Cryptogenic Stroke

Posted by Carla Rothaus • May 27th, 2016

2016-05-23_14-38-46Cryptogenic ischemic strokes are symptomatic cerebral infarcts for which no probable cause is identified after adequate diagnostic evaluation. In general, the percentage of ischemic strokes that are classified as cryptogenic has declined over time as diagnostic testing has advanced. However, stroke that is cryptogenic after a standard diagnostic evaluation remains a common clinical challenge, accounting for 20 to 30% of all ischemic strokes and therefore occurring in 120,000 to 180,000 patients each year in the United States. As compared with strokes of determined origin, cryptogenic ischemic strokes typically result in less severe presenting neurologic deficits, less final disability, and lower mortality.

One quarter of ischemic strokes are cryptogenic (no obvious cause). Additional investigation involves assessment for arteriopathies, cardiac sources of embolism (in particular, occult low-burden atrial fibrillation), and disturbances of coagulation. A new Clinical Practice summarizes.

Clinical Pearl

• What are some of the causes of cryptogenic stroke that may be discovered after more specialized testing?

In patients with ischemic stroke that is considered to be cryptogenic after standard evaluation, causes that are most often found after more specialized testing include occult atherosclerosis, including nonstenosing but unstable plaques at intracranial and cervical sites or stenosing plaques at the thoracic origins of the common carotid and thoracic vertebral arteries; nonatherosclerotic arteriopathies, such as dissection or vasculitis; hypercoagulable states; cardioembolism from medium-grade sources, such as low-burden paroxysmal atrial fibrillation or dilated cardiomyopathy of moderate degree; and paradoxical embolism.

Clinical Pearl

• What is the most common cause of cryptogenic stroke in young adults?

The age of the patient influences the likelihood of various causes. In young adults 18 to 30 years of age, dissection is most common, but thrombophilias and congenital cardiac disease are also noteworthy causes. In persons 31 to 60 years of age, early-onset atherosclerosis and acquired structural cardiac disease are increasingly common. In patients older than 60 years of age, occult atrial fibrillation becomes more frequent.

Morning Report Questions

Q: What patient characteristics increase the likelihood that protracted cardiac monitoring will reveal occult atrial fibrillation? 

A: Technology to detect infrequent paroxysmal atrial fibrillation has dramatically improved over the past decade, with the development of mobile cardiac telemetry systems that may be worn externally for 2 to 4 weeks, subcutaneous loop recorders with battery lives enabling detection for 1 to 3 years, and in patients needing therapeutic internal pacemakers or defibrillators, implantable therapeutic devices with the capability to detect atrial fibrillation for 3 years or more. Among patients whose ischemic strokes are cryptogenic after conventional inpatient evaluation, prolonged outpatient cardiac monitoring detects low-burden atrial fibrillation in 15%. Patients with low-burden paroxysmal atrial fibrillation have a lower risk of stroke than patients with chronic or high-burden paroxysmal atrial fibrillation. However, their risk of stroke is higher than that among persons without atrial fibrillation. As little as a single 1-hour episode of atrial fibrillation during 2 years of monitoring has been associated with a doubling in the risk of ischemic stroke. The characteristics of patients that increase the likelihood that protracted monitoring will uncover low-burden atrial fibrillation include older age and higher CHA2DS2-VASc score (on which scores range from 0 to 9, with higher scores indicating greater risk), cerebral infarct topographic features (such as multiple vascular territories and cortical location), and indexes of left atrial cardiopathy, including left atrial dilatation, strain, and reduced emptying fraction, left atrial appendage size and single-lobe morphologic features, p-wave dispersion on ECG [electrocardiogram], frequent atrial premature beats, and elevated N-terminal pro–brain natriuretic peptide serum levels.

Q: When a patent foramen ovale is found during the work up of cryptogenic stroke, how is one to know if it is causally related?

A: A patent foramen ovale is present in approximately one quarter of the general patient population but in one half of patients with cryptogenic stroke. A Bayesian attributable risk analysis of pooled data from 12 studies suggested that among patients with cryptogenic stroke who had a patent foramen ovale, the patent foramen ovale is probably causally related to the stroke in approximately half. Features that increase the likelihood of a causal relationship include younger age; Valsalva maneuver at the onset of stroke; extended plane or car travel preceding the stroke; concomitant venous thrombosis in the leg or pelvis; coexisting venous hypercoagulable state; coexisting atrial septal aneurysm; history of migraine with aura; cortical location, multiplicity, and large size of cerebral infarcts; and absence of hypertension, diabetes, and smoking.

Figure 1. Algorithm for the Identification and Diagnostic Evaluation of Patients with Cryptogenic Ischemic Stroke or Transient Ischemic Attack (TIA).

Table 1. Suggestive Findings on History and Physical Examination in Patients with Cryptogenic Stroke.

