Mastocytosis and Related Disorders

Posted by Carla Rothaus • July 10th, 2015

Mast-Cells-PITA new review article provides an overview of recent developments concerning the physiology and pathobiology of mast cells and discusses current diagnostic and therapeutic approaches to mast-cell disorders, with an emphasis on mastocytosis.

Pathologic conditions involving mast cells appear to be more common than once thought. The diagnosis and treatment of such disorders are challenging, given protean symptoms and the presence of coexisting conditions. In patients with severe symptoms or those with allergies to hymenoptera venom, the investigation of mast-cell monoclonality may provide the diagnosis. Most symptoms can be managed with histamine-receptor antagonists or other drugs that interfere with mast-cell mediators, along with blockers of mast-cell activation.

Table 1. Conditions That Can Mimic Mast-Cell Disorders.

Figure 1. Clinically Relevant Mediators Released from Mast Cells and Putative Effects.

Clinical Pearls

Describe the variants of mastocytosis and the associated clinical features.

The most common form of mastocytosis in children, cutaneous mastocytosis, is diagnosed in the first years of life. It is commonly characterized by multiple hyperpigmented macular or maculopapular lesions that become urticarial when rubbed or scratched (Darier’s sign). In most children with cutaneous mastocytosis, the condition resolves or improves by puberty. The categories of systemic mastocytosis, which is characterized by mast-cell infiltration of various internal organs (most commonly bone marrow), are indolent mastocytosis, aggressive mastocytosis, mastocytosis associated with a hematologic non-mast-cell-lineage disease, and mast-cell leukemia. Among patients with indolent systemic mastocytosis, which is the most common variant, life expectancy is similar to that in the general population. Aggressive systemic mastocytosis, which is characterized by specific tissue damage associated with mast cells, is most commonly identified in the bone marrow, liver, gastrointestinal tract, and cortical bone. Portal hypertension and ascites, malabsorption, cytopenias, and large osteolytic lesions with pathologic fractures may ultimately develop in these patients. Patients with systemic mastocytosis and associated hematologic disease often have evidence of an additional myeloproliferative or myelodysplastic syndrome.

What mutation is seen in a majority of patients with mastocytosis?

Almost all patients with indolent systemic mastocytosis and approximately 80% of all patients with systemic mastocytosis have a somatic “gain-of-function” mutation in KIT, most commonly in codon 816 (D816V), where a valine is substituted for an aspartate.

Cutaneous mastocytosis is associated with gain-of-function KIT mutations in approximately 60 to 80% of cases.

Morning Report Questions

Q: What are the diagnostic criteria for mastocytosis?

A: The diagnosis of systemic mastocytosis is based on the presence of one major and one minor criterion or three minor criteria established by the World Health Organization. The major criterion is multifocal clustering of mast cells (>15 mast cells per cluster) identified by means of tryptase immunohistochemical analysis, KIT immunohistochemical analysis, or both in an extracutaneous organ, commonly the bone marrow. Minor criteria include abnormal morphologic features of mast cells (e.g., spindle shapes with cytoplasmic projections and sometimes bilobed and multilobed nuclei), the presence of the KIT D816V mutation, expression of CD2 or CD25 on mast cells, and an increased basal serum tryptase level (greater than or equal to 20 ng per milliliter).

Q: What laboratory findings suggest mast-cell activation in patients in whom mast-cell counts are normal?

A: Patients with increased numbers of mast cells, as is the case in systemic mastocytosis, may not always have symptoms of mast-cell activation. Conversely, mast-cell activation is often seen in patients in whom the mast-cell burden is normal, as in patients with allergic rhinitis or those presenting with anaphylaxis in whom serum tryptase levels reportedly increase during the attack but later return to normal values. However, mast-cell activation and severe anaphylactic reactions are more common in patients with systemic mastocytosis than in healthy controls. The symptoms may be subtle in a patient who has a less severe form of mast-cell activation. Serum tryptase levels that increase by 20% above the baseline level plus an additional 2 ng per milliliter if measured within 4 hours after the onset of the acute event suggest mast-cell involvement. In some patients with primary severe mast-cell activation, there is evidence of mast-cell clonality (a KIT mutation or CD25+ mast cells) that may fulfill the diagnostic criteria for systemic mastocytosis. In other patients, there is evidence of clonal mast-cell expansion, but the criteria for systemic mastocytosis are not met and these patients are known to have monoclonal mast-cell activation, which is increasingly recognized in patients with hymenoptera-induced or idiopathic anaphylaxis.

Figure 2. Algorithm for Evaluation of Possible Mastocytosis.

 

A Man with Fever and Bacteremia

Posted by Carla Rothaus • July 10th, 2015


Man-with-Fever-and-Bacteremia-PITIn the latest Case Record of the Massachusetts General Hospital, fever developed in a 37-year-old American man living in Vietnam. He was transferred from a local infirmary to an international hospital. A blood culture grew Streptococcus constellatus; fever resolved with antibiotics. The patient was transferred for further evaluation.

The finding of Streptococcus constellatus bacteremia mandates a search for an abscess.

Clinical Pearls

What is the most common type of visceral abscess?

Liver abscess is the most common type of visceral abscess, accounting for about 13% of intraabdominal abscesses. Risk factors include diabetes, hepatobiliary or pancreatic diseases, or Klebsiella pneumoniae infection due to host factors (e.g., glucocorticoid therapy, alcoholism, chronic disease, or neoplasia). The mortality rate associated with a liver abscess can be as high as 12%.

What is the distinguishing feature of S. constellatus?

S. constellatus is a member of the S. milleri group, which is a member of the viridans group of streptococci. S. milleri are commensal organisms; they are usually not pathogenic. S. constellatus is part of the normal flora of the human oral cavity. Despite the usual commensal status of S. constellatus, the bacteria is considered to be a true pathogen when it is found in the blood. It is a facultative anaerobe whose distinguishing feature is its ability to cause abscesses.

Morning Report Questions

Q: What anatomic sites may be infected by S. milleri?

A: S. milleri infections usually affect the mouth and throat, causing dental, peritonsillar, or sinus abscesses. Spread of abscesses to deep spaces can lead to septic thrombophlebitis of the jugular vein (Lemierre’s syndrome). Bacteremia can occur, leading to metastatic abscess formation in the lung, brain, liver, kidney, and other tissues. Endocarditis can also occur, usually in a patient with an abnormal heart valve.

Q: What are some of the reported sequelae of fish-bone ingestion?

A: There have been many case reports of fish-bone ingestion in the literature. Most of these cases occur in Southeast Asia, because some of the fish there have smaller bones, as compared with the fish in Western regions. A common complication is a liver abscess, but esophageal perforation with deep-neck infection, a thyroid abscess, and tongue and mediastinal abscesses have also been reported. A 1999 case report from Japan included a review of seven previously reported cases of fish-bone ingestion. Hepatic abscess had occurred in all cases; in four cases, the fish bones penetrated the stomach wall (three penetrated the left lobe of the liver and one penetrated the right lobe), and in three cases, the fish bones pierced the duodenum. The case report from Japan also noted that few patients were aware that they had ingested a fish bone.

Loss of FEV1 and the pathogenesis of COPD

Posted by Rachel Wolfson • July 8th, 2015

Insight-picture-7-8-15For years, the dominant model for the pathogenesis of chronic obstructive pulmonary disease (COPD) has been that exposure to particulate matter (usually tobacco smoke) leads to a rapid decline in lung function, i.e., more than 40ml of FEV1 per year. This paradigm has recently come into question, but a careful study to test this model has yet to be performed.

In this week’s issue of NEJM, Lange et al. report the results of an analysis of three longitudinal cohort studies in which there was an initial spirometry assessment performed at around age 40-the “baseline”- and at least one subsequent measurement. The authors stratified the patients into two groups: those with a FEV1 below 80% at baseline (657 individuals) and those with baseline FEV1 greater than or equal to 80% (2207). In the former group, 26% had COPD after 22 years, while in the latter group 7% had COPD (P<0.001). Of the 332 individuals with COPD at the end of observation, about half had a normal FEV1 at the beginning of the trial and subsequently experienced a rapid decline of FEV1 (mean loss of 53 ml/year), while the other half had a reduced FEV1 at the start of the trial and a reduced rate of lung function decline (mean loss of 27 ml/year), despite similar rates of smoking between these two groups.

