Control of Hypertension in Pregnancy

Posted by Carla Rothaus • January 30th, 2015

In a trial comparing less-tight control of hypertension (target diastolic blood pressure, 100 mm Hg) with tight control (85 mm Hg) among pregnant women, rates of pregnancy loss, high-level neonatal care, and serious maternal complications were similar between groups.

Blood-pressure targets for women with nonsevere hypertension during pregnancy are much debated. Relevant randomized, controlled trials have been small and of moderate or poor quality; tight control (the use of antihypertensive therapy to normalize blood pressure) has been associated with maternal benefits (e.g., a decrease in the frequency of severe hypertension and possibly in the rate of antenatal hospitalization) but sometimes, though not consistently, with perinatal risks (e.g., poor fetal growth and well-being). The Control of Hypertension in Pregnancy Study (CHIPS) was designed to compare less-tight control with tight control of nonproteinuric, nonsevere hypertension in pregnancy with respect to perinatal and maternal outcomes.

Clinical Pearls

- How common is hypertension among pregnant women?

Almost 10% of pregnant women have hypertension; hypertension is preexisting in 1% have preexisting hypertension, gestational hypertension without proteinuria develops in 5 to 6%, and preeclampsia develops in 2%. Preexisting hypertension and gestational hypertension before 34 weeks are associated with an increased risk of perinatal and maternal complications.

- How does tight control as compared to less-tight control of nonsevere, nonproteinuric hypertension in pregnant women affect perinatal outcomes?

In the study by Magee et al., the frequency of the primary outcome – pregnancy loss or high-level neonatal care for more than 48 hours – did not differ significantly between the groups. The primary-outcome rates were similar among 493 women assigned to less-tight control and 488 women assigned to tight control (31.4% and 30.7%, respectively; adjusted odds ratio, 1.02; 95% confidence interval [CI], 0.77 to 1.35). Most high-level neonatal care for more than 48 hours was related to complications of prematurity. There were no significant between-group differences with respect to other perinatal outcomes, including the proportion of newborns who were small for gestational age and the frequency of respiratory complications and treatment.

Table 2. Primary and Other Perinatal Outcomes.

Morning Report Questions

Q: How does tight control as compared to less-tight control of nonsevere, nonproteinuric hypertension in pregnant women affect serious maternal complications and other outcomes?

A: The frequency of the secondary outcome — serious complications (including death) — was also similar in the two groups. There were no maternal deaths. The most common maternal complication was the receipt of blood products. The frequency of abruption did not differ significantly between the groups. The gestational age at delivery and the frequency of cesarean delivery did not differ significantly between the groups.

Table 3. Secondary and Other Maternal Outcomes.

Q: Were there any significant between-group differences in this study?

A: Severe hypertension (equal to or greater than 160/110 mm Hg) developed in 40.6% of the women in the less-tight-control group and 27.5% of the women in the tight-control group (P<0.001).

Figure 2. Blood-Pressure Values among Women with Severe Hypertension.

Allergic Rhinitis

Posted by Carla Rothaus • January 30th, 2015

Allergic rhinitis is common and is often associated with asthma. Treatment includes intranasal glucocorticoids, oral and nasal antihistamines, leukotriene-receptor antagonists, and, when pharmacotherapy is not effective or produces unacceptable side effects, allergen immunotherapy. Read the latest Clinical Practice review on this topic.

The frequency of sensitization to inhalant allergens is increasing and is now more than 40% in many populations in the United States and Europe. Allergic rhinitis contributes to missed or unproductive time at work and school, sleep problems, and among affected children, decreased involvement in outdoor activities.

Clinical Pearls

- What is the relation between allergic rhinitis and other atopic
conditions?

The presence of allergic rhinitis (seasonal or perennial) significantly increases the probability of asthma: up to 40% of people with allergic rhinitis have or will have asthma. Atopic eczema frequently precedes allergic rhinitis. Patients with allergic rhinitis usually have allergic conjunctivitis as well. The factors determining which atopic disease will develop in an individual person and the reasons why some people have only rhinitis and others have rhinitis after eczema or with asthma remain unclear.

- What is included in the differential diagnosis for rhinitis, and how is allergic rhinitis diagnosed?

