A Man in an Unresponsive State

Posted by • July 14th, 2016

2016-07-08_11-07-57Clinical care for patients with acute liver failure should focus on preventing and treating associated complications, identifying the cause so that targeted therapy (if available) can be initiated, and determining the patient’s transplant eligibility.

A 32-year-old man was admitted to this hospital after being found in an unresponsive state in his jail cell. He had jaundice and encephalopathy; results of liver-function tests were abnormal, and CT revealed cerebral edema. Diagnostic tests were performed. A new Case Records of the Massachusetts General Hospital summarizes.

Clinical Pearl

• What factors are associated with an increased risk for acetaminophen-induced hepatotoxicity?

Even therapeutic doses of acetaminophen can occasionally result in acute liver failure under certain circumstances. This phenomenon has been referred to as therapeutic misadventure and has been reported in patients who have chronic alcoholism and limited food intake that results in malnutrition and glutathione deficiency. This combination of factors leads to hepatic glutathione deficiency, which results in an inability of the liver to detoxify acetaminophen metabolites and causes oxidative injury to hepatocytes. In addition, the concomitant administration of opioids, such as oxycodone, can slow intestinal motility and enhance acetaminophen toxicity.

Clinical Pearl

• What are some of the therapies for hepatic encephalopathy in patients with acute liver failure?

Therapies for hepatic encephalopathy in patients with acute liver failure target elevated intracranial pressure; such therapies include hyperosmotic therapies such as mannitol and hypertonic saline, hyperventilation, and the induction of hypothermia. In contrast, lactulose is not indicated for the treatment of hepatic encephalopathy due to acute liver failure, because it may worsen electrolyte abnormalities and dehydration and does not address the underlying defect, the loss of ammonia detoxification.

Morning Report Questions

Q: How can a patient with remote hepatitis B virus (HBV) serologic test results that included a positive test for HBV surface antibodies be susceptible to acute HBV infection?

A: There are several possibilities to consider. First, a test result for HBV surface antibodies years earlier might have been a false positive; however, analytical false positives are uncommon with this assay. Second, patients with a positive test for HBV surface antibodies because of an HBV infection in the past can, on rare occasion, be infected with HBV again because of incomplete protection afforded by these antibodies against another HBV serotype. Third, a breakthrough infection in a vaccinated person is possible; however, of patients who have an antibody response to the HBV vaccine, even those who have a waning serum level of HBV surface antibodies, the majority retain immunologic memory and would be expected to have a protective HBV surface antibody response on reexposure to HBV. When such breakthrough infections have been documented in apparently immunocompetent persons, they have typically been transient and asymptomatic.

Q: What serologic findings characterize the inactive-carrier phase of chronic HBV infection?

A: In patients in whom acute HBV infection does not resolve but rather progresses to chronic infection, the disease can evolve through several phases — including immunotolerant, immunoactive, and inactive-carrier phases — that are influenced by the infected patient’s immunologic response. During the inactive-carrier phase, serum HBV DNA levels are low or even undetectable, serum aminotransferase levels are typically normal, HBV surface antigen can be lost, and seroconversion of HBV surface antibodies can occur. The HBV genome persists in a stable form in the nuclei of infected hepatocytes, even in the absence of detectable circulating HBV surface antigen, and infection can reactivate at a later time, at which point both HBV surface antigen and HBV core IgM antibodies may become detectable in the serum. Reactivation is sometimes seen in patients who are immunosuppressed (e.g., owing to the administration of glucocorticoids or cancer chemotherapy agents or to progressive HIV infection), but reactivation can also occur spontaneously.

Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting

Posted by • July 13th, 2016

2016-07-08_11-11-05Patients are fearful of nausea and vomiting during the course of cancer treatment, as it is an expected side effect of chemotherapy. Senior oncology physicians describe the early days of cancer treatment when large bowls lined the ward, positioned close to each patient. In the present age, we are still concerned about chemotherapy-induced nausea and vomiting (CINV). New agents such as 5-hydroxytryptamine-3 (5HT3) receptor antagonists, neurokinin-1 (NK-1) receptor antagonists, and long-established drugs such as dexamethasone are within the oncologist’s armamentarium. Despite a combination of these agents, patients can still suffer from severe nausea and vomiting, which may lead to hospital admissions, delays in treatment and plenty of misery.