A Pregnant Woman with Fever

Posted by Carla Rothaus • May 27th, 2016

104Listeriosis is a rare but notorious cause of chorioamnionitis. Listeriosis is caused by Listeria monocytogenes, an environmentally ubiquitous, facultative, anaerobic gram-positive bacillus. In humans, listeriosis is almost exclusively a foodborne disease, and unheated processed meats and unpasteurized soft cheeses can be contaminated with listeria; pregnant women should avoid eating such foods. Listeriosis is a nationally notifiable disease in the United States.

A 31-year-old woman who was pregnant with dichorionic, diamniotic twins presented at 35 weeks of gestation with fever, rigor, malaise, myalgias, anorexia, and loose stools. A chest radiograph revealed patchy right basilar opacities. Diagnostic test results were received. A new Case Records of the Massachusetts General Hospital summarizes.

Clinical Pearl

• What are some of the risk factors for chorioamnionitis?

Chorioamnionitis complicates 1 to 4% of births in the United States. It is typically caused by ascending infection with endogenous vaginal or cervical bacteria. Associated risk factors before the onset of labor or membrane rupture include bacterial vaginosis, maternal alcohol or tobacco use during the pregnancy, and colonization of the mother’s vagina, rectum, or urinary tract with group B streptococcus.

Clinical Pearl

• How does the rate of listeriosis in pregnant women compare to that in the general population?

In 2010 in the United States, the overall reported rate of listeriosis was only 2.7 cases per 1 million people. Pregnant women, however, are particularly susceptible to listeria and contract the disease at a rate that is 10 to 20 times the rate in the general population; up to 1 in every 4 reported cases of listeriosis in the United States occurs in a pregnant woman. The overwhelming majority of affected women are otherwise healthy. Most diagnoses are made in women who are in the third trimester of pregnancy. Women with multiple gestations are at an increased risk.

Morning Report Questions

Q: What are some of the clinical features and potential complications of listeriosis in pregnant women? 

A: The onset of listeriosis can occur anytime from 3 to 70 days after exposure; the typical incubation period for invasive disease is longer in pregnant women (2 to 4 weeks) than in nonpregnant persons (1 to 14 days). Pregnant women with listeriosis may be asymptomatic or present with an influenza-like or nonspecific febrile illness, sometimes accompanied by gastrointestinal symptoms. Malaise, nausea, loose stools, rigors, arthralgias, and myalgias are typical of the disease. Most pregnant women with listeriosis have leukocytosis. Pregnancy-associated L. monocytogenes infections can have catastrophic results, such as fetal loss, preterm delivery, serious neonatal illness, or neonatal death. As a consequence of maternal bacteremia and transplacental transmission of infection, infants may have an early-onset sepsis syndrome that occurs at birth or shortly thereafter.

Figure 2. Blood Specimens.

Q: What is the usual treatment of severe infections with listeria? 

A: Ampicillin and gentamicin are active against L. monocytogenes. These antibiotics are typically used in combination for the treatment of severe infections with listeria, although no controlled trials have established a standard antibiotic choice or duration of treatment for this infection.

Primary Prevention of Cardiovascular Events — A Pragmatic Approach

Posted by James Yeh, M.D. M.P.H. • May 25th, 2016

2016-05-06_16-09-35Ms. Barnstable is a 66 year-old woman who is seeing you for an annual physical check-up today.  She does not take any medications and is a smoker.  She asks if there are drugs that she should be taking to lower her risks for heart attacks and strokes. Besides smoking cessation counseling, what do you tell her about drugs for primary prevention of CV events?

What is the Heart Outcomes Prevention Evaluation (HOPE)-3 trial?

In this trial, recently reported in three papers in NEJM, investigators asked whether giving fixed doses of rosuvastatin and candesartan/hydrochlorothiazide to adults who do not have cardiovascular disease but have an intermediate risk of cardiovascular events (annual risk of about 1%) regardless of cholesterol levels, inflammatory markers status, or hypertension status can prevent future cardiovascular events.

The investigators employed a 2 x 2 factorial design to simultaneously test multiple different hypotheses. They randomized 12,705 adults (men ≥55 year-old and women ≥65 year-old) from 21 countries to receive either rosuvastatin (10 mg daily) or placebo, and to receive either candesartan/hydrochlorothiazide (16mg/12.5 mg daily) or placebo.

Three comparisons were analyzed:

There were two co-primary outcomes:

  • The composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke
  • The first composite outcome plus resuscitated cardiac arrest, heart failure, and revascularization

Who are in the study?

The mean age was 65.7 years and 46% of the participants were women. The baseline mean LDL cholesterol level was 128 mg/dL and mean blood pressure was 138/82 mm Hg.

What were the results?

During the median follow-up time of 5.6 years, rosuvastatin lowered the mean LDL cholesterol level by 35 mg/dL and the anti-hypertensive drugs lowered the mean systolic/diastolic BP by 6/3 mm Hg.