The differential diagnosis includes forms of rhinitis that are nonallergic in origin such as a noninflammatory rhinopathy (also known as vasomotor rhinitis) and nonallergic chronic rhinosinusitis. Seasonal symptoms can be caused by viral infections, especially if the patient is a child or lives with children; rhinovirus has a marked peak in incidence in September and a smaller peak in the spring. The diagnosis of allergic rhinitis is often made clinically on the basis of characteristic symptoms and a good response to empirical treatment with an antihistamine or nasal glucocorticoid. Formal diagnosis is based on evidence of sensitization, measured either by the presence of allergen-specific IgE in the serum or by positive epicutaneous skin tests (i.e., wheal and flare responses to allergen extracts) and a history of symptoms that correspond with exposure to the sensitizing allergen. Epicutaneous skin testing and testing for allergen-specific IgE have similar sensitivity, although they do not identify sensitization in an entirely overlapping group of patients.

Morning Report Questions

Q: What pharmacologic treatment is available for allergic rhinitis?

A: Pharmacologic treatment options include H1-antihistamines, intranasal glucocorticoids, and leukotriene-receptor antagonists. Therapy usually starts with oral antihistamines, frequently initiated by the patient. H1-antihistamines are also available as nasal sprays by prescription. The intranasal preparations appear to be similar to oral preparations in efficacy but may be less acceptable to patients owing to a bitter taste. The effect of antihistamines on symptoms, especially nasal congestion, is modest. They can be combined with oral decongestants, and the combination can improve nasal airflow in the short term (on the basis of data from trials lasting 2 to 6 weeks), at the cost of some side effects. Topical nasal decongestants are more effective than oral agents, but there are reports of rebound congestion (rhinitis medicamentosa) or reduced effectiveness beginning as early as 3 days after treatment, and only short-term use is recommended. In one study, adding an intranasal glucocorticoid reversed the reduced effectiveness of a topical decongestant. Intranasal glucocorticoids are the most effective pharmacotherapy for seasonal allergic rhinitis, yet the overall efficacy is moderate. Although the clinical effects appear within a day, the peak effect in cases of perennial rhinitis is not reached for several weeks. The superiority of intranasal glucocorticoids over antihistamines in the treatment of perennial allergic rhinitis is uncertain. The effect of leukotriene-receptor antagonists on the symptoms of allergic rhinitis is similar to or slightly less than that of oral antihistamines, and some randomized trials have shown a benefit of adding the leukotriene-receptor antagonist montelukast to an antihistamine. Although the majority of trials have favored intranasal glucocorticoids over this combination, data are inconsistent; this combination should be considered for patients whose symptoms are inadequately controlled with an antihistamine and who do not wish to
use a glucocorticoid nasal spray. There is no significant benefit of adding an oral antihistamine or montelukast to a nasal glucocorticoid. However, in randomized trials, the combination of an intranasal antihistamine plus an intranasal glucocorticoid has been shown to be superior to either agent alone.

Q: What types of immunotherapy are available in the United States?

A: Although allergen immunotherapy has traditionally been administered subcutaneously in the United States, rapidly dissolving tablets for sublingual administration were recently approved by the Food and Drug Administration for treatment of grass and ragweed allergy. With immunotherapy, unlike pharmacotherapy, the effect persists after the discontinuation of therapy. If there is improvement in the first year, injections are generally continued for at least 3 years. Data from randomized trials are lacking to guide decisions about the duration of therapy. Subcutaneous immunotherapy carries a risk of systemic reactions, which occur in 0.1% of injection visits, in rare cases leading to life-threatening anaphylaxis (1 reaction per 1 million injection visits). Although subcutaneous immunotherapy has not been compared with sublingual immunotherapy in large head-to-head trials, indirect comparisons suggest that subcutaneous immunotherapy is more effective for symptom relief. However, sublingual immunotherapy has a clear advantage in terms of safety, with very few reports of anaphylactic reactions.

Table 1. Pharmacotherapy and Immunotherapy for Allergic Rhinitis.

Abdominal Pain, Dyspnea, and Diplopia

Posted by Carla Rothaus • January 27th, 2015

Peripheral causes of acute generalized weakness include motor neuronopathies, acute acquired polyneuropathies, myopathies, and presynaptic and postsynaptic neuromuscular-transmission disorders.