Olanzapine, an antipsychotic drug that blocks several neurotransmitters, is not licensed for use in CINV. However, small single center studies have suggested that this drug is a useful treatment in cases of poorly controlled emesis. Olanzapine received approval for use in 1996, and since 2011 it has been available in a generic formulation. In a double-blind phase III study published in this week’s NEJM, Navari and colleagues investigated the role of olanzapine in CINV. All eligible patients were administered highly emetogenic chemotherapy regimens that included cisplatin (>70mg/m2), or doxorubicin (60mg/m2) and cyclophosphamide (600mg/m2). Patients who were chemotherapy naïve were randomly assigned to receive olanzapine (10mg/day, oral) or placebo over the first four days of one treatment cycle. All patients were also treated with 5-HT3 receptor antagonists, NK-1 receptor antagonists, and dexamethasone in accordance with international anti-emetic guidelines.

The primary endpoint compared the number of patients with no nausea in the acute (0-24 hours post chemotherapy), delayed (24-120 hours post-chemotherapy) and the overall (0-120 hours post-chemotherapy) periods among those receiving highly emetogenic chemotherapy.

The trial participants were from 46 academic or community practice institutions within the United States. The final analysis included 186 patients in the olanzapine arm and 183 patients in the placebo group. The proportion of patients with no nausea was significantly higher in the olanzapine arm compared to placebo arm in the acute (74% vs. 45% p=0.0015), delayed (42% vs. 25%, p=0.0015) and overall periods (37% vs. 22%, p=0.0015). Complete responses, which measured the absence of emesis and no use of rescue anti-emetics, were also significantly higher among patients treated with olanzapine in all three time periods. Among adverse events, patients receiving olanzapine reported more undesired sedation on day 2 post-chemotherapy; however, patients did not discontinue treatment and these side effects resolved.

This placebo-controlled trial shows the benefit of olanzapine in the treatment of CINV in combination with other anti-emetics. However, the study protocol was only used in one cycle of highly emetogenic chemotherapy. Optimal dosing, safety and efficacy in multiple chemotherapy cycles have not yet been determined, and the authors suggest future clinical trials address these issues.

In an era of enormous costs of cancer care, this is a useful trial that demonstrates a new use for an available, inexpensive drug. Oncology is continuing to apply new agents with novel mechanisms of action to the treatment of cancers; however, chemotherapy is likely to remain a foundation of cancer treatment. Management of CINV will continue to be a difficult problem for patients receiving intense, multi drug chemotherapy.

A Bruising Loss

Posted by • July 7th, 2016

2016-07-01_10-18-50Whereas inherited clotting-factor deficiencies are typically clinically evident from birth, the sudden appearance of a bleeding diathesis in a previously healthy adult is suggestive of an acquired factor inhibitor. Although inhibitors to most of the major clotting factors have been described, factor VIII inhibitors are the most common; however, factor VIII inhibitors are still rare, with an estimated incidence of one to two persons per million per year.

A 32-year-old woman presented to her physician with a 3-week history of spontaneous bruising on her arms, legs, and back. The bruising began shortly after she had had sore throat, coryza, and malaise for several days, symptoms that had resolved without intervention. A new Clinical Problem-Solving summarizes.

Clinical Pearl

• What laboratory findings suggest the presence of a factor inhibitor?

A factor inhibitor should be suspected in any patient who has spontaneous bruising and an unexplained new elevation in aPTT (activated partial-thromboplastin time), particularly if the aPTT fails to be corrected after the patient’s plasma is mixed in a 1:1 ratio with normal plasma. The appearance of factor VIII inhibitors in postpartum women (usually after the first or second child), is classic. They have also been described in patients who have an underlying autoimmune disease or an underlying malignant condition, or in older patients in the absence of recognized diseases.

Clinical Pearl

• What is the Bethesda assay?