The rate of the first co-primary outcome (composite of CV death, nonfatal stroke, and nonfatal MI) was significantly lower in the combination therapy group compared to dual-placebo (3.6% vs. 5.0%; HR 0.71, 95% CI 0.56 to 0.9; P=0.005).  The rate of the second co-primary outcome (composite of first co-primary plus resuscitated cardiac arrest, heart failure, and revascularization) was also lower with combination therapy (4.3% vs. 5.9%; HR 0.72; 95% CI 0.57 to 0.89; P=0.003).

What were the results of blood-pressure treatment alone and statin therapy alone?

The rate of the first co-primary outcome was lower with rosuvastatin versus placebo (3.7% vs. 4.8%; HR 0.76; 95% CI 0.64 to 0.91; P=0.002). These results were consistent in subgroup analyses regardless of baseline cholesterol level, C-reactive protein level, blood pressure, and race or ethnic group.

The rate of the first co-primary outcome was not different with candesartan/hydrochlorothiazide than with placebo (4.1% vs. 4.4%; HR 0.93; 95% CI 0.79 to 1.10; P=0.40).  In a pre-specified subgroup analysis, blood pressure treatment when compared to placebo did lower the incidence of the co-primary outcome of CV death, nonfatal stroke, and nonfatal MI in the tertile of study participants with systolic BP > 143.5 mm Hg (4.8% vs. 6.5%) but did not have a significant effect in either of the two lower tertiles (P for trend =0.02) .

So should everyone receive combination therapy of statin and anti-hypertensives?

The addition of anti-hypertensive regime with fixed doses of candesartan/hydrochlorothiazide to fixed rosuvastatin did not differ significantly than rosuvastatin therapy alone in reducing the incidence of CV death, nonfatal stroke, and nonfatal MI (3.6% vs. 3.8%).

How do I reconcile the blood-pressure intervention results with the SPRINT trial?  

In an accompanying editorial, William Cushman (Veterans Affairs Medical Center, Memphis) and David Goff (University of Colorado Anschutz Medical Campus) caution that the overall negative results of the blood-pressure–lowering component of HOPE-3 could be due to the treatment of a lower-risk group in HOPE-3 than the SPRINT trial, where participants had subclinical CV disease or a ten-year Framingham CV risk score > 15%.  Further more, “the difference in systolic blood pressure between the active-treatment and control groups that was seen in SPRINT was twice the difference seen in HOPE-3 because the treatment regimen was more intensive.” Therefore, the low doses of the anti-hypertensive agents used in HOPE-3 may help explain the result.

What is my take-away?

For patients at intermediate risks for cardiovascular events, irrespective of the cholesterol level or hypertension status, taking a fixed dose of statin reduced this risk. The addition of fixed doses of anti-hypertensives to the statin therapy did not reduce this risk unless the patient was hypertensive.

Don’t miss the NEJM Quick Take video summary of the SPRINT trial:

A Man with Olfactory Hallucinations

Posted by Carla Rothaus • May 20th, 2016

2016-05-13_13-00-38Involvement of the nervous system is reported in 5 to 15% of patients with sarcoidosis, although autopsy series indicate that the frequency of lesions in the nervous system may be higher.

A 32-year-old man presented with a 1-year history of olfactory hallucinations and a 6-week history of intermittent numbness and paresthesias on the left side. MRI revealed a nodular focus of enhancement in the medial right temporal lobe. A diagnostic procedure was performed. A new Case Records of the Massachusetts General Hospital summarizes.

Clinical Pearl

• What is the most common abnormality reported in cases of neurosarcoidosis?

Basilar meningeal involvement with an associated cranial neuropathy (usually involving the facial nerve) is the most common abnormality reported. Involvement of the facial nerve can be either unilateral or bilateral, and bilateral involvement can be simultaneous or sequential.

Clinical Pearl

• What are some of the other clinical manifestations of neurosarcoidosis?

Optic nerve involvement may occur alone or in association with other lesions. Leptomeningeal involvement, either focal or diffuse, may be observed in association with cranial neuropathies or in isolation. Disease in the region of the infundibular stalk may result in endocrinopathies caused by alteration of the hypothalamic–pituitary axis. Dural involvement may be manifested by a discrete mass that may mimic meningioma. Neurosarcoidosis with parenchymal involvement is less frequent than neurosarcoidosis with meningeal involvement.

Figure 1. MRI of the Head.

Figure 2. Brain-Biopsy Specimen (Hematoxylin and Eosin).

Morning Report Questions

Q: What is the prognosis of neurosarcoidosis? 