Clinical Pearls

- Is botulism a presynaptic or postsynaptic neuromuscular-transmission disorder?

Botulism is a toxin-mediated disease that results in the presynaptic blockade of acetylcholine transmission across the neuromuscular junction. 

- What is adult intestinal toxemia?

Adult intestinal toxemia is a rare form of botulism that is caused by colonization of the gut by toxigenic clostridium bacteria. In adult intestinal toxemia, C. baratii is more frequently the pathogen than C. botulinum.

Morning Report Questions

Q: What are the clinical features of botulism? 

A: Patients typically present with blurred vision, ptosis, and diplopia. Impaired bulbar function is manifested as facial weakness, dysarthria, and dysphagia. Descending muscle weakness affects head control and subsequently arm, respiratory, and leg musculature. The weakness typically has a proximal-to-distal pattern and is bilateral. Autonomic symptoms, including nausea, vomiting, ileus, poor pupil reactivity, and alterations in blood pressure and heart rate, are common; the gastrointestinal symptoms may precede the neurologic symptoms. Intact sensorium, preserved sensation, and absence of fever are typical. Results of cerebrospinal fluid, blood, and urine tests and imaging studies are usually normal.

Q: How is botulism managed?  

A: The mainstays of botulism management are rapid clinical recognition and notification of public health authorities, which enables the prompt investigation of the toxin source and possible other cases and the prompt delivery and administration of antitoxin. The effectiveness of antitoxin is greatest if it is given early after the onset of neurologic symptoms, ideally within 24 hours, and thus antitoxin should be administered, after consultation with public health authorities, on the basis of the clinical diagnosis and without awaiting the results of diagnostic testing. Antibiotic therapy has not been shown to improve neurologic recovery and is not recommended. There is no person-to-person transmission of botulism, and in the health care setting, patients can be treated with standard precautions.     

PD-1 Blockade with Nivolumab

Posted by Carla Rothaus • January 23rd, 2015

Preclinical studies suggest that Reed-Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. An ongoing phase 1 study tests the hypothesis that nivolumab, a PD-1-blocking antibody, can inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin’s lymphoma.

Clinical Pearls

- How do tumors exploit the PD-1 [programmed death 1] pathway?

The PD-1 pathway serves as a checkpoint to limit T-cell-mediated immune responses. Both PD-1 ligands, PD-L1 and PD-L2, engage the PD-1 receptor and induce PD-1 signaling and associated T-cell “exhaustion,” a reversible inhibition of T-cell activation and proliferation. By expressing PD-1 ligands on the cell surface and engaging PD-1 receptor-positive immune effector cells, tumors can co-opt the PD-1 pathway to evade an immune response from the patient.

- Why might PD-1 blockade provide an effective therapy for Hodgkin’s lymphoma?

Classic Hodgkin’s lymphomas include small numbers of malignant Reed-Sternberg cells within an extensive but ineffective inflammatory and immune-cell infiltrate. The genes encoding the PD-1 ligands, PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively), are key targets of chromosome 9p24.1 amplification, a recurrent genetic abnormality in the nodular-sclerosis type of Hodgkin’s lymphoma. The 9p24.1 amplicon also includes JAK2, and gene dose-dependent JAK-STAT activity further induces PD-1 ligand transcription. These copy-number-dependent mechanisms and less frequent chromosomal rearrangements lead to overexpression of the PD-1 ligands on Reed-Sternberg cells in patients with Hodgkin’s lymphoma. Epstein-Barr virus (EBV) infection also increases the expression of PD-1 ligands in EBV-positive Hodgkin’s lymphomas. The complementary mechanisms of PD-1 ligand overexpression in Hodgkin’s lymphoma suggest that this disease may have genetically determined vulnerability to PD-1 blockade.

Morning Report Questions

Q: What are the adverse events that have been reported to date after nivolumab administration?