The titer of the factor VIII inhibitor is determined through the use of the Bethesda assay, in which the patient’s plasma is serially diluted with normal plasma to measure the potency of anticlotting factor activity. One Bethesda unit is defined as the inverse of the dilution of the patient’s plasma that results in 50% residual factor activity when the patient’s plasma is mixed with fixed amounts of normal plasma; any value over 5 Bethesda units is considered to be a high titer.

Morning Report Questions

Q: What is the treatment for acquired factor VIII inhibitors? 

A: Treatment of patients who have acquired factor VIII inhibitors is initially directed at controlling bleeding; longer-term therapy is also initiated to suppress inhibitor production. Whereas patients with congenital hemophilia in whom acquired inhibitors develop have a response to high doses of factor VIII, this treatment is rarely useful for acquired inhibitors that develop in patients without congenital hemophilia. Instead, treatment with recombinant factor VIIa or activated prothrombin complex concentrates should be used. Both compounds effectively negate the need for intrinsic factor VIII activity, which acts to amplify the activation of factor X; this step is not absolutely required for the generation of thrombin and can be bypassed either by adding activated factor VII plus inactive factors IX, X, and prothrombin, as in activated prothrombin complex concentrates, or by adding supraphysiologic doses of activated factor VII alone. Both agents have been associated with serious thromboembolic events, including catastrophic strokes, even in patients with severe bleeding. The rarity of these events has precluded the identification of risk factors for thrombosis, but given the risk, the agents should not be continued once the bleeding has stopped. Glucocorticoid therapy plus cyclophosphamide is the traditional first-line approach to therapy aimed at suppressing inhibitor production, but rituximab also appears to have efficacy. Patients with very high titers of inhibitors (>100 Bethesda units) may require more aggressive therapy, with all three agents simultaneously, with intravenous immunoglobulin, or with both approaches.

Figure 1. Mechanism of Factor VIII Inhibitors and Therapeutic Agents.

Q: Do factors VIII inhibitors ever clear without therapy?

A: The natural history of spontaneously acquired factor VIII inhibitors varies. A report published before the introduction of immunosuppressive therapy described rare cases in which factor VIII inhibitors acquired post partum spontaneously cleared in patients within 12 to 18 months after presentation, but the accumulated data suggest that this outcome is much more the exception than the rule.

Polycystic Ovary Syndrome

Posted by • July 7th, 2016

2016-07-01_10-26-33The polycystic ovary syndrome is a disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries.

The polycystic ovary syndrome increases the risk of infertility, endometrial cancer, abnormal glucose metabolism, and dyslipidemia. Strategies such as lifestyle modification, hair removal, and combined oral contraceptive therapy and other pharmacotherapies are reviewed. A new Clinical Practice summarizes.

Figure 1. Basic Pathophysiology of Hyperandrogenemia in the Polycystic Ovary Syndrome.

Clinical Pearl

• How are “polycystic ovaries” defined?

Polycystic ovarian morphologic features are currently defined as 12 or more antral follicles (2 to 9 mm in diameter) in either ovary, an ovarian volume that is greater than 10 ml in either ovary, or both. A transvaginal transducer with frequencies of 8 MHz or greater commonly detects an antral follicle count in this range in asymptomatic women (in ≥50% of asymptomatic women in some series), and some experts recommend a criterion with a higher antral follicle count (≥25) for sufficient specificity. Appropriate use of either criterion requires an experienced ultrasonographer; an unqualified report of “polycystic ovaries” is inadequate for diagnostic purposes. Ovarian ultrasonography is not required for diagnosis when both hyperandrogenism and ovulatory dysfunction are present.

Clinical Pearl

• How is the polycystic ovary syndrome diagnosed?