A: Clinical experience and a few long-term studies have shown that the response to therapy and the prognosis depend on the clinical syndrome. Lymphocytic meningitis, mononeuropathies of the facial nerves, multiple cranial neuropathies, and polyradiculoneuropathies respond to relatively short courses of glucocorticoids, are associated with a good long-term prognosis, and are generally not debilitating. In contrast, patients with sarcoidosis affecting the parenchyma of the brain, the spinal cord, or the conus medullaris and cauda equina or with granulomatous involvement of the optic nerves and hypothalamic and pituitary regions often have a protracted and progressive course over a period of years. Such patients respond partially to glucocorticoids and glucocorticoid-sparing immunosuppressive medications, such as methotrexate, azathioprine, and mycophenolate, but they require treatment for years.

Q: How is neurosarcoidosis treated? 

A: Immunosuppressive drugs, predominantly glucocorticoids, are the backbone of therapy for neurosarcoidosis in all its forms, but biologics such as TNF-α inhibitors are now an important part of the treatment. TNF-α inhibitors may be useful when the usual immunosuppressive therapy is inadequate or is associated with an unacceptable side-effect profile. The rationale for the use of TNF-α inhibitors is evidence of the role of the cytokine TNF-α, which is generated in granulomas, in causing tissue damage and perpetuating the granulomatous process. The most commonly used TNF-α inhibitor is infliximab, which is a chimeric monoclonal antibody that inhibits both soluble and membrane-bound TNF-α.

Coronary-Artery Bypass Grafting

Posted by Carla Rothaus • May 20th, 2016

93Appropriate selection of patients for coronary-artery bypass grafting (CABG) is critical to ensure good outcomes. The evaluation of patients for CABG relies on a systematic assessment of the characteristics and coronary anatomy known to be associated with a survival benefit from CABG as compared with medical therapy or percutaneous coronary intervention (PCI). There is increasing evidence that treatment decisions for patients with complex coronary artery disease are best made through a process of shared decision making that includes the patient, the patient’s family, an interventional cardiologist, a cardiac surgeon, and ideally, the patient’s general cardiologist or primary care physician.

Coronary-artery bypass grafting (CABG) is very commonly performed. CABG improves survival among patients with multivessel coronary disease; those with more severe coronary disease, diabetes, or left ventricular dysfunction are especially likely to benefit. A new Review Article summarizes.

Clinical Pearl

• What is the most serious complication of CABG?

Stroke remains the most serious complication of CABG, occurring in 1 to 2% of patients in the perioperative period. Notable risk factors for stroke include a history of neurologic events, advanced age, peripheral or cerebrovascular disease, and diabetes. Aortic atherosclerosis is also a major risk factor for stroke after CABG because of the necessary manipulation or clamping of the ascending thoracic aorta. The use of a single aortic cross-clamp and epiaortic ultrasonography during CABG have been associated with a reduction in the risk of stroke over the past decade.

Clinical Pearl

• In patients with coronary artery disease, what coexisting conditions are associated with a benefit of CABG over PCI?

Patients with multivessel coronary artery disease and diabetes have an increased cardiovascular risk as compared with those without diabetes, and they have a survival benefit from CABG as compared with PCI. Patients with left ventricular dysfunction or mitral-valve disease also have an increased cardiovascular risk and have a survival benefit from CABG.

Morning Report Questions

Q: What were the results of the Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) study regarding the relative benefits of CABG versus PCI? 

A: Recent trials and observational studies have updated previous work by including higher-risk patients and reflecting changes in practice. The most important was the SYNTAX study, which randomly assigned 1800 patients with either three-vessel or left main coronary artery disease to CABG or PCI. Evaluation of each participant included determination of the SYNTAX score (a measure of the extent and complexity of coronary artery disease) and the anticipated complexity of PCI. SYNTAX scores are used to classify the complexity of coronary artery disease as low (≤22), intermediate (23 to 32), or high (≥33). Overall, patients with three-vessel disease in the SYNTAX trial had a survival benefit with CABG as compared with PCI (rate of death, 9.2% vs. 14.6%, P=0.006). In patients with the least complex three-vessel disease (SYNTAX score ≤22), PCI was noninferior to CABG. In patients with more complex disease (SYNTAX score ≥23), CABG was superior to PCI. The survival benefit of CABG over PCI for patients with multivessel coronary artery disease has been confirmed in other studies and appears to be consistent when PCI is performed with second-generation drug-eluting stents. In the SYNTAX study, the outcomes of the two procedures were indistinguishable in patients with isolated left main coronary artery disease or left main coronary artery disease and single-vessel coronary artery disease (SYNTAX score <33). However, in patients with left main and two- or three-vessel coronary artery disease (SYNTAX score ≥33), there was a significant reduction in the rate of the composite end point of death, myocardial infarction, stroke, or repeat revascularization with CABG as compared with PCI (29.7% vs. 46.5%, P=0.003).

Q: Are there studies comparing CABG to PCI in patients with acute coronary syndromes? 

A: The evidence in favor of CABG is almost entirely based on studies of patients with stable ischemic heart disease. Nevertheless, the recommendations for CABG are commonly extended to include patients with acute coronary syndromes, including unstable angina and stable non–ST-segment elevation myocardial infarction. In practice, more than 60% of CABG procedures are performed during an acute care hospitalization and 29% follow a recent myocardial infarction. The best initial treatment for patients with acute ST-segment elevation myocardial infarction is reperfusion therapy with either PCI or fibrinolytic therapy. As compared with CABG, PCI restores coronary blood flow more rapidly, preserves myocardium, and improves outcomes. In this patient population, CABG is reserved for those who have a coronary anatomy that is not amenable to PCI or who have mechanical complications, such as ventricular septal defect, myocardial rupture, or papillary-muscle rupture with acute, severe mitral regurgitation.

Figure 1. Coronary-Artery Bypass Grafting.

Table 1. Indications for Coronary-Artery Bypass Grafting (CABG).

Rate Control versus Rhythm Control for Atrial Fibrillation after Cardiac Surgery

Posted by Ravi Parikh, M.D., M.P.P. • May 18th, 2016

2016-05-06_15-56-46Whether you are a resident on the cardiology, surgery, or general medicine service, encountering patients with atrial fibrillation is common. Many patients, particularly after cardiac surgery, go in and out of atrial fibrillation so often that residents caring for them often ignore the blinking lights and loud alarms from telemetry machines after a while. However, atrial fibrillation has adverse consequences– postoperative atrial fibrillation and its sequelae cost the US healthcare system up to $1 billion each year. While anticoagulation can reduce the risk of the dreaded complication of stroke, it is also important to treat atrial fibrillation to prevent structural consequences of rapid ventricular response, such as tachycardia-mediated cardiomyopathy. Two strategies – controlling the heart rate (rate control) and converting the patient’s heart to sinus rhythm (rhythm control) – are used as medical treatments for atrial fibrillation.

Taking an historical perspective, in the 1980s and 1990s, when large clinical trials demonstrated the large stroke risk of atrial fibrillation, a slew of antiarrythmic drugs came onto the market. The logic was simple– if atrial fibrillation led to devastating consequences, it made sense to try to restore sinus rhythm. However, antiarrythmic drugs came with potentially dangerous side effects. Some practitioners thought that decreasing the risk of rapid ventricular response through rate control might confer a similar benefit without the potentially harmful side effects of rhythm control. The landmark Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, published in NEJM in 2002, found that in 4000 nonsurgical patients with prior atrial fibrillation, rhythm control offered no difference in survival compared to rate control, but resulted in more hospitalizations and more adverse events. The smaller Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) trial, also published in NEJM in 2002, reported similar findings in 522 patients with persistent atrial fibrillation.

However, as in most of medicine, it is difficult to generalize. This is particularly true after cardiac surgery, when up to 50% of patients develop atrial fibrillation. While a joint 2014 American College of Cardiology (ACC), American Heart Association (AHA), and Heart Rhythm Society (HRS) guideline recommended rate control with beta-blockers for postoperative atrial fibrillation, considerable variation in practice continues.

In this week’s NEJM, Gillinov et al. report the results of a multi-center (23 centers) randomized controlled trial designed to answer this question. Investigators enrolled patients who were undergoing elective cardiac surgery for either coronary artery disease or valvular disease and developed persistent or recurrent postoperative atrial fibrillation. Patients with a history of prior atrial fibrillation were excluded. From 2014-2015, 523 patients with postoperative atrial fibrillation were randomized to receive either a rate control or rhythm control strategy. The rate control arm received medications to slow the heart rate to a target of less than 100 beats per minute. The rhythm control arm received a standard loading dose of amiodarone for pharmacologic rhythm control. If atrial fibrillation persisted for 24-48 hours after randomization, patients received cardioversion. If any patient in either arm had atrial fibrillation for longer than 24-48 hours after randomization, they received anticoagulation.

The investigators found that atrial fibrillation was present after cardiac surgery in 30% of patients – and in 50% of patients who had received combined coronary artery bypass graft and valve surgery. Adults (mean age 68.8 years) receiving rate control had similar numbers of hospital days (6.4 vs 7.0, respectively; P=0.76); length of stay for the index hospitalizations (5.5 vs 5.8 respectively; P=0.88); and rates of rehospitalization (P=0.88). At 60-days, 93.2% of individuals in the rate control group remained in sinus rhythm, compared to 97.9% of patients in the rhythm control group (P=0.02). There were no significant differences in the overall rates of serious adverse events, strokes, or serious bleeding in the rate- or rhythm-control groups. Similar numbers of patients in both arms received anticoagulation prior to discharge; while rate control resulted in slower resolution to sinus rhythm, the duration of anticoagulation was similar between both arms (median 45 days).

There are several limitations to the study, including the large rates of crossover between treatment strategies, as well as treatment discontinuation in the two arms. However, the study’s greatest strength lies in numbers—it is a large (N=523) randomized trial of post-operative atrial fibrillation management. The findings of Gillinov et al. suggest that whereas rhythm control may offer faster time to sinus rhythm, it comes with the potential side effects of antiarrythmic drugs, in this case, amiodarone, with no shorter duration of anticoagulation. Since rhythm control strategies are complex and offered no definitive clinical benefit, many would interpret the study’s results as in clear favor of rate control. Hugh Calkins, M.D., Director of the Cardiac Arrhythmia Service at the Johns Hopkins Hospital, writes in an accompanying editorial: “The all too frequent knee-jerk reaction to cardiovert patients with postoperative atrial fibrillation with hopes of reducing stroke risk, the need for anticoagulation, and the duration of hospitalization seems hard to justify given the well-known risks and costs associated with such interventions and the absence of clear beneficial effects of the rhythm control strategy.” The Gillinov et al. study clarifies the risks and benefits of either treatment strategy in post-operative atrial fibrillation and argues for shared decision-making with patients prior to heart surgery.

A Woman with Psychosis

Posted by Carla Rothaus • May 13th, 2016

2016-05-06_13-34-48The combination of malabsorption and autoimmunity strongly suggests the possibility of celiac disease, which is not always associated with gastrointestinal symptoms. Although neurologic and psychiatric symptoms of celiac disease are not widely recognized, they have been reported.

Examination of a 37-year-old woman with adult-onset psychosis revealed weight loss, a thyroid nodule, anemia, and micronutrient deficiencies. Diagnostic tests were performed. A new Case Records of the Massachusetts General Hospital summarizes.

Clinical Pearl

• What historical or clinical findings should make one consider celiac disease?

Celiac disease should be considered in patients with gastrointestinal symptoms and in patients with extraintestinal problems, such as iron-deficiency anemia that is unresponsive to treatment, arthritis, or elevated levels of liver enzymes; it should also be considered in high-risk patients, including those with a family history of celiac disease, those with type 1 diabetes mellitus, and those with autoimmune thyroid disease.

Clinical Pearl

• What serologic tests are useful when celiac disease is suspected?

Serologic tests — including tests for IgA tissue transglutaminase antibodies, endomysial antibodies, and deamidated gliadin peptide antibodies — help to identify persons who may benefit from duodenal biopsy. General consensus regarding these studies is that the test for IgA tissue transglutaminase antibodies is the most reliable and cost-effective.

Morning Report Questions

Q: What is the appropriate management when test results for IgA tissue transglutaminase antibodies are abnormal? 

A: Patients with abnormal test results for IgA tissue transglutaminase antibodies or those in whom celiac disease is highly suspected must be referred to a gastroenterologist for confirmatory testing with endoscopy and biopsy. The diagnostic standard for celiac disease is a biopsy of the small intestine. The patient must remain on a gluten-containing diet for testing to be accurate. A trial of a gluten-free diet is not appropriate unless celiac disease has been ruled out; once the patient is on a gluten-free diet, a clinician cannot distinguish between celiac disease and other gluten-related disorders, including nonceliac gluten sensitivity, because both can have extraintestinal manifestations. If a patient has initiated a gluten-free diet without having had the proper testing, a genetic test may be helpful to identify whether there is a need to reintroduce gluten for confirmatory testing for celiac disease.

Figure 1. Initial Biopsy Specimen of the Duodenum.

Figure 2. Subsequent Biopsy Specimen of the Duodenum (Hematoxylin and Eosin).

Q: Is there a connection between celiac disease and neuropsychiatric disease?

A: Celiac disease was classically described as a gastrointestinal condition that almost exclusively affects white children. Now celiac disease is described as an autoimmune disorder that can affect persons of any age or race and can involve any tissue or organ of the body. The typical gastrointestinal symptoms (diarrhea, bloating, failure to thrive, and weight loss) can be easily understood by the underlying intestinal damage caused by the autoimmune attack that occurs after the ingestion of gluten, but the many extraintestinal symptoms that patients with celiac disease often have are more difficult to explain. New insights on the pathogenesis of celiac disease suggest that it is truly a systemic disease that can spread from the intestine to any tissue or organ of the body. One of the most intriguing yet controversial clinical presentations of celiac disease involves the nervous system as a preferred target. Patients with celiac disease often have chronic headache, short-term memory loss, irritability, anxiety, and depression and more rarely have seizures, ataxia, autism, attention-deficit disorders, and psychosis. Although we do not have a definitive explanation of the way in which an inflammatory process in the intestine affects the brain, there is growing evidence of close functional and organic interactions between these two systems, which are typically described as the gut–brain axis.

Table 1. Extraintestinal Manifestations of Celiac Disease.

Table 2. Neuropsychiatric Symptoms Associated with Celiac Disease.

Caregivers of Critically Ill Patients

Posted by Carla Rothaus • May 13th, 2016

2016-05-06_13-44-08Unpaid caregivers (typically family or close friends) are essential to the sustainability of North American health care systems, because their unpaid labor annually accounts for $27 billion in Canada and $642 billion in the United States. Although caregiver assistance can be beneficial for patients, such care may have negative consequences for caregivers, including poor health-related quality of life, emotional distress, a subjective sense of burden, and symptoms of post-traumatic stress disorder. Cameron et al. used hospital data and self-administered questionnaires to collect information on caregiver and patient characteristics in a prospective cohort of caregivers of patients who had received mechanical ventilation for a minimum of 7 days in the ICU and had survived to discharge. The objectives were to describe health outcomes in caregivers, identify subgroups of caregivers with distinct health trajectories, and identify variables associated with poor caregiver outcomes.

Investigators evaluated the caregivers of patients who had received mechanical ventilation for at least 7 days in an ICU. Although there was a large burden of depressive symptoms soon after discharge, the burden diminished in magnitude, in most caregivers, during the subsequent year. A new Original Article summarizes.

Clinical Pearl

• Is physical health affected to the same degree as mental health in caregivers who provide care for an ill patient at home?

In the study by Cameron et al., the caregivers’ mean age was 53 years, 70% were women, and 61% were caring for a spouse. Caregivers of patients who had received mechanical ventilation in the ICU for at least 7 days were at risk for poor mental health outcomes, whereas their physical health was similar to population norms.

Clinical Pearl

• To what extent do the specific characteristics of patients affect the health outcomes of those who care for them?

Cameron et al. found that caregiver outcomes did not appear to be related to patient demographic and clinical characteristics or to changes in patient functional and psychological outcomes over time. Multivariable mixed-effects models were not able to identify any patient characteristics that were significantly associated with caregiver outcomes during the 1-year follow-up. Together, these analyses suggested that patients’ severity of illness, functional abilities, cognitive status, and neuropsychological well-being, were not associated with caregiver outcomes.

Morning Report Questions

Q: How substantial is the risk of clinical depression among caregivers of critically ill patients? 

A: Findings of the study by Cameron et al. suggest that a substantial percentage of caregivers may be at risk for clinical depression. Previous research has shown that the Center for Epidemiologic Studies Depression (CES-D) scale is a good screening tool for clinical depression. In the Cameron study, 43% of caregivers had a score of more than 15 on the CES-D scale at 12 months after the patients for whom they were caring were discharged from the ICU, suggesting persistent symptoms of clinical depression. This rate is substantially higher than the rate in the Canadian adult population (12%) and is also higher than the rate observed in a large sample of caregivers of persons with dementia (32%). Although the mental status of caregivers before patients’ critical illness events was not known, depressive symptoms did decrease over time for most caregivers except within a subgroup who had more severe symptoms than the rest of the sample at all time points.

Figure 1. Caregiver Outcomes during the First Year after Patient Discharge from an Intensive Care Unit (ICU).

Q: What characteristics of caregivers of critically ill patients are associated with better health outcomes in the caregivers? 

A: In the Cameron study, caregivers had better health outcomes when they were older, were caring for a spouse, had higher income, and had better social support and sense of control and when caregiving had less of a negative effect on their everyday lives. The findings are consistent with previous pilot data from Choi et al., who identified two trajectory groups with respect to depressive symptoms and identified caregiver characteristics (younger age, female sex, financial difficulty, and poor health behaviors) but no patient characteristics (diagnosis at admission, ICU length of stay, age, illness severity, and abilities to perform activities and instrumental activities of daily living) that were associated with poor caregiver outcomes.

Table 1. Characteristics of the Caregivers at Baseline.

COPD Is Not the Whole Story

Posted by Rachel Wolfson • May 11th, 2016

79Many diagnostic guidelines use black or white parameters – either patients meet the criteria and have the disease, or they don’t. While guidelines like this can be useful for developing clear definitions, in practice many patients fall within a gray area. The current diagnosis of Chronic Obstructive Pulmonary Disease (COPD), for example, relies on spirometry results that show airflow limitation (i.e. a ratio of FEV1/FVC<0.70). Some smokers who do not meet this criterion, however, have reported symptoms suggestive of COPD and are potentially even being treated for COPD.

To better define this potential patient population, Woodruff et al report the results of an observational study, SPIROMICS, in this week’s NEJM. The authors enrolled over 2,000 ever-smokers (current and former smokers) and never-smokers (non-smoking controls) into the study. They then subdivided the ever-smokers into those with FEV1/FVC≥0.70 (i.e. with a diagnosis of COPD) or those without a diagnosis of COPD based on spirometry parameters. Using the COPD Assessment Test (CAT), they found that 50% of ever-smokers with preserved spirometry had symptoms of COPD, which was a bit less than the prevalence in ever-smokers with COPD (65%, p<0.001), but greater than the prevalence of symptoms in never-smokers (16%, p<0.001). Further, they followed these patients over time and found that ever-smokers with preserved spirometry had higher rates of exacerbations, reduced exercise tolerance, and higher rates of airway wall thickening on chest imaging in comparison to asymptomatic ever-smokers and never-smoking controls.

These data are an initial foray into defining a new population of patients who do not meet the criteria for COPD diagnosis, but who nonetheless suffer from symptoms suggestive of COPD due to their smoking history. Now that this population has been provisionally identified, Leonardi Fabbri, MD posits, in an accompanying editorial, that more work must be done to define treatments for this group. This means running more clinical trials to find treatments that can help these patients that fall in the gray area.

Don’t miss the NEJM Quick Take video summary on this study:

Eye of the Beholder

Posted by Carla Rothaus • May 6th, 2016

73Dermatomyositis, polymyositis, and necrotizing autoimmune myopathy all cause proximal muscle weakness. Proximal weakness is often progressive, with patients reporting difficulty in raising their arms above their head, climbing stairs, or standing from a seated position. Clinically, dermatomyositis is distinguished from polymyositis and necrotizing autoimmune myopathy by its distinctive dermal findings.

A 47-year-old man presented to an urgent care ambulatory clinic with a 3-day history of swelling around his left eye and a sensation of tightness in his throat. It had become difficult for him to swallow solids, and he felt as though food was sticking in his throat. A new Clinical Problem-Solving summarizes.

Clinical Pearl

• What are the characteristic dermal findings associated with dermatomyositis?

Dermatomyositis is distinguished from polymyositis and necrotizing autoimmune myopathy by its distinctive dermal findings, including Gottron’s papules (violaceous papules on the dorsum of the metacarpalphalangeal and interphalangeal joints), Gottron’s sign (nonpalpable macules over the extensor surfaces of joints), heliotrope rash (a violaceous rash involving the periorbital skin), V sign (also known as shawl sign), in which there are macular erythematous lesions over the anterior chest and back, and holster sign, in which these lesions appear over the upper lateral thighs. Patients may have dilated nail-fold capillaries (which can be visualized with a dermatoscope) and ragged or thickened cuticles. In rare instances, the characteristic cutaneous features of dermatomyositis develop without muscle involvement, in a condition that is designated amyopathic dermatomyositis or dermatomyositis sine myositis.

Clinical Pearl

• What laboratory findings may be seen in dermatomyositis?

Elevation in creatine kinase levels is characteristic of all the inflammatory myopathies, with levels rising up to 50 times as high as the upper limit of the normal range in patients with dermatomyositis. Myositis-specific antibodies are often measured, since findings can have prognostic significance. The most common such antibody is anti–Jo-1, which is present in up to 20% of patients with polymyositis or dermatomyositis. The anti–Jo-1 antibody is associated with the antisynthetase syndrome, a constellation of arthritis, Raynaud’s phenomenon, mechanic’s hands (in which there is cracking along the distal tip and edges of the fingers), and interstitial lung disease, which is associated with a poorer prognosis in patients with an inflammatory myopathy.

Morning Report Questions

Q: What is the nature of the cancer risk in patients with dermatomyositis? 

A: A reported 15 to 25% of patients with dermatomyositis have had prior cancer or have concurrent cancer, or cancer will develop in them. However, there does not appear to be a correlation between dermatomyositis and a particular type of cancer; in most patients, the diagnosis of dermatomyositis comes after the diagnosis of cancer. There are no consensus guidelines for cancer screening in patients with inflammatory myositis. It is prudent to ensure age-appropriate cancer screening; some experts recommend chest, abdominal, and pelvic imaging for further assessment in patients without a known cancer, although data are lacking in regard to the associated cost-effectiveness and outcomes. Anti–transcriptional intermediary factor 1γ (also referred to as anti-p155) and anti–nuclear matrix protein 2 are associated with an increased risk of cancer in adults with dermatomyositis; the former, which is included in the myositis-specific antibody panel at most laboratories, has been reported to have a positive predictive value of 78% and a specificity of 89%.

Q: What medications are used for the initial treatment of dermatomyositis? 

A: Although there is a paucity of controlled trials on the treatment of dermatomyositis, glucocorticoids are the mainstay of treatment for dermatomyositis, polymyositis, and autoimmune necrotizing myositis — largely on the basis of clinical experience. Oral prednisone is often started at a dose of 0.75 to 1 mg per kilogram of body weight, with intravenous glucocorticoids reserved for severe or progressive cases; doses are tapered gradually, primarily on the basis of the patient’s symptoms. Additional immunosuppressants are often added as glucocorticoid-sparing agents — most often methotrexate or azathioprine, although mycophenolate and cyclosporine have also been used.