this patient’s survival?
Degree of pancreatic dilation
Invasion of the superior mesenteric vein
Invasion of the celiac artery

Answer: C. Invasion of the celiac artery.
Pancreatic cancer is a frequently occult malignancy; in half of patients, the disease is already significantly advanced when first detected. Chronic inflammation is a major predisposing factor, and patients with chronic pancreatitis from alcohol abuse have a higher incidence of pancreatic cancer and an earlier age of onset. [22] The classic presentation is painless jaundice from a pancreatic head mass. A gross pathology image of adenocarcinoma resected from the body and tail of the pancreas is shown here. Surgical excision offers the best chance of cure, but recurrence is very common. [23] Newer surgical techniques may allow resection of the superior mesenteric or portal veins, but involvement of the arterial system is an absolute contraindication to surgical treatment. The 1-year survival rate is 24%, and the 5-year survival rate is only 5%. Pancreatic cancer is responsible for 3% of all new cancer cases and 7% of all cancer deaths in the United States, according to the SEER Program. [24]

Cardiac Disease
Although low to moderate alcohol intake can provide cardiovascular protection, higher levels of alcohol use for an extended period induces a number of pathologic changes in the heart. [25] Alcohol’s toxic effects directly weaken heart muscle; alcohol also increases blood pressure, oxidative stress, and the risk of thrombosis, while negatively impacting the conductive system (resulting in arrhythmias). [17] The classic manifestation of chronic alcohol use is heart failure from dilated cardiomyopathy. Dilated cardiomyopathy represents an irreversible process in which the ventricular wall thickness remains normal but the ventricular chambers become enlarged, giving the appearance of thinned walls (shown). Patients have subsequent systolic dysfunction and are at risk for arrhythmias, thromboembolism, and sudden death.
Holiday heart syndrome refers to the development of rhythm disturbances after alcohol use in patients without structural heart disease. [26] Atrial fibrillation is the most common disturbance, and most cases are self-limiting.

Brugada syndrome, a genetic disease with an autosomal dominant inheritance, is a cardiac channelopathy that places patients at risk for sudden death. Electrocardiographic (ECG) tracings will reveal an incomplete right bundle branch block with one of three patterns of ST elevation in the anterior precordial leads (shown). Alcohol is a known trigger for Brugada syndrome that can unmask or exacerbate the ECG changes. [27] Patients may develop ventricular tachyarrhythmias, leading to syncope, cardiac arrest, or sudden cardiac death. Brugada syndrome is thought to be responsible for 20% of sudden deaths in patients with structurally normal hearts.

Immune Suppression
The above autopsy image reveals the brain of a person with alcoholism who died of pneumococcal meningitis.
Chronic alcohol abuse suppresses the immune system. Indeed, although many clinicians believe that lower levels of alcohol are immunoprotective, higher levels have a clear deleterious effect. The chemotactic ability of neutrophils becomes impaired, leading to poor response to injury and infection. Studies have shown that alcoholics with bacterial meningitis have a higher incidence of complications. [28] Tumor surveillance is also inhibited in alcohol abuse, suppressing the ability of the body to detect and attack aberrant cells. The mechanism by which chronic alcohol consumption increases cancer risk is poorly understood and is an active area of study. [29]

Fetal Alcohol Syndrome
A 35-year-old woman presents to the clinic with her husband after discovering that she is pregnant. She does not know when her last menstrual period was, but US confirms a gestational sac (blue arrow) with yolk sac (red arrow). Your triage nurse determines that the patient has been drinking alcohol, sometimes to excess. The patient and her husband are concerned about complications to the pregnancy. You advise them that maternal alcohol consumption can be associated with fetal alcohol syndrome (FAS).
During which period of pregnancy does maternal alcohol consumption pose an especially high risk of FAS?
First trimester
Second trimester
Third trimester
Postdates (postterm)
None of the above; the effect is equivalent throughout pregnancy

Answer: A. First trimester.
FAS is caused by maternal consumption of alcohol during pregnancy, especially in the first trimester. Alcohol moves unimpeded between the fetal and maternal bloodstreams. The incidence of FAS in some parts of the United States has been estimated to be 0.2-1.5 cases per 1000 live births, although prevalence estimates vary among studies. [30]
A formal diagnosis is made on the basis of characteristic craniofacial anomalies, growth retardation, and central nervous system involvement, including cognitive impairment, learning disabilities, and behavioral abnormalities. A smooth philtrum, a thin upper lip, and short palpebral fissures are typical features; midface hypoplasia, microphthalmia, strabismus, and ptosis may also occur but are less common. FAS is associated with mental retardation and seizures.

Neurologic Disorders
The coronal brain scans shown here demonstrate, in a 60-year-old man with alcoholism, thinning of the corpus callosum and enlargement of the ventricles (on MRI), as well as reduced delineation of the white matter tracts (on diffusion tensor imaging [DTI]).
Alcohol-related brain damage can be induced by a number of factors, including alcohol’s direct neurotoxic effects, as well as those of the alcohol metabolite acetaldehyde. Alcohol abuse–associated thiamine deficiency, cerebrovascular disease, hepatic encephalopathy, and head trauma can also result in brain damage. [31]
Thiamine deficiency in chronic alcohol abuse can lead to Wernicke encephalopathy, which is characterized by ataxia, ophthalmoplegia, and confusion. Another neurologic complication, Korsakoff syndrome, which is often preceded by Wernicke encephalopathy, causes anterograde and retrograde amnesia, frequently accompanied by confabulation. [32]
In Marchiafava-Bignami disease (MBD), a rare condition that is also seen in cases of chronic alcoholism, demyelination of the corpus callosum occurs. [33] Emotional and psychotic symptoms may present initially, as may decreased consciousness, depression, apathy, aggression, hemiparesis, ataxia, apraxia, and seizures. The acute form can quickly lead to death. The subacute form is characterized by several signs and symptoms, including confusion, behavioral abnormalities, and memory deficits, while the chronic form gives rise to mild dementia (which can be progressive). [34]

This French poster, from the turn of the 20th century, shows a man on his deathbed, suffering from delirium tremens (DTs). The subheading, “L’alcool tue,” means “alcohol kills.”
DTs is a severe form of alcohol withdrawal that can occur in chronic alcohol abuse. It results, when alcohol use has ceased, from the loss of inhibitory regulation of excitatory neurotransmitters and neuroreceptors. This loss can lead to tremors, diaphoresis, tachycardia, anxiety, delirium, and seizures. [35]

#How to Diagnose Aortic Dissection Without Breaking the Bank

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By Anton Helman | on November 13, 2017

Living Art Enterprises / Science Source

Living Art Enterprises / Science Source
It used to be said that missing the clinical diagnosis of aortic dissection was “the standard” as it is rare and often presents atypically. The diagnosis rate of aortic dissection changed with the landmark International Registry of Acute Aortic Dissection (IRAD) study in 2000, which deepened our understanding of the presentation.1 Nonetheless, aortic dissection remains difficult to diagnose, with one in six missed at the initial ED visit.

Herein lies the difficulty. Aortic dissection must be considered in all patients with chest, abdominal, or back pain; syncope; or stroke symptoms. Yet, we shouldn’t be working up every one of them, creating a resource utilization disaster. However, early, timely diagnosis is essential because each hour that passes from the onset of symptoms correlates with a 1 percent to 2 percent increase in mortality.

In this column, I’ll elucidate how to improve your diagnosis rate, without overimaging, by explaining five pain pearls, the concepts of “CP +1” and “1+ CP,” physical exam nuances, and how best to initially utilize tests.

The Five Pain Pearls of Aortic Dissection

Ask the following three things of all patients with torso pain:
What is the quality of pain? (The pain from aortic dissection is most commonly described as “sharp,” but the highest positive likelihood ratio [+LR] is for “tearing.”)
What was the pain intensity at onset? (It is abrupt in aortic dissection.)
What is the radiation of pain? (It is in the back and/or abdomen in aortic dissection.)
A 1998 study that reviewed a series of aortic dissection cases showed that for the 42 percent of physicians who asked about these three things, the diagnosis was suspected in 91 percent. When fewer than three questions were asked, dissection was suspected in only 49 percent.2

Think of aortic dissection as the subarachnoid hemorrhage of the torso. Just like a patient who presents with a new-onset, severe, abrupt headache should be suspected of having a subarachnoid hemorrhage, if a patient describes a truly abrupt onset of severe torso pain with maximal intensity at onset, think aortic dissection.
If you find yourself treating your chest pain patient with IV opioids to control severe colicky pain, think about aortic dissection.
Migrating pain has a +LR of 7.6.1 In addition to the old adage, “Pain above and below the diaphragm should heighten your suspicion for aortic dissection,” severe pain that progresses and moves in the same vector as the aorta significantly increases the likelihood of aortic dissection.
The pain can be intermittent as dissection of the aortic intima stops and starts. The combination of severe migrating and intermittent pain should raise the suspicion for aortic dissection.
Painless Aortic Dissection

While IRAD reported a painless aortic dissection rate of about 5 percent, a more recent study out of Japan reported that 17 percent of aortic dissection patients had no pain.3 These patients presented more frequently with a persistent disturbance of consciousness, syncope, or a focal neurological deficit. Cardiac tamponade was more frequent in the pain-free group as well.

The Concepts of “CP +1” and “1+ CP”

The intimal tear in the aorta can devascularize any organ from head to toe, including the brain, heart, kidneys, and spinal cord. Thus, 5 percent of dissections present as strokes, and these certainly are not the kind of stroke patients who should be receiving tPA! An objective focal neurologic deficit in the setting of acute, unexplained chest pain (CP) has +LR of 33 for aortic dissection, almost diagnostic. Some of the CP +1 phenomena to think about include torso pain, cerebrovascular accident, paralysis, hoarseness (recurrent laryngeal nerve), and limb ischemia.

These three coronal reconstructions from contrast enhanced CT angiograms of the chest show an extensive dissection of the thoracic aorta. This is a De Bakey type I or Standord A aortic dissection.

(click for larger image) These three coronal reconstructions from contrast enhanced CT angiograms of the chest show an extensive dissection of the thoracic aorta. This is a De Bakey type I or Standord A aortic dissection.
Source: Living Art Enterprises / Science Source
In addition to thinking of CP +1, it may help to think backwards in time (1+ CP) and ask patients who present with end-organ damage if they had torso pain prior to their symptoms of end organ damage. For example, ask patients who present with stroke symptoms if they had torso pain before the stroke symptoms.

Anyone under the age of 40 years who presents to the emergency department with unexplained torso pain should be asked if they have Marfan syndrome. In the IRAD analysis of those under 40 years, 50 percent of the aortic dissection patients had Marfan syndrome, representing 5 percent of all dissections.1

Look. The patient doesn’t always know they have Marfan syndrome, so you need to look for arachnodactyly (elongated fingers), pectus excavatum (sternal excavation), and lanky limbs.
Listen. A new aortic regurgitation murmur has a surprisingly high +LR of 5.
Feel. Feel for a pulse deficit, which has a +LR of 2.7, much higher than that of interarm blood pressure differences.
The patient’s blood pressure needs to be interpreted with caution and insight. Do not assume that the patient with a normal or low blood pressure does not have an aortic dissection. We know from the IRAD data that only about half of patients are hypertensive at initial presentation. Patients with aortic dissections that progress into the pericardium, resulting in cardiac tamponade, are often hypotensive. Patients with dissection who have a wide pulse pressure should be considered preterminal and usually require immediate surgery.

There is a lot more to chest radiograph interpretation for suspected aortic dissection than looking for a wide mediastinum. One-third of chest radiographs in aortic dissection are normal to the untrained eye, and a common pitfall is to assume that if the chest X-ray is normal, the patient does not have an aortic dissection. There are about a dozen X-ray findings associated with dissection, but two of them are especially important: loss of the aortic knob/aortopulmonary window and the calcium sign.

Look for a white line of calcium within the aortic knob, then measure the distance from there to the outer edge of the aortic knob. A distance >0.5 cm is considered a positive calcium sign, and a distance >1.0 cm is considered highly suspicious for aortic dissection. It is always wise to compare to an old film to see if there’s been an interval change.

Eighteen percent of patients with aortic dissection will have a positive troponin test, so if you suspect the diagnosis based on other clinical findings, don’t assume isolated acute coronary syndrome when the troponin comes back positive.5 Remember that fewer than one in 100 patients with a dissection will have associated coronary ischemia in any coronary distribution (most commonly inferior).

While D-dimer seems like it might be appealing to help rule out the diagnosis in low-risk patients, for such a rare diagnosis and poor test characteristics of D-dimer for dissection, guidelines do not recommend the use of D-dimer for the workup of aortic dissection.6

Aortic dissection can be considered the retinal detachment of the torso. While the sensitivity of point-of-care ultrasound (POCUS) by emergency physicians to detect an intimal flap is only 67 percent, the specificity has been shown to be 99 percent to 100 percent.7 For patients suspected of the diagnosis, look for an intimal flap that looks similar to a retinal detachment on POCUS and look for a pericardial effusion indicative of a retrograde dissection into the pericardium.8

Take-Home Points

Remember the big pain pearls when taking a history:
Ask the three important questions.
Aortic dissection should be considered the subarachnoid hemorrhage of the torso.
Migrating pain, colicky pain, plus need for IV opioids should raise your suspicion.
Intermittent pain can still be a dissection.
Look for Marfan syndrome, listen for an aortic regurgitation murmur, and feel for a pulse deficit.
Think not only about CP +1 but also 1+ CP.
Know the radiographic findings of loss or aortic knob/aortopulmonary window and the calcium sign, and use POCUS to look for an intimal flap and pericardial effusion.
Don’t be misled by a troponin or D-dimer.
Thanks to David Carr for his expert contributions to the EM Cases podcast that inspired this article.



Hagan PG, Nienaber CA, Isselbacher EM, et al. The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease. JAMA. 2000;283(7):897-903.
Rosman HS, Patel S, Borzak S, et al. Quality of history taking in patients with aortic dissection. Chest. 1998;114(3):793-795.
Imamura H, Sekiguchi Y, Iwashita T, et al. Painless acute aortic dissection: diagnostic, prognostic and clinical implications. Circ J. 2011;75(1):59-66.
Singer AJ, Hollander JE. Blood pressure: assessment of interarm differences. Arch Intern Med. 1996;156(17):2005-2008.
Leitman IM, Suzuki K, Wengrofsky AJ, et al. Early recognition of acute thoracic aortic dissection and aneurysm. World J Emerg Surg. 2013;8(1):47.
Diercks DB, Promes SB, Schuur JD, et al. Clinical policy: critical issues in the evaluation and management of adult patients with suspected acute nontraumatic thoracic aortic dissection. Ann Emerg Med. 2015;65(1):32-42.
Sobczyk D, Nycz K. Feasibility and accuracy of bedside transthoracic echocardiography in diagnosis of acute proximal aortic dissection. Cardiovasc Ultrasound. 2015;13:15.
Fojtik JP, Constantino TG, Dean AJ. The diagnosis of aortic dissection by emergency medicine ultrasound. J Emerg Med. 2007;32(2):191-96.

#Immediate #antifibrinolytics improve survival by 70% in #severe bleeding

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Trauma patients should be treated with antifibrinolytics at the scene of injury, and post-partum haemorrhage should be treated as soon as the diagnosis is made, suggests new research.

The study, published in The Lancet, examined the impact of treatment delay on the effectiveness of antifibrinolytics in 40,138 patients from two randomised trials of tranexamic acid in acute severe bleeding due to trauma and post-partum haemorrhage.

It found treatment significantly increased overall survival from bleeding (odds ratio [OR] 1·20), with no heterogeneity by site of bleeding. Immediate treatment improved survival by more than 70 per cent. However, treatment delay reduced the treatment benefit, with survival decreasing by 10 per cent for every 15 minutes of treatment delay until three hours, after which there was no benefit.

“Responding quickly can be the difference between life and death, and that means patients must be treated urgently at the scene of injury or as soon as the diagnosis of haemorrhage is made. We have to make sure tranexamic acid is available before patients reach the hospital and whenever a woman gives birth,” said Professor Ian Roberts from the London School of Hygiene & Tropical Medicine, UK, who initiated the study.

#Los #anticoagulantes directos no conllevan aumento del #riesgo de hemorragia en #tromboembolia venosa

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Sue Hughes

Un análisis de casi 60.000 pacientes con tromboembolia venosa ha demostrado resultados tranquilizantes sobre el riesgo de hemorragia con dabigatrán, apixabán, y rivaroxabán, los anticoagulantes orales de acción directa.[1]

El estudio observacional, publicado el 17 de octubre en la versión electrónica de BMJ, informó que en pacientes adultos con tromboembolia venosa, el tratamiento con anticoagulantes orales directos no se relacionaba con incremento en el riesgo de hemorragia grave o de mortalidad por todas las causas, en comparación con la warfarina en los primeros 10 meses del tratamiento.

“Nuestros resultados demuestran que no hubo aumento del riesgo de hemorragia grave con los nuevos anticoagulantes, en comparación con la warfarina, y sí hubo una tendencia hacia una tasa más baja. Esto es congruente con lo que se ha visto en los estudios clínicos aleatorizados, pero nuestros resultados amplían los hallazgos a una gama más amplia de pacientes”, dijo a Medscape Noticias Médicas la autora principal, la Dra. Brenda Hemmelgarn de la University of Calgary en Alberta, Canadá.

“Se han publicado varios estudios aleatorizados controlados que comparan los nuevos anticoagulantes orales con la warfarina, pero estos se han enfocado principalmente en la eficacia”, añadió. “Y mientras que, desde luego, estos estudios también evalúan tolerabilidad, y han señalado tasas similares o más bajas de hemorragia con los nuevos fármacos, las poblaciones en los estudios aleatorizados normalmente son muy selectivas y a menudo se incluye a los pacientes con más riesgo de hemorragia. Por consiguiente, es importante analizar la hemorragia en la vida real. Aunque algunos estudios observacionales han analizado esto con anterioridad, nuestro estudio es el más extenso hasta el momento”, señaló.

La Dra. Hemmelgarn también puntualizó que en estudios clínicos, los pacientes son monitorizados de manera más estrecha, de manera que se reduce el riesgo de hemorragia. “Es tranquilizante ver que el riesgo de hemorragia relacionado con los nuevos fármacos no aumenta en comparación con la warfarina fuera de las condiciones de estudio clínico”.

Advirtiendo que estos datos observacionales no pueden determinar definitivamente la relación de causa y efecto debido a que todavía puede haber factores de confusión que no se tomen en cuenta, dijo: “Creo que estos resultados proporcionan evidencia que respalda la tolerabilidad de estos fármacos en la vida real”.

Para el estudio, los investigadores analizaron los códigos diagnósticos de ingreso hospitalario y datos de prescripción de seis jurisdicciones en Canadá y Estados Unidos.

Los pacientes fueron elegibles para incluirse en el estudio si tenían un nuevo diagnóstico de tromboembolia venosa, definido como al menos un código diagnóstico de tromboembolia venosa en los últimos 30 días antes de la fecha de la primera prescripción de warfarina o uno de los nuevos fármacos anticoagulantes.

Cada paciente que recibió uno de los nuevos fármacos fue equiparado con hasta cinco pacientes que recibieron warfarina tomando en cuenta edad, género, fecha de entrada en la cohorte y una puntuación de propensión que refleja la probabilidad de tratarse con uno de los nuevos fármacos. La puntuación incluyó datos sobre información demográfica, trastornos concomitantes y prescripción de otra medicación.

#La #trombosis aparece cada vez a edad más joven debido al aumento del # sedentarismo

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La trombosis está directamente relacionada con las principales causas de muerte cardiovascular, y el aumento del sedentarismo desde edades cada vez más precoces contribuye a que los casos se estén produciendo también en pacientes cada de vez más jóvenes.

“Hay más casos de enfermedad tromboembólica en gente más joven y, aunque el sedentarismo no es el único factor, la suma de todos ellos influye (…) Y el sedentarismo aumenta de forma tremenda, y no solo en los adultos”, declara la jefa de sección del Servicio de Medicina Interna del Hospital Universitario de La Paz (Madrid), María del Carmen Fernández Capitán, con motivo del Día Mundial de la Trombosis que se celebrado el pasado 13 de octubre.

Esta especialista participó junto con la periodista Susana Guasch en una campaña de sensibilización organizada por Bayer y el Metro de Madrid para animar a los viajeros a “despedirse” de sus sillones y llevar una vida más activa.

Según Fernández Capitán, uno de los graves problemas que más influye en el aumento de casos de trombosis constatado en los últimos años es la falta de actividad física a cualquier edad, incluidos los niños.

“Antes cuando éramos pequeños nos pasábamos el día corriendo y jugando, pero ahora la distracción es el videojuego o el ordenador, y el sedentarismo se está empezando a inculcar desde pequeños a los niños y el riesgo es tremendo. Y en las personas mayores pasa lo mismo, ya que uno entra al metro y la gente se ‘pega’ por un asiento”, lamenta.

Cuando los coágulos tienen lugar en las arterias pueden causar infartos de miocardio o ictus, mientras que cuando afectan a las venas pueden causar enfermedad tromboembólica venosa, tanto en piernas como embolismo pulmonar, cuando el coágulo viaja hasta el corazón y los pulmones.

En total se estima que afectan a en torno a un 1% de la población, y aunque normalmente el riesgo aumenta a partir de los 60 años, la falta de actividad física y otros factores como la obesidad, el consumo de alcohol o una dieta poco adecuada contribuyen a que aparezca antes.

Lo importante, según esta experta, es que todos estos factores de riesgo son prevenibles empezando por una mayor práctica de ejercicio “sin necesidad de ser atletas ni ir al gimnasio”, adaptando esta actividad a las posibilidades de cada uno.

“Caminar todos los días al menos media hora es asequible para todos, bajándote del metro dos paradas antes, subiendo por las escaleras en lugar del ascensor. Y si queremos hacer un ejercicio algo más intenso, hacerlo tres veces por semana es ya suficiente”.

Además, Fernández Capitán ha reconocido que una vez que se ha producido la enfermedad también hay buenos tratamientos para abordarla, como los fármacos antiagregantes, que impiden que se junten las plaquetas para formar coágulos, o los anticoagulantes, “los reyes del tratamiento de la trombosis”.

No obstante, esta experta ha lamentado que el acceso a los nuevos anticoagulantes orales directos siga estando “muy restringido” en España y su financiación varíe entre unas comunidades autónomas u otras.

“En la fibrilación auricular, hay una serie de ítems que te permiten solicitarlos y se concede -su financiación pública- pero en enfermedad tromboembólica venosa no se financia, es excepcional”, ha criticado, pese a que “son igual de eficaces pero más seguros y requieren menos control periódico, lo que va a repercutir en un mejor tratamiento y un menor gasto”.

#Ciclo circadiano na #prática clínica: as lições do #Nobel de medicina

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Dr. Fabiano M. Serfaty

Na ciência nunca foi fácil responder efetivamente a perguntas sobre os verdadeiros mecanismos de funcionamento do relógio biológico. Recentemente, três biólogos americanos, Jeffrey Hall, Michael Rosbash e Michael Young, foram laureados com o prêmio Nobel de Medicina de 2017 pela descoberta dos genes principais que controlam os ritmos circadianos do corpo e os mecanismos que controlam as respostas circadianas do organismo à luz e à escuridão.

No século 18, o francês Jean-Jacques d’Ortous de Mairan notou que as plantas mantidas a uma temperatura constante em um armário escuro mantiveram inesperadamente o ritmo diário de abrir e fechar as folhas. A conclusão de de Mairan foi que isso acontecia porque podiam “sentir o sol sem nunca vê-lo”.

Foi somente quando Hall, Rosbash e Young usaram moscas-da-fruta para isolar um gene que controla o ritmo do cotidiano de um organismo vivo, que os cientistas obtiveram o primeiro vislumbre real do mecanismo de manutenção do tempo que explica como planta e animais (incluindo os seres humandos) adaptam os próprios ritmos biológicos para que sejam sincronizados com as mudanças na Terra.

Usando moscas-da-fruta, a equipe identificou o gene Period, que codifica uma proteína dentro da célula durante a noite, que depois se degrada ao longo do dia.

Os cientistas descobriram que o mesmo gene também existe nos mamíferos. Nestes, ele é expresso em uma pequena área cerebral chamada núcleo supraquiasmático, ou NSC. De um lado, está ligado à retina no olho, e do outro lado se conecta à glândula pineal do cérebro, produzindo a melatonina, o “hormônio do sono”.

Muito se fala e continua se falando sobre o assunto, mas quais são as implicações práticas que o entendimento da fisiologia do ciclo circadiano pode nos trazer hoje?

Estilo de vida

A vida moderna não pode mais ser limitada pelo nascer e pelo pôr-do-sol, mas a luz continua sendo uma das influências mais poderosas no comportamento e no bem-estar humano. Frequentemente a rotina diária, sobretudo a do médico, vem acompanhada de luzes brilhantes antes da hora de dormir, e/ou passar o dia inteiro de trabalho em um ambiente fechado, como um consultório, um hospital, ou um escritório com má iluminação.

Isto pode alterar o ciclo circadiano natural, deixando qualquer pessoa em um “crepúsculo mental” contínuo — cansados pela manhã e alertas à noite, antes de adormecerem.

Há evidências crescentes de que esta alteração do ciclo circadiano natural pode ter, em longo prazo, consequências para a saúde muito mais abrangentes do que apenas o cansaço. Na verdade, pequenos relógios biológicos estão presentes dentro de quase todos os tipos de células humanas, antecipando as necessidades diárias. Esta rede de relógios não só mantém a ordem em relação ao mundo exterior, mas mantém praticamente tudo no organismo, desde a secreção de hormônios e enzimas digestivas no intestino, até o controle da pressão arterial. Tudo isso é influenciado de maneira importante pelo ciclo circadiano de cada um.


A relação entre determinadas doenças e condições, e o período do dia em que elas são mais propensas a acontecerem, já é algo bem estudado. Sabe-se, por exemplo, que 49% dos pacientes são mais propensos a sofrer um acidente vascular cerebral entre 6h e 12h, do que em qualquer outro momento do dia, e um padrão semelhante é observado em relação a infarto agudo do miocárdio. Isto está ligado a um aumento circadiano da pressão arterial no início da manhã, o que ocorre mesmo se o paciente estiver deitado na cama em repouso.


O sistema intrínseco que controla o ciclo circadiano modula muitos sistemas fisiológicos como o apetite, a temperatura corporal[1,2,3] e o ciclo sono-vigília. O sistema intrínseco de sincronização circadiana modula o sono, a vigília e muitos outros sistemas fisiológicos, incluindo ritmos diários na temperatura corporal central, o cortisol e o apetite. [4]

Os distúrbios do ritmo sono-vigília resultam de anormalidades intrínsecas no próprio sistema circadiano, ou de fatores extrínsecos como viagens aéreas e trabalho por turnos e/ou plantões, que causam desalinhamento entre o ciclo claro-escuro e o ritmo circadiano interno de um indivíduo. [5,6]

O sono aumenta fisiologicamente durante a vigília, e um ciclo circadiano alinhado aumenta a capacidade do indivíduo dormir durante a noite, particularmente na segunda metade da noite, ajudando a manter a consolidação do sono até o tempo normal de despertar[7].

Na ausência de informações de tempo, o sistema de cronograma circadiano intrínseco oscila com um período ligeiramente maior que o de 24 horas: cerca de 24,2 horas em adultos[8], e 24,3 horas em adolescentes[9]. Para manter a sincronização com o dia de 24 horas, o sistema circadiano deve se ajustar, todos os dias, por meio de “pistas” de tempo, também chamados zeitgebers. O zeitgeber mais potente é o ciclo claro-escuro[10].


A palavra zeitgeber vem do alemão (zeite = tempo e geber = doador), e pode ser traduzida como que pode ser traduzida, nesse contexto, como sincronizador. O termo foi introduzido na ciência em 1954 por Jurgen Aschoff, então diretor do Instituto Max-Planck em Erling Andechs, para definir um agente ou evento ambiental que fornece “pistas” para configurar ou reiniciar o relógio biológico. O zeitgeber mais importante da natureza é a luz.

Fatores sociais, fatores químicos e atividades também podem servir como zeitgebers.

A luz é um zeitgeber do tipo fótico, enquanto a atividade física, por exemplo, é chamada de zeitgeber não-fótico para o relógio biológico.

O papel da luz

O efeito da luz no sistema circadiano depende de quando ocorre a exposição a ela. Quando essa exposição se dá durante as últimas horas do período típico do sono, e durante o início da manhã, ela pode mover o ritmo circadiano para mais cedo (avanço de fase). Por outro lado, a exposição à luz durante o período noturno, e a na primeira metade do período habitual de sono, pode mover o ritmo circadiano para mais tarde (atraso de fase)[11]. As alterações do sistema que controla o ciclo circadiano, muitas vezes resultam em sintomas clinicamente significativos de insônia e sonolência diurna excessiva, além de comprometimento físico, emocional, neurocognitivo e social[12].


Há também um ritmo circadiano natural para a fome. Afinal, se fosse simplesmente devido à ingestão de alimentos, estaríamos constantemente com fome na parte da manhã, após o período de jejum noturno. No entanto, as evidências científicas confirmam que a fome é menor pela manhã. Isto é paradoxal, porque a refeição do horário da manhã segue o período mais longo do dia sem alimentos. O café da manhã é tipicamente a menor, e não a maior refeição do dia. Isso indica que existe um ritmo circadiano que é independente de quando e do que se ingere[1,8]. O “hormônio da fome”, a grelina, mostra um ritmo circadiano marcante com seu nível mais baixo às 8:00 da manhã. Com o jejum, picos de grelina se dão em geral nos dois primeiros dias e então os níveis deste hormônio caem constantemente. Isso se alinha com o que se vê clinicamente: durante um jejum, a fome é o pior problema no primeiro e no segundo dia. Muitas pessoas nos jejuns mais longos relatam que a fome normalmente desaparece após o segundo dia.[3,6]

A fome geralmente cai ao seu nível mais baixo às 7h50 da manhã, e picos em geral ocorrem às 7:50 da noite. Isso se aplica a quase todos os alimentos.

Implicação prática na alimentação

Em geral durante a manhã, a fome é suprimida ativamente pelo ritmo hormonal circadiano. Forçar alguém a se alimentar é contraproducente, pois comer não leva a perda de peso. Forçar a alimentação em um momento em que não se está com fome não é definitivamente uma estratégia de sucesso. Individualizar a abordagem do paciente, entendendo melhor a rotina dele, orientando uma dieta na qual ele deve comer “com fome”, evitando excesso de carboidratos e de gorduras trans, é uma estratégia muita mais adequada e baseada em evidência científica suficiente para se usar o relógio biológico a favor da perda de peso.

Quadros clínicos associados às alterações no ciclo sono-vigília

Obesidade: há evidência da relação entre o entre o quanto as pessoas dormem e a obesidade. Em geral, crianças e adultos que dormem pouco tendem a pesar mais do que aqueles que dormem de acordo com a própria necessidade de sono[12,13,14].

Jet-lag : indivíduos com jet-lag têm dificuldade para adormecer ou manter o sono durante a noite após viagem aérea através de dois ou mais fuso-horários. Uma sonolência diurna excessiva também ocorre devido ao tempo de sono total reduzido, bem como ao desalinhamento circadiano. Esses distúrbios persistem até que o sistema circadiano se ajuste ao novo ciclo luz-escuro no destino.

Distúrbios ocasiionados por trabalho em turnos:  estes são decorrentes das dificuldades com sono ou vigília impostas por turnos de trabalho exercidos contra o ciclo luz-escuro. Como resultado, os indivíduos acumulam “dívidas de sono”, erros na execução de suas atividades, e têm um risco aumentado de acidentes, entre outros resultados adversos para a saúde.

Distúrbios psiquiátricos: a depressão apresenta associação com fase do ciclo sono-vigília atrasada. Os distúrbios do humor também podem acompanhar distúrbios circadianos.

Alterações no padrão do ciclo sono-vigília: seis distúrbios do sono-vigília do ritmo circadiano são reconhecidos e definidos por padrões específicos de interrupção do sono-vigília, resultando em insônia ou sonolência diurna excessiva. O padrão da alteração clínica em relação ao sono e à vigília pode se apresentar de diversas maneiras. Essas condições também podem ter um impacto negativo no desempenho neurocomportamental, na saúde mental e física, e no funcionamento social e ocupacional.

Tal como acontece com qualquer distúrbio que resulta em duração inadequada ou perda de qualidade do sono, os pacientes podem ter problemas no local de trabalho, em casa ou nos estudos. Acredita-se que essas alterações resultam do funcionamento neurocomportamental sub-óptimo em regiões do cérebro responsáveis pela concentração, pela memória e pela velocidade de processamento. A fadiga física também pode contribuir para estas alterações.

Para todos os distúrbios circadianos do ciclo sono-vigília, os seguintes três critérios gerais devem estar presentes , de acordo com a Classificação Internacional de Distúrbios do Sono, Terceira Edição (ICSD-3):[12]

  • Padrão de sono-vigília alterado, por alterações de funcionamento do sistema circadiano;
  • Queixa de insônia, sonolência excessiva ou ambos;
  • Desempenho sub-óptimo em uma área importante da vida do indivíduo (trabalho, aprendizagem, vida social, saúde mental ou física).

Além destes critérios gerais, cada desordem tem critérios específicos com base no padrão de ruptura da fase circadiana estabelecida por história, revisão de diário de sono ou actigrafia. A dosagem de melatonina para avaliação do ciclo sono-vigília não é rotineiramente utilizada em contextos clínicos, mas pode ser útil em casos desafiadores[13,14]. A polissonografia só é indicada na suspeita de uma comorbidade relacionada ao sono, como a apneia obstrutiva do sono.

As estratégias de tratamento para distúrbios circadianos do ritmo do sono vigília são específicas para cada tipo de transtorno. O principal objetivo do tratamento é realinhar o ciclo circadiano com o período de sono-vigília desejado ou requerido[15,16]. Dependendo do distúrbio, abordagens úteis podem incluir terapias comportamentais, manipulações cuidadosas dos períodos e horas de sono, uso de melatonina apropriadamente indicada, uso de agonistas de receptores de melatonina, e terapia de luz[15,16].