Three sets of criteria for the polycystic ovary syndrome in women have been developed. Each set involves different combinations of hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphologic features. The polycystic ovary syndrome is a diagnosis of exclusion. Nonclassic congenital adrenal hyperplasia can closely mimic this syndrome. An early-morning, early follicular-phase plasma level of 17-hydroxyprogesterone of less than 200 ng per deciliter effectively rules out 21-hydroxylase deficiency, which is the most common cause of nonclassic congenital adrenal hyperplasia. Androgen-secreting ovarian or adrenal tumors are rare, but they should be considered in patients with abrupt, rapidly progressive, or severe hyperandrogenism, marked hyperandrogenemia, or both.

Table 1. Diagnostic Criteria for the Polycystic Ovary Syndrome.

Morning Report Questions

Q: Name some of the conditions for which women with the polycystic ovary syndrome are at increased risk.

A: Among women with this syndrome, 50 to 80% are obese. Impaired glucose tolerance is reported in 30 to 35% of U.S. women with classic polycystic ovary syndrome, and type 2 diabetes mellitus is reported in 8 to 10%; the risk of these conditions is influenced by age, adiposity, and a family history of diabetes. Subclinical vascular disease (e.g., impaired endothelial function, increased carotid-artery intima–media thickness, and elevated coronary-artery calcium scores) has also been reported in women with the polycystic ovary syndrome and appears to be at least partly independent of adiposity. The risk of endometrial cancer is estimated to be 2.7 times as high among women with the polycystic ovary syndrome as among women without the syndrome, and the lifetime risk of endometrial cancer among women with the syndrome is 9%. Women with the polycystic ovary syndrome also have increased risks of pregnancy complications (e.g., gestational diabetes and preeclampsia), obstructive sleep apnea, and emotional distress (e.g., depression and anxiety).

Q: What are some of the general approaches to management of the polycystic ovary syndrome?

A: Treatment decisions are informed by patient priorities, the likely effectiveness and potential risks of available therapies, and whether the woman wishes to become pregnant. Typical therapeutic targets include hirsutism, irregular menses (and the risk of endometrial hyperplasia), and infertility. Mechanical hair removal (e.g., shaving and plucking) may be adequate to address hirsutism, but when pharmacologic therapy is needed, combined hormonal (estrogen–progestin) oral contraceptives are considered to be first-line agents. Other benefits of combined oral contraceptives include amelioration of acne, regular withdrawal bleeding that contributes to prevention of endometrial hyperplasia, and contraception. Oral spironolactone is an androgen-receptor antagonist that can reduce the growth of terminal hair. Spironolactone is typically used as an add-on therapy to combined oral contraceptives. Metformin reduces hyperinsulinemia and lowers serum testosterone levels by approximately 20 to 25% in women with the polycystic ovary syndrome. Metformin is recommended for women with the polycystic ovary syndrome and impaired glucose tolerance or type 2 diabetes that does not respond adequately to lifestyle modification. Clomiphene is generally considered to be the first-line agent for induction of ovulation in women with the polycystic ovary syndrome.

Table 2. Anticipated Effects of Common Therapeutic Options for the Polycystic Ovary Syndrome.

Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit

Posted by • July 6th, 2016

2016-07-06_12-55-31Ms. G is a 42-year-old woman admitted to your ICU with septic shock in the setting of a urinary tract infection.  She was started on a norepinephrine infusion in the emergency room. Her labs reveal a creatinine of 3.0 mg/dL, increased from a prior baseline of 0.6 mg/dL; pH is 7.3 and potassium is 4.9 mEq/L. Her urine output is dropping, despite the fact that she received crystalloids for fluid resuscitation. In other words, she has clear signs of acute kidney injury (AKI). You remember the “AEIOUs,” the mnemonic for the indications for urgent dialysis – acidosis, electrolyte derangement, intoxications, overload, uremia. Ms. G doesn’t meet any of these criteria yet, but you are worried about her.  Will delaying dialysis cause her harm?