These results suggest that our current understanding of COPD may be neglecting another subtype of the disease. While some patients do indeed experience a rapid decline in lung function, it appears that others may have lower lung function at baseline, and experience a slow decline in lung function resulting in slower onset of COPD. However, these results do not rule out the possibility that a rapid decline in FEV1 occurred in the individuals with low FEV1 at baseline before the commencement of the trial. Thus, as Frank Speizer, MD, and James Ware, PhD, point out in an accompanying editorial, the ideal trial design would involve tracking lung function measurements from soon after birth through old age.

Another interesting question that arises is, if indeed there are subtypes of COPD, does this distinction reflect differences in the underlying pathogenesis, and would these patients respond differently to treatment? Although further studies will be needed to answer these important questions it will be a long time before we can get data about the lifetime changes in FEV1. As always the message for patients is that they are better off not smoking- that we know now.

Apply to Be an NEJM Editorial Fellow

Posted by Karen Buckley • July 6th, 2015

The NEJM invites applications for two one-year, full-time, paid editorial fellowships beginning in July 2016 from medical professionals at any career stage. Applications are due by September 1, 2015.

The editorial fellows review and edit Images in Clinical Medicine submissions, organize the Clinical Decisions series and write the Quick Takes under the supervision of senior editors. The fellows also moderate commenting at NEJM.org, review topic tagging for the NEJM website, write Insights posts for the Now@NEJM blog, and contribute to other Journal work according to their skills and inclinations. In addition, the fellows participate in the day-to-day editorial activities of the Journal, including attending the editorial meetings.

We are looking for candidates who have good medical judgment, can communicate that judgment in good written English, and can work independently. Applicants are not required to be U.S. citizens, but successful candidates must reside in the Boston area for the duration of the fellowship. Please send curriculum vitae and a letter of interest to Pam Miller, 10 Shattuck St., Boston, MA 02115 or editorial@nejm.org by September 1, 2015.

For more insight on the NEJM fellowship experience, see the article by Dr. Terry Schraeder, a former NEJM fellow, “NEJM Fellowship: The Ultimate Journal Club,” in Science Editor. Although written 10 years ago, it remains applicable to today’s fellowship.

A Man with Fever and Rash

Posted by Carla Rothaus • July 2nd, 2015

Man-with-a-fever-and-a-rash3In the latest Clinical Problem-Solving article, a 67-year-old man with hairy-cell leukemia presented to the clinic after 3 days of fevers, night sweats, arthralgias, and an erythematous vesicular-appearing rash on his back. He had not had headache, shortness of breath, bleeding episodes, vomiting, or diarrhea.

When caring for an immunocompromised patient, the clinician must continually reevaluate the differential diagnosis if the patient has not had the expected response to therapy, bearing in mind that multiple, concurrent disease processes may be present.

Clinical Pearls

What type of lymphocyte is primarily affected in hairy cell leukemia?

Hairy-cell leukemia is primarily a disorder of B cells, although T cells are also impaired.

What type of hematologic neoplasm is most commonly associated with a neutrophilic dermatosis?

A neutrophilic dermatosis can be seen with virtually any type of hematologic neoplasm, although it is most often associated with acute myeloid leukemia.

Morning Report Questions

Q: What is Sweet’s syndrome?

A: Sweet’s syndrome is an acute, febrile, neutrophilic dermatosis that can be associated with drugs, infection, inflammatory bowel disease, pregnancy, cancer, and many other illnesses. The syndrome is characterized by painful inflammatory nodules, papules, and plaques and is often accompanied by malaise, arthralgias, myalgias, and headaches. Dermal edema may lead to a pseudovesicular pattern. The pathogenesis of Sweet’s syndrome is not well understood, but it may be a hypersensitivity reaction in which the body’s response to an infection, cancer, or other illness stimulates the production of cytokines, including granulocyte colony-stimulating factor. This process eventually activates neutrophils and promotes abnormal migration of these neutrophils into dermal tissues.

Figure 1. Rash on the Patient’s Back at Presentation.

Q: How is Sweet’s syndrome diagnosed?

A: A commonly used diagnostic algorithm for Sweet’s syndrome requires confirmation of two major criteria and at least two of four minor criteria. The major criteria are the abrupt onset of painful or tender erythematous plaques or nodules and histologic findings that reveal a dense neutrophilic infiltration in the dermis without leukocytoclastic vasculitis. The minor criteria are malaise and fever, with a temperature higher than 100.4 degrees F (38 degrees C); association with an underlying cancer, inflammatory disease, pregnancy, vaccine administration, or nonspecific infection; substantial response to treatment with systemic glucocorticoids or second-line agents such as dapsone, colchicine, or potassium iodide; and three of the following abnormal laboratory values: erythrocyte sedimentation rate greater than 20 mm per hour, an elevated level of C-reactive protein, leukocytosis in which the white-cell count is greater than 8000 per cubic millimeter, and a percentage of neutrophils in the differential count that is greater than 70% as determined on a peripheral-blood smear.

Figure 3. Skin Biopsy.

Potassium Homeostasis

Posted by Carla Rothaus • July 2nd, 2015

Potassium-Homeostasis2The plasma potassium level is normally maintained within narrow limits by multiple mechanisms. The latest article in the Fluids and Electrolytes series reviews the mechanisms that regulate potassium homeostasis and describes the important role that the circadian clock exerts on these processes.

The plasma potassium level is normally maintained within narrow limits (typically, 3.5 to 5.0 mmol per liter) by multiple mechanisms that collectively make up potassium homeostasis. Such strict regulation is essential for a broad array of vital physiologic processes. The importance of potassium homeostasis is underscored by the well-recognized finding that patients with hypokalemia or hyperkalemia have an increased rate of death from any cause. In addition, derangements of potassium homeostasis have been associated with pathophysiologic processes, such as progression of cardiac and kidney disease and interstitial fibrosis.

Clinical Pearls

What systems regulate the balance between potassium intake and renal potassium excretion?

External potassium homeostasis regulates renal potassium excretion to balance potassium intake, minus extrarenal potassium loss and correction for any potassium deficits. External potassium balance involves three control systems. Two systems can be categorized as “reactive,” whereas a third system is considered to be “predictive.” A negative-feedback system reacts to changes in the plasma potassium level and regulates the potassium balance. Potassium excretion increases in response to increases in the plasma potassium level, leading to a decrease in the plasma level. A reactive feed-forward system that responds to potassium intake in a manner that is independent of changes in the systemic plasma potassium level has also been recognized. A predictive system appears to modulate the effect of reactive systems, enhancing physiologic mechanisms at the time of day when food intake characteristically occurs — typically, during the day in humans and at night in nocturnal rodents. This predictive system is driven by a circadian oscillator in the suprachiasmatic nucleus of the brain and is entrained to the ambient light-dark cycle. The central oscillator (clock) entrains intracellular clocks in the kidney that generate the cyclic changes in excretion. When food intake is evenly distributed over 24 hours, and physical activity and ambient light are held constant, this system produces a cyclic variation in potassium excretion.

Figure 3. Circadian Rhythm of Urinary Potassium Excretion in Humans during Two Levels of Potassium Intake.

What is “internal potassium homeostasis?”

Internal potassium homeostasis is the maintenance of an asymmetric distribution of total body potassium between the intracellular and extracellular fluid (approximately 98% intracellular and only a small fraction, approximately 2%, extracellular), which occurs by the balance of active cellular uptake by sodium-potassium adenosine triphosphatase, an enzyme that pumps sodium out of cells while pumping potassium into cells (called the sodium-potassium pump rate), and passive potassium efflux (called the leak rate). Little increase in the plasma potassium level occurs during potassium absorption from the gut in normal persons owing to potassium excretion by the kidney and potassium sequestration by the liver and muscle. Insulin, catecholamines, and mineralocorticoids stimulate potassium uptake into muscle and other tissues. Between meals, the plasma potassium level is nearly constant, as potassium excretion is balanced by the release of sequestered intracellular potassium.

Figure 1. Overview of Potassium Homeostasis.

Morning Report Questions

Q: What factors influence renal potassium handling?

A: The healthy kidney has a robust capacity to excrete potassium, and under normal conditions, most persons can ingest very large quantities of potassium (400 mmol per day or more) without clinically significant hyperkalemia. Potassium that is filtered at the glomerulus is largely reabsorbed in the proximal tubule and the loop of Henle. Consequently, the rate of renal potassium excretion is determined mainly by the difference between potassium secretion and potassium reabsorption in the cortical distal nephron and collecting duct. Both of these processes are regulated — potassium ingestion stimulates potassium secretion and inhibits potassium reabsorption. Factors that regulate potassium secretion and reabsorption can be divided into those that serve to preserve potassium balance (homeostatic) and those that affect potassium excretion without intrinsically acting to preserve potassium balance (contra-homeostatic). Examples of the latter include flow rate in the renal tubular lumen and the luminal sodium level. The acid-base balance also affects potassium excretion. The predominant effect of acidosis is to inhibit potassium clearance, whereas the predominant effect of alkalosis is to stimulate potassium clearance.

Table 1. Factors Regulating Potassium Secretion and Potassium Reabsorption.

Figure 2. Model of the Major Cell Types of the Cortical Collecting Duct.

Q: How are the central and peripheral biological clocks synchronized?

A: In vertebrates, a central clock in the suprachiasmatic nucleus of the brain and peripheral clocks that are present in virtually all cells regulate circadian rhythms. Among the many physiologic functions in humans that show circadian rhythms, few are more consistent and stable than the circadian rhythm of urinary potassium excretion. The timing signals from the central clock to the peripheral clocks remain uncertain, but adrenal corticosteroids and agents from other loci have been proposed or identified. Although the action of cortisol in promoting potassium excretion would suggest a direct (nonclock) hormonal effect, studies by Moore-Ede and colleagues indicate that cortisol serves as a clock synchronizer. Aldosterone also affects certain circadian clocks and, in particular, acutely induces the expression of period circadian clock 1 (PER1) in the kidney.

Advanced Dementia

Posted by Carla Rothaus • June 26th, 2015

Advanced dementia is a leading cause of death in the United States. A new Clinical Practice article covers treatment decisions guided by the goals of care — comfort is usually the primary goal, and tube feeding is not recommended.

In 2014, Alzheimer’s disease affected approximately 5 million persons in the United States, a number that is projected to increase to approximately 14 million by 2050.

Clinical Pearls

What are the features of advanced dementia?

The features of advanced dementia include profound memory deficits (e.g., inability to recognize family members), minimal verbal abilities, inability to ambulate independently, inability to perform any activities of daily living, and urinary and fecal incontinence.

Are there barriers to hospice care in the United States for patients with advanced dementia?

Eligibility guidelines for the Medicare hospice benefit require that patients with dementia have an expected survival of less than 6 months, as assessed by their reaching stage 7c on the Functional Assessment Staging tool (a scale ranging from stage 1 to stage 7f, with stage 7f indicating the most severe dementia) and having had one of six specified complications in the past year. However, these eligibility guidelines do not accurately predict survival. Although hospice enrollment of patients with dementia has increased over past decade, many barriers to accessing hospice care persist, particularly the requirement of having a life expectancy of less than 6 months. Given the challenge of predicting life expectancy among patients with advanced dementia, access to palliative care should be determined on the basis of a desire for comfort care, rather than the prognostic estimates.

Table 1. Hospice Guidelines for Estimating Survival of Less Than 6 Months in a Patient with Dementia.

Morning Report Questions

Q: What are some of the concerns regarding current management of patients with advanced dementia, especially when comfort is the goal of treatment?

A: Infections are very common in patients with advanced dementia. The Study of Pathogen Resistance and Exposure to Antimicrobials in Dementia (SPREAD), which prospectively followed 362 nursing home residents with advanced dementia, showed that in a 12-month period, two thirds were suspected to have infections, most commonly of the urinary or respiratory tract. In SPREAD, 75% of suspected infections were treated with antimicrobials, but less than half of all treated infections and only 19% of treated urinary tract infections met minimal clinical criteria for the initiation of antimicrobials. An estimated 75% of hospitalizations may be medically unnecessary or are discordant with the patients’ preferences and are thus avoidable. The goal of care for most patients is comfort, and hospitalization seldom promotes that goal, except in rare cases, such as in the treatment of hip fractures and when palliative care is unavailable. Daily medications should align with the goals of care, and drugs of questionable benefit should be discontinued. In 2008, an expert panel declared that the use of certain medications is inappropriate (i.e., not clinically beneficial) in patients with advanced dementia for whom comfort is the goal. Cross-sectional analyses of a nationwide pharmacy database showed that 54% of nursing home residents with advanced dementia were prescribed at least one of those medications. Of all the inappropriate medications prescribed, the most common were cholinesterase inhibitors (36%), memantine (25%), and statins (22%). Medications with questionable benefits accounted for 35% of the mean 90-day medication expenditures for the nursing home residents with advanced dementia to whom they were prescribed.

Q: What is the recommended approach to the care of patients with advanced dementia?

A: Advance care planning is a cornerstone of the care of patients with advanced dementia. Providers should educate health care proxies about the disease trajectory (i.e., the final stage of an incurable disease) and expected clinical complications (e.g., eating problems and infections). Providers should also counsel proxies about the basic tenet of surrogate decision making, which is to first consider written or oral advance directives previously expressed by patients and then choose treatment options that align with these advance directives (e.g., a do-not-hospitalize order) before acute problems arise, and ideally, avoid treatments that are inconsistent with the patients’ wishes. In the absence of clear directives, proxies will have to either exercise substituted judgment according to what they think the patient would want or make a decision based on the patient’s best interests. Some observational studies showed that patients with advanced dementia who had advance directives had better palliative care outcomes (e.g., less tube feeding, fewer hospitalizations, and greater enrollment in hospice) than those without advance directives. Treatment decisions for patients with advanced dementia should be guided by the goals of care; providers and patients’ health care proxies must share in the decision making.

A Newborn Girl with Hyperbilirubinemia

Posted by Carla Rothaus • June 26th, 2015

In the latest Case Record of the Massachusetts General Hospital, a newborn girl was transferred to this hospital because of hypotension, coagulopathy, anemia, and hyperbilirubinemia. Generalized edema, anuria, and respiratory distress developed, and the trachea was intubated. Diagnostic procedures were performed.

Neonatal hemochromatosis is the most common cause of neonatal liver failure and the leading indication for liver transplantation in infants. It is characterized by progressive iron deposition during the fetal period, predominantly targeting the liver, pancreas, heart, and thyroid and salivary glands but sparing the reticuloendothelial system.

Clinical Pearls

Is neonatal hemochromatosis a genetic disease?

Neonatal hemochromatosis was considered for decades to be part of the hemochromatosis family and to have a genetic cause. Despite multiple attempts, no candidate genes were identified. Also known as gestational alloimmune liver disease, neonatal hemochromatosis is now recognized to be a congenital alloimmune hepatitis and is defined as the association of severe neonatal liver disease with iron deposition (siderosis) in extrahepatic tissue. Neonatal hemochromatosis is associated with a high recurrence rate (80 to 92%) in subsequent pregnancies, a pattern that cannot be explained by genetic inheritance but is consistent with an alloimmune pathogenesis.

What are typical clinical features associated with this disease?

Extensive liver injury is typically present at birth, and some signs– such as placental edema, oligohydramnios, intrauterine growth retardation, prematurity, and stillbirth — can be detected antenatally. Hypoalbuminemia, hypoglycemia, coagulopathy, a low fibrinogen level, thrombocytopenia, and eventual multiorgan failure are the hallmarks of the disease. Low aminotransferase levels at birth are consistent with a long-standing antenatal process.

Morning Report Questions

Q: What diagnostic tests are obtained when clinical and laboratory findings suggest a diagnosis of neonatal hemochromatosis?

A: Gradient-echo MRI has become the standard noninvasive diagnostic procedure for neonatal hemochromatosis. All newborns have a relatively large amount of iron deposited in the liver because of prenatal maternal transfer; therefore, to make the diagnosis of neonatal hemochromatosis, abnormal iron storage in the pancreas, which is not seen in healthy newborns, must also be established.T1-weighted and T2-weighted MRI images can be helpful in detecting iron deposits in the liver, pancreas, and thyroid glands. The presence of iron deposits in the biopsy specimens of affected organs has become the standard in establishing the diagnosis. Since marked coagulopathy makes a liver biopsy exceedingly difficult to perform, biopsy of the minor salivary gland offers an excellent alternative.

Biopsy of the minor salivary gland is a useful method for detecting evidence of extrahepatic hemosiderosis and is a highly sensitive and specific test for neonatal hemochromatosis.

Figure 1. MRI Scans of the Liver.

Figure 2. Biopsy Specimens.

Q: What treatment options are available, and what survival rates are associated with this disease?

A: Therapy for neonatal hemochromatosis includes treatment for liver failure with antioxidant cocktails (including vitamin E, N-acetylcysteine, prostaglandins, and selenium), fresh-frozen plasma, and cryoprecipitate. Infusions of intravenous immune globulin (IVIG) and exchange transfusion have also been suggested. Exchange transfusion is performed to remove any maternal alloantibodies remaining in the fetal circulation, and IVIG is administered to displace specific reactive IgG antibodies that are bound to target antigens and to bind with circulating complement. Favorable outcomes among patients with neonatal hemochromatosis have been described; however, the prognosis remains seriously guarded, and the disease is associated with an overall survival of 36%. In a large case series, the survival rate was 51% among patients who had undergone a liver transplantation and 22% among those who had not undergone a transplantation.

New Interactive Medical Case: Test Your Skills

Posted by Karen Buckley • June 24th, 2015

Approximately 10 minutes after being stung on the right lower leg by a yellow jacket (a type of wasp), a 45-year-old man began to feel lightheaded and nauseated.  He called emergency medical services, and paramedics arrived 10 minutes later.  They found him to be alert but anxious, with scattered areas of erythema on his trunk and a small, localized area of tenderness, swelling and erythema at the site of the sting.  His blood pressure was 70/45 mm Hg, and his heart rate was 108 beats per minute.

Test your diagnostic and therapeutic skills with this new Interactive Medical Case on NEJM.org.  Receive feedback on your choices and learn more about the condition and optimal treatment steps.

Browse previous Interactive Medical Cases. Try one or all 37 cases and earn CME credit or MOC points now!

Ischemic Optic Neuropathies

Posted by Carla Rothaus • June 19th, 2015

A new review article covers the diagnosis, pathophysiological features, and prognosis of ischemic optic neuropathy, a relatively common cause of visual loss in older patients, including visual loss after cardiac surgery. It must be distinguished from inflammatory optic neuritis.

ION refers to all ischemic causes of optic neuropathy. ION is classified as anterior ION or posterior ION depending on the segment of optic nerve that is affected. Anterior ION accounts for 90% of ION cases. Anterior ION and posterior ION are further categorized into nonarteritic or arteritic. The term arteritic refers to ION caused by small-vessel vasculitis, most often giant-cell arteritis.

Clinical Pearls

What is the clinical presentation of nonarteritic anterior ischemic optic neuropathy, and how is it diagnosed?

Nonarteritic anterior ION is manifested as isolated, sudden, painless, monocular vision loss with edema of the optic disc. Progressive worsening of vision over a period of a few days or a few weeks is not uncommon, presumably related to worsening ischemia in the context of a local compartment syndrome associated with the disc edema. The severity of vision loss varies from normal visual acuity with visual-field defects to profound vision loss. The diagnosis of acute nonarteritic anterior ION is primarily clinical and relies on demonstration of vision loss with a relative afferent pupillary defect and edema of the optic disc, which consists of the optic-nerve head. A crucial finding on examination is the presence of a small, crowded optic-nerve head with a small physiological cup. This small cup-to-disc ratio defines a “disc at risk.” Although this finding is difficult to see during the acute phase of nonarteritic anterior ION when the optic disc is swollen, examination of the normal eye should show a disc at risk. Imaging of the optic nerve is typically normal in patients with nonarteritic anterior ION.

Figure 1. Blood Supply to the Optic Nerve and Anatomy of the Optic-Nerve Head.

What causes nonarteritic anterior ischemic optic neuropathy, and can it be successfully treated?

Although nonarteritic anterior ION results from disease of the small vessels supplying the anterior portion of the optic nerve, its exact cause remains unknown. A disc at risk is essential for the development of nonarteritic anterior ION. Other optic-nerve anomalies resulting in crowding of the optic-nerve head, such as optic-nerve drusen and papilledema, may also confer a predisposition to nonarteritic anterior ION. The absence of a disc at risk in a patient with presumed nonarteritic anterior ION should raise the possibility of arteritic anterior ION or another cause of optic neuropathy. There is no established treatment for nonarteritic anterior ION such as there is for the arteritic type of anterior ION. Thus, the most important management concerns are distinguishing nonarteritic anterior ION from arteritic anterior ION and detecting and controlling vascular risk factors in cases of nonarteritic anter ION. Most proposed therapeutic interventions in nonarteritic anterior ION are based on the presumed mechanism and cascade of events. Although multiple therapies have been attempted, most have not been adequately studied, and animal models of nonarteritic anterior ION have emerged only in the past several years. Given the paucity of data regarding the exact pathophysiology of nonarteritic anterior ION and its treatment, the maxim “first, do no harm” is most important in the management of this devastating optic neuropathy.

Figure 2. Presumed Pathophysiology of Nonarteritic Anterior ION and Potential Treatment Strategies.

Figure 3. Nonarteritic Anterior ION in the Context of a Disc at Risk.

Morning Report Questions

Q: How do the clinical findings of posterior ischemic optic neuropathy differ from those of anterior ischemic optic neuropathy, and is the diagnostic evaluation the same for both?

A: When the posterior portion of the optic nerve is ischemic, there is no visible disc edema and the term “posterior ION” is used. Nonarteritic posterior ION is exceedingly rare, as compared with nonarteritic anterior ION. The typical presentation of nonarteritic posterior ION is isolated, painless, sudden loss of vision in one eye, with a relative afferent pupillary defect and a normal-appearing optic-nerve head. As expected with any optic neuropathy, optic-disc pallor develops 4 to 6 weeks later. The clinical diagnosis of nonarteritic posterior ION is difficult and remains a diagnosis of exclusion, with other causes of posterior optic neuropathy (e.g., inflammatory and compressive causes) ruled out by high-quality MRI of the brain and orbits with contrast and with fat suppression and by an extensive workup for underlying systemic inflammatory disorders. Giant-cell arteritis is the most common cause of posterior ION, and must be considered in every patient older than 50 years of age who has posterior ION.

Q: What clinical findings may help to distinguish arteritic from nonarteritic anterior ischemic optic neuropathy?

A: The clinical presentation of arteritic ION is similar to that of nonarteritic ION, but several “red flags” should raise clinical suspicion for arteritic ION. Systemic symptoms of giant-cell arteritis may precede visual loss by months; however, about 25% of patients with biopsy-confirmed giant-cell arteritis present with isolated ION without any systemic symptoms (so-called occult giant-cell arteritis). The degree of visual loss is often more severe in arteritic anterior ION than in nonarteritic anterior ION. In one study, 54% of the patients with arteritic anterior ION were unable to count fingers as compared with 26% of the patients with nonarteritic anterior ION. Untreated arteritic ION becomes bilateral in days to weeks in at least 50% of cases. The affected swollen optic nerve is often pale immediately in giant-cell arteritis, whereas pallor is delayed in nonarteritic anterior ION. The finding of associated retinal or choroidal ischemia in addition to ION is highly suggestive of giant-cell arteritis. Finally, a disc at risk is not necessary for arteritic anterior ION; the absence of a crowded optic disc in the second eye of a patient with anterior ION should make the diagnosis of nonarteritic anterior ION unlikely and should increase the probability of arteritic anterior ION.