A: Adverse events that are commonly associated with PD-1-blocking antibodies include pruritus, rash, and diarrhea. Immune-mediated pneumonitis, colitis, hepatitis, hypophysitis, and thyroiditis are
less common toxic effects of PD-1 blockade. In the study by Ansell et al., a total of 23 patients with relapsed or refractory Hodgkin’s lymphoma have been enrolled since August 2012. Results are reported through June 16, 2014. Adverse events were mainly of grade 1 or 2. Overall, drug-related adverse events were reported in 18 patients (78%). The most common were rash (in 22%) and a decreased platelet count (in 17%). Drug-related grade 3 adverse events, which were reported in 5 patients (22%), included the myelodysplastic syndrome, pancreatitis, pneumonitis, stomatitis, colitis, gastrointestinal inflammation, thrombocytopenia, an increased lipase level, a decreased lymphocyte level, and leukopenia. There were no drug-related grade 4 or 5 adverse events. There were no treatment-related deaths.

Table 2. Drug-Related Adverse Events in the 23 Patients.

Q:What is the efficacy of nivolumab in patients with relapsed or refractory Hodgkin’s lymphoma?

A: In heavily pretreated patients with relapsed or refractory Hodgkin’s lymphoma, the majority of whom had had a relapse after autologous stem-cell transplantation and brentuximab treatment, the use of nivolumab was associated with an overall response rate of 87% and a rate of progression-free survival of 86% at 24 weeks. Given the limited therapeutic options for patients with Hodgkin’s lymphoma whose disease progresses after autologous stem-cell transplantation and the relatively short-lived responses to brentuximab after relapse, nivolumab-mediated PD-1 blockade may represent a promising targeted treatment for these patients.

Table 3. Clinical Activity in Nivolumab-Treated Patients.

Figure 1. Response Characteristics and Changes in Tumor Burden in
Patients with Hodgkin’s Lymphoma Receiving Nivolumab
.

Infant Mortality through the Years

Posted by Rena Xu • January 21st, 2015

Prematurity has long been recognized as a major contributor to infant mortality. One in every four infants born extremely prematurely (between 22 and 29 weeks’ gestation) does not survive. A large number die within the first 12 hours after birth, and many more never make it out of the hospital, most commonly dying from a respiratory condition.

Efforts have been made to improve the prognosis for these infants. Neonatal care has evolved in its use of glucocorticoids, antibiotics, surfactant, and ventilation, to name just a few examples of interventions targeting pulmonary-related deaths. Have these changes in practice changed the state of infant mortality?

A study published this week in NEJM looked at the incidence and causes of death among extremely premature infants from 2000 to 2011. The investigators prospectively collected data on over 22,000 extremely premature infants born in one of 25 Neonatal Research Centers. They followed them from birth to 120 days (or to death, discharge, or hospital transfer, if one of these occurred first). If hospitalized for more than 120 days, infants were evaluated for death until 1 year of age.

Roughly one fourth of the infants died during their birth hospitalization (6075 deaths). Over 40% of deaths occurred in the first 12 hours after birth. Earlier gestational age at birth was linked to a worse outcome; infants who died had a mean gestational age a little over 24 weeks, versus 26 weeks in the infants who survived. Their mothers were also less likely to have received prenatal glucocorticoids (62% versus 88%).

Overall, through the years, mortality declined. The number of deaths per 1000 live births was 275 in the 2000-2003 period; 285 in the 2004-2007 period; and 258 in the 2008-2011 period (P=0.003). The study detected significant changes in neonatal care across these periods. There was an increase in the percentage of women receiving any prenatal care, as well as the percentage receiving prenatal glucocorticoids. Use of prenatal antibiotics decreased, while use of high-frequency ventilation increased, more than doubling among the most premature infants.

Trends in cause of mortality also shifted. The number of deaths attributed to respiratory distress syndrome and bronchopulmonary dysplasia decreased from the 2000-2003 period to the 2008-2011 period (from 83 to 68 per 1000 live births). This decrease accounted for more than half the decline in overall mortality. The number of deaths attributed to immaturity, infection, or central nervous system injury also fell. There was, however, an increase in the number of deaths attributed to necrotizing enterocolitis (from 23 to 30 per 1000 live births).

“The increase in mortality attributed to necrotizing enterocolitis may be related to improvements in the early survival of infants who would have otherwise died before they reached the typical postnatal age at which necrotizing enterocolitis occurs,” the authors hypothesized.

While this study was not designed to evaluate causality, it identified an improvement in overall and pulmonary-related mortality among extremely premature infants concurrent with changes in neonatal practice. The authors concluded, “Our findings underscore the continued need to develop and implement strategies for reducing the potentially lethal complications of premature birth.”

Abdominal Pain, Syncope, and Hypotension

Posted by Carla Rothaus • January 16th, 2015

In the latest Case Record of the Massachusetts General Hospital, a 25-year-old man was admitted to the hospital because of abdominal pain, syncope, and hypotension that occurred while he was lifting heavy boxes. An abdominal ultrasound examination revealed a hypoechoic lesion in the liver. A diagnostic test was performed.

Rupture or leak of hydatid-cyst fluid due to accidental or surgical trauma or extreme physical activity is a well-documented cause of anaphylaxis. There have been rare cases of anaphylaxis due to spontaneous rupture.

Clinical Pearls

The definitive hosts for E. granulosus are dogs and other canines. Stray dogs often feed on carcasses or offal of slaughtered animals and thus acquire parasites, including cestodes (tapeworms) such as Taenia saginata, T. solium , and four species of echinococcus — Echinococcus granulosus, E. multilocularis, E. vogeli, and E. oligarthrus. These parasites can cause IgE-mediated anaphylaxis. A human becomes the accidental host with the ingestion of infected embryonated eggs shed by stray dogs. The eggs, which contain the infectious oncospheres, penetrate the intestinal wall and enter the bloodstream. Although most oncospheres lodge in the liver and develop into hydatid cysts, such cysts can also occur in the lungs, bones, brain, heart, and muscle.

What are the clinical manifestations of hydatid cysts?

Clinical manifestations of hydatid cysts occur after a highly variable incubation period. The majority of persons with hydatid cysts remain asymptomatic for years, but symptoms related to infection of a cyst occur in approximately 25% of such persons. Occasionally, a hydatid cyst of the liver causes problems such as rupture into the biliary tree, obstruction, fibrosis, and enterocutaneous fistula. Hydatid cysts have also been associated with the development of bacterial infection. In rare cases, a cyst ruptures into the peritoneal cavity and causes anaphylaxis.

Morning Report Questions

Q: When imaging shows a suspected hydatid cyst in the liver, how is the diagnosis of echinococcal infection confirmed?

A: In general, diagnostic aspiration is not routinely recommended in patients with hydatid cysts because of the risk of fluid leakage resulting in an anaphylactic reaction and possible dissemination of the disease. Antibody detection is the most commonly used diagnostic method. Sensitivity and specificity vary among tests, depending on the type of antigen and the stage and location of the disease.

Q: How are hydatid cysts treated?

A: The choice of therapy is guided by the radiographic appearance of the cyst and the patient’s clinical symptoms. Small cysts that have a stable cyst wall and no daughter cysts may require only clinical observation without intervention or may be treated with antihelminthic agents alone, whereas large cysts with multiple septations or daughter cysts typically require invasive intervention. For large cysts (>5 cm in diameter) or those that are complex, patients may undergo surgery (either cystectomy or partial liver resection) or percutaneous aspiration by means of the PAIR (puncture, aspirate, inject, and reaspirate) procedure. The PAIR procedure is performed by inserting a catheter through the germinal layer of the cyst, aspirating the contents, injecting fluid that is lethal to the protoscolices (e.g., ethanol or hypertonic saline), and then repeatedly flushing the cyst. Surgery is favored for cysts with many compartments that may not be amenable to complete evacuation and for very large cysts that cause compressive symptoms; surgery is also favored when cysts are in close proximity to the biliary tree, because the PAIR procedure can result in leakage of cyst contents or scolicidal solution into the biliary system, causing cholangitis.

Multiple-System Atrophy

Posted by Carla Rothaus • January 16th, 2015

Multiple-system atrophy is a neurodegenerative disease characterized by progressive autonomic failure, parkinsonism, and cerebellar and pyramidal tract symptoms. Glial cytoplasmic inclusions of α-synuclein are a defining histologic feature. There is no curative treatment. A new review on this topic comes from Innsbruck Medical University’s Alessandra Fanciulli, M.D., and Gregor K. Wenning, M.D., Ph.D.

Multiple-system atrophy is an adult-onset, fatal neurodegenerative disease characterized by progressive autonomic failure, parkinsonian features, and cerebellar and pyramidal features in various combinations. It is classified as the parkinsonian subtype if parkinsonism is the predominant feature and as the cerebellar subtype if cerebellar features predominate.

Clinical Pearls

What is known about the epidemiology and pathogenesis of multiple-system atrophy?

The estimated mean incidence is 0.6 to 0.7 cases per 100,000 person-years, with a range of 0.1 to 2.4 cases per 100,000 person-years. Cases of the parkinsonian subtype outnumber cases of the cerebellar subtype in most countries by 2:1 to 4:1, although the cerebellar subtype is more frequent in Japan, with genetic or epigenetic factors possibly exerting an influence. Disease onset is usually in the sixth decade of life, with both sexes equally affected. The mean survival from the onset of symptoms is 6 to 10 years, with few patients surviving more than 15 years. No environmental factors are known to affect the risk of multiple-system atrophy. Multiple-system atrophy is generally considered a sporadic disease. Variable degrees of olivopontocerebellar atrophy and striatonigral degeneration are typically found at postmortem examination of patients with multiple-system atrophy, which broadly reflect the presence of ataxia and parkinsonism during life. Although the pathogenic mechanisms underlying multiple-system atrophy remain partially unclear, converging evidence from preclinical models and postmortem studies suggests that it is a primary oligodendrogliopathy. Proteinaceous oligodendroglial cytoplasmic inclusions (also called Papp–Lantos bodies) are the histologic hallmark of multiple-system atrophy.

What are the motor and non-motor features of multiple-system atrophy?

Like Parkinson’s disease, multiple-system atrophy has a prodromal premotor phase in 20 to 75% of cases. Parkinsonism, with slowness of movements, rigidity, and a tendency to fall, characterizes the motor presentation of the parkinsonian subtype of multiple-system atrophy. Parkinson-like “pill-rolling” rest tremor is unusual, whereas irregular postural and action tremor with superimposed jerks is seen in as many as 50% of patients with multiple-system atrophy. Cerebellar ataxia predominates in the motor presentation of the cerebellar subtype of multiple-system atrophy. Cerebellar features consist of a wide-based gait, uncoordinated limb movements, action tremor, and spontaneous, gaze-evoked, or positional downbeat nystagmus. Spasticity or pyramidal weakness should cast doubts on a diagnosis of multiple-system atrophy, but generalized hyperreflexia, as well as a Babinski sign, may occur in 30 to 50% of cases. Early and severe autonomic failure is a key feature of multiple-system atrophy, and the most frequently affected domains are urogenital and cardiovascular. Severe orthostatic hypotension, defined as a blood pressure decrease of 30 mm Hg systolic or 15 mm Hg diastolic within 3 minutes after a passive head-up tilt or standing from the recumbent position, is the main feature of cardiovascular autonomic failure in clinically established multiple-system atrophy. Respiratory disturbances are characteristic of multiple-system atrophy. Diurnal or nocturnal inspiratory stridor develops in as many as 50% of patients at some time but is more frequent in advanced disease than in earlier stages, and sleep apneas affect about 40% of patients. Dementia or visual hallucinations are not consistent with a diagnosis of multiple-system atrophy; these symptoms in the presence of parkinsonism and autonomic failure should prompt consideration of dementia with Lewy bodies.

Figure 2. Multidisciplinary Presentation of MSA.

Morning Report Questions

Q: How is multiple-system atrophy diagnosed and treated?

A: Because of its protean manifestations, multiple-system atrophy may be misdiagnosed, especially at disease onset. The consensus guidelines define three degrees of certainty for the diagnosis of multiple-system atrophy: definite, probable, and possible. Only symptomatic therapy is available at present, including pharmacologic and nonpharmacologic approaches. Unfortunately, the evidence level is low for these approaches, with few exceptions. Most of the commonly used drugs are prescribed off- label.

Table 1. Diagnostic Criteria for Multiple-System Atrophy (MSA).

Q: What is the usual clinical course of a patient diagnosed with multiple-system atrophy?

A: Multiple-system atrophy is characterized by a relentless worsening of motor and nonmotor symptoms during an average time frame of 10 years, with more rapid progression at the onset. Approximately 50% of patients require walking aids within 3 years after the onset of motor symptoms, 60% require a wheelchair after 5 years, and the median time before the patient is bedridden is 6 to 8 years. Counseling patients on life expectancy can be challenging for the treating physician, because there are reports of both aggressive variants with a disease duration of less than 3 years and more benign cases with prolonged survival.

Figure 3. Natural History of MSA.

Complicated Grief

Posted by Carla Rothaus • January 9th, 2015

Complicated grief is intense grief after the death of a loved one that lasts longer than expected according to social norms and causes functional impairment. Psychotherapy directed at the loss and at restoring activities and effective functioning is recommended.

The condition of complicated grief, which is also called prolonged grief disorder, affects about 2 to 3% of the population worldwide. This condition is characterized by intense grief that lasts longer than would be expected according to social norms and that causes impairment in daily functioning. Complicated grief can follow the loss of any close relationship. Clinical experience suggests that without treatment, symptoms of complicated grief diminish slowly and can persist.

Clinical Pearls

What are the symptoms of complicated grief?

The hallmark of complicated grief is persistent, intense yearning, longing, and sadness; these symptoms are usually accompanied by insistent thoughts or images of the deceased and a sense of disbelief or an inability to accept the painful reality of the person’s death. Rumination is common and is often focused on angry or guilty recrimination related to circumstances of the death. Avoidance of situations that serve as reminders of the loss is also common, as is the urge to hold onto the deceased person by constantly reminiscing or by viewing, touching, or smelling the deceased person’s belongings. People with complicated grief often feel shocked, stunned, or emotionally numb, and they may become estranged from others because of the belief that happiness is inextricably tied to the person who died. They may have a diminished sense of self or discomfort with a changed social role and are often confused by their seemingly endless grief.

What are the risk factors for complicated grief?

Risk factors include a history of mood or anxiety disorders, alcohol or drug abuse, and multiple losses. Depression in persons who have been caregivers during a loved one’s terminal illness and depression early in bereavement are predictors of complicated grief later in bereavement. Personal factors such as these may interact with characteristics of the relationship with the deceased or with the circumstances, context, or consequences of the death to increase the risk. Losing someone with whom one has had a close relationship can be especially hard if the bereaved person had a difficult upbringing or if there are unusually stressful consequences of the death, inadequate social supports, serious conflicts with friends or relatives, or major financial problems after the death.

Morning Report Questions

Q: How can clinicians identify patients with complicated grief?

A: Questions about important losses should be part of a standard diagnostic evaluation, especially in the case of older patients, for whom loss is common. Patients are sometimes ashamed of their persistently intense grief, so it is important for clinicians to ask direct questions in a sensitive and empathic way. A semistructured-interview format to facilitate assessment of complicated grief is a shortened version of a validated instrument. The Brief Grief Questionnaire and the Inventory of Complicated Grief are self-report questionnaires that can be used to screen patients for complicated grief. The clinical evaluation of a bereaved person should also include screening for other psychiatric and medical disorders, since coexisting conditions are common.

Table 1. Provisional Proposed Guidelines for the Diagnosis of Prolonged Grief Disorder in the International Classification of Diseases, 11th Revision.

Table 2. Differential Diagnosis of Complicated Grief, Major Depression, and Post-Traumatic Stress Disorder (PTSD).

Q: What treatments are recommended for complicated grief?

A: Randomized, controlled trials have shown that psychotherapy is efficacious for complicated grief, so it is the first-line treatment. A short-term approach called complicated grief treatment is the treatment that has been most extensively studied to date. Its objectives are to identify and resolve complications of grief and to facilitate adaptation to loss. Trials suggest that interventions that include strategies to reduce avoidance of thoughts about the death and avoidance of activities and places that are reminders of the loss are more effective than those that do not. Although data are lacking from randomized trials to inform the use of pharmacotherapy for complicated grief, antidepressant medication is used commonly in practice. Five open-label trials that involved a total of 50 patients suggested improvement in patients who received antidepressants, but not benzodiazepines.

Table 3. Core Components of Treatment for Complicated Grief.

Dengue Vaccine

Posted by Carla Rothaus • January 9th, 2015

Dengue is a mosquito-borne viral illness that causes hundreds of millions of infections each year. No specific therapy exists. In a randomized, controlled trial involving Latin American children, a tetravalent dengue vaccine showed significant protective efficacy.

Several dengue vaccine candidates are in development. As part of the clinical development of a recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV), twin phase 3 clinical trials were initiated in Asia and Latin America to assess the efficacy of a schedule of three doses (administered at 0, 6, and 12 months) against symptomatic, virologically confirmed dengue (VCD).

Clinical Pearls

How have rates of dengue infection in endemic areas changed over the past decade?

Dengue is a mosquito-borne disease that is present in many parts of the world. From 2003 through 2013, the number of dengue cases that were reported to the Pan American Health Organization (PAHO) increased by a factor of five. The disease is caused by one of four closely related virus serotypes from the genus flavivirus. Mosquitoes that transmit the virus are present in tropical and subtropical regions worldwide and in some temperate areas of the United States, Europe, Africa, and the Middle East. Dengue is an increasing public   health problem despite efforts to manage epidemics through vector control.

Is there evidence that the CYD-TDV vaccine under development is effective?

In the Latin American trial, the CYD-TDV vaccine had an efficacy of 60.8% against symptomatic VCD after a three-dose vaccination schedule among children between the ages of 9 and 16 years. In the per-protocol analysis, the vaccine efficacy was 60.8% (95% confidence interval [CI], 52.0 to 68.0), on the basis of 176 cases of VCD in the vaccine group and 221 in the control group that were diagnosed more than 28 days after the third dose. In the intention-to-treat         analysis, which included all children who received at least one injection from month 0 to 25, the vaccine efficacy was 64.7% (95% CI, 58.7 to 69.8). These efficacy results are consistent with those of the similarly designed Asian trial.

Table 2. Vaccine Efficacy against Any Serotype of Dengue.

Morning Report Questions

Q: Is the CYD-TDV vaccine effective against all 4 dengue serotypes, and in both seropositive and seronegative recipients?

A: In the two studies, efficacy was higher against serotypes 3 and 4 than against serotypes 1 and 2. In Asia, efficacy against serotype 2 was 35% after the third injection, which was not significant in comparison with placebo, whereas in the Latin American study, the point estimate was 42.3%, which was significant. Efficacy in the small subgroup of children who had seronegative status at baseline was 43.2%, which was not significant in comparison with placebo but was similar to that in the Asian study (35.5%).

Table 3. Serotype-Specific Vaccine Efficacy.

Q: Is this vaccine safe?  

A: In the Latin American study, safety and reactogenicity profiles from 25 months of active surveillance were consistent with previous reports that identified no major concerns. No pattern of serious adverse events was identified.

Table 4. Safety Analysis and Subgroup Analysis of Reactogenicity Events Reported within 28 Days after Any Injection.

New Series: International Health Care Systems

Posted by Karen Buckley • January 5th, 2015

A new series of Perspective articles on the health care systems of selected countries around the world begins with Sweden.

The Public–Private Pendulum in Sweden

The Swedish health care system is largely the product of past Social Democratic governments, which emphasized equity and reliance on the public sector. But since 1990, more centrist governments have turned to privatization, competition, and greater consumer choice.

Working with the Commonwealth Fund, a private foundation whose international program in health policy supports its mission of promoting high-performing health care systems in the United States and elsewhere, NEJM has commissioned articles on health policies in place or under development in Europe, Asia, North America, South America, Africa, and Australasia. Each article will present one or several aspects of a national health care system, chosen by the authors as distinctive, new, innovative, or potentially instructive for other countries.

To facilitate comparisons among countries, each entry in the series will include two brief case studies, following two typical patients through the country’s system — one a young, pregnant woman, the other a middle-aged man with a myocardial infarction. In addition, each piece will include a table covering a set of key system parameters. That information will also be used to construct an interactive graphic that permits specific international comparisons.  As the article series builds, so will the breadth and complexity of the graphic.

For more information, read the full editorial introducing the series.  And, look for the next article, on Canada’s health care system, on February 5.