A study published online in May and appearing in this week’s NEJM aims to answer this clinical question.  Prior studies have suggested a possible mortality benefit from early renal-replacement therapy (RRT), which can facilitate tighter control of volume status and potential prevention of uremic complications such as coagulopathy and encephalopathy.  This present trial, which took place in 31 ICUs in France, enrolled adult patients with severe acute kidney injury (AKI) from acute tubular necrosis and who required mechanical ventilation, vasopressors or both and randomized them either an early or delayed strategy for renal-replacement therapy. Dialysis was initiated as soon as possible after randomization in the early strategy, while the patients in the delayed-strategy group were dialyzed only if they met one of several specific indications, such as hyperkalemia, acidemia, uremia, severe oliguria or anuria. Patients in both groups could be treated with either intermittent hemodialysis (HD) or continuous veno-venous hemofiltration (CVVH).

Of 620 patients enrolled, 312 were randomized to early strategy and 308 to delayed strategy.  98% of the patients in the early-strategy group underwent dialysis, as compared with only 51% patients in the delayed-strategy group. The primary outcome was mortality at 60 days, which did not differ between the two groups (48.5% in early vs. 49.7% in delayed group). There was also no difference between the two groups in a number of pre-specified secondary outcomes, including number of ventilator-free days, vasopressor-free days, length of stay in the ICU, and need for RRT at day 28 and 60. The delayed-strategy group had fewer days with dialysis catheters, and notably also fewer bloodstream infections.

Almost 50% of patients in the delayed-strategy group never received dialysis. The patients in the delayed-strategy group also were observed to have more rapid recovery of renal function.

The authors acknowledge several limitations to their study. Notably, 50% of the patients received HD initially, and only 30% received solely CVVH during their treatment. While prior meta-analyses have not supported a benefit of one method of RRT over another in the critical care setting, there are possible downsides to HD that could influence outcomes.  The authors are careful not to overreach the claims based on the trial results; they recommend careful surveillance when deciding to delay RRT and rapid initiation of dialysis if and when acute indications arise.

In an accompanying editorial, Dr. Ravinda Mehta, Professor of Medicine in the Division of Nephrology at the University of California, San Diego, notes that the trial has good methodology and clear outcomes, but highlights the need for “dynamic risk-stratification tools to identify patients who will not need renal replacement therapy.”

So, based on the results of this trial, you opt for a strategy of careful active surveillance for Ms. G. You continue to monitor her urine output and electrolytes closely, not initiating dialysis for now.  You are relieved when she never meets any indications for dialysis.   Her renal function improves, and she makes a full recovery.

The authors of this paper are available to answer your questions and discuss their research from July 6-16 on the NEJM Group Open Forum.  Join the discussion now!

Axial Spondyloarthritis

Posted by • July 1st, 2016

2016-06-27_11-33-18The classic clinical description of ankylosing spondylitis was made in the late 1800s and was refined by the addition of radiographic descriptions during the 1930s. Pathological investigation revealed the importance of enthesitis (inflammation at sites of ligamentous attachment to bone) and synovitis. The identification in 1973 of a very strong association with human leukocyte antigen B27 (HLA-B27) led to heightened awareness of the disorder. The concept of spondyloarthritis was proposed in 1974 to emphasize the interrelatedness of ankylosing spondylitis and several other conditions that had previously been described separately. Spondyloarthritis is currently classified as predominantly axial, affecting the spine, pelvis, and thoracic cage, or predominantly peripheral, affecting the extremities.

This new Review Article summarizes the clinical definition of ankylosing spondylitis and axial spondyloarthritis, discusses the pathogenesis of these conditions, and reviews approaches to management.

Table 1. Current and Classic Classifications of Spondyloarthritis.

Clinical Pearl

• Name some features of the inflammatory back pain that characterizes axial spondyloarthritis.

Spondyloarthritis is differentiated from other causes of back pain when the nature and pattern of the pain and the age of the patient are considered. The most typical symptom is inflammatory back pain. Such pain is usually dull and insidious in onset and is felt deep in the lower back or buttocks. Another prominent feature is morning back stiffness that lasts for 30 minutes or more, diminishes with activity, and returns after inactivity. Although initially the back pain is intermittent, over time it becomes more persistent. Nocturnal exacerbation of pain is common, particularly during the second half of the night, forcing the patient to rise and move around. Pain is often present in the thoracic spine as well. Cervical involvement typically occurs late but can predominate. Pain in the chest occurs in more than 40% of patients with spondyloarthritis. If the source of the pain is not accurately diagnosed, patients may be subject to unnecessary diagnostic workups for cardiovascular disease or other intrathoracic diseases. Inflammatory back pain occurs in 70 to 80% of patients with ankylosing spondylitis and is relatively uncommon in patients whose pain has another source.

Table 2. Characteristics of Inflammatory Back Pain.

Clinical Pearl

• What are the classification criteria for axial spondyloarthritis?

In 2009, the Assessment of Spondylo Arthritis International Society (ASAS) formulated classification criteria for axial spondyloarthritis that were based on imaging, clinical, and laboratory criteria. With these criteria, the diagnosis is established in persons who have had back pain for 3 or more consecutive months before reaching 45 years of age, who have had the presence of sacroiliitis confirmed on MRI or plain radiography, and who have at least one clinical or laboratory finding that is characteristic of spondyloarthritis. Alternatively, persons with this history who have a positive test result for HLA-B27 plus two features of spondyloarthritis as detected on clinical examination or laboratory analysis also fulfill the criteria for a diagnosis of axial spondyloarthritis. The various criteria have an additive effect on the certainty of diagnosis. The ASAS criteria for axial spondyloarthritis have been criticized for introducing additional diagnostic heterogeneity, both by including both the imaging and nonimaging diagnostic groups together within the category of nonradiographic axial spondylitis and by including nonradiographic axial spondyloarthritis and ankylosing spondylitis together within the category of axial spondyloarthritis. These criteria will probably undergo further revision in coming years.

Figure 2. Algorithm for the Diagnosis or Exclusion of Axial Spondyloarthritis.

Figure 3. Pathogenic Mechanisms in Axial Spondyloarthritis.

Morning Report Questions

Q: What are some of the extra-articular manifestations of ankylosing spondylitis?

A: Acute anterior uveitis has a lifetime prevalence of 30 to 40% in patients with ankylosing spondylitis. Psoriasis occurs in more than 10% of patients with ankylosing spondylitis, and inflammatory bowel disease in 5 to 10%, with Crohn’s disease being more common than ulcerative colitis. Osteoporosis of the spine and peripheral bones is common in ankylosing spondylitis. The combination of spinal rigidity from the formation of syndesmophytes and osteoporosis within trabecular bone contributes to a spinal fracture rate that is as high as 10% among these patients and is associated with a high risk of devastating spinal cord injury.

Q: How is axial spondyloarthritis managed?

A: Treatment goals for axial spondyloarthritis include reducing symptoms, improving and maintaining spinal flexibility and normal posture, reducing functional limitations, maintaining the ability to work, and decreasing the complications associated with the disease. Nonsteroidal antiinflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase 2, are the first-line drug treatment for pain and stiffness. Continuous NSAID treatment is recommended for persistently active, symptomatic disease, with doses adjusted in accordance with the severity of symptoms. For patients whose symptoms are not controlled by NSAID therapy or for whom NSAIDs have unacceptable side effects, the use of tumor necrosis factor (TNF) inhibitors is strongly recommended. In 13 randomized, controlled trials and many open-label studies, five TNF inhibitors —  infliximab, etanercept, adalimumab, golimumab, and certolizumab — have produced rapid, profound, and sustained improvement in both objective and subjective indicators of disease activity and patient functioning. Approximately 60% of patients have an adequate and usually sustained response to TNF inhibitors, often with partial or full remission of symptoms. The long-term use of systemic glucocorticoids is relatively contraindicated, partly because of the increased risk of vertebral osteoporosis, but may be unavoidable in some patients with severe uveitis or inflammatory bowel disease. Whether spondyloarthritis is active or stable, patients are advised to follow an active exercise program designed to maintain posture and range of motion.

A Man with Cloudy Vision

Posted by • July 1st, 2016

2016-06-27_11-38-42Syphilis can cause uveitis and retinitis. The uveitis can be anterior, posterior, or both (panuveitis) and can occur with or without a hypopyon (usually without).

A 50-year-old man with psoriatic arthritis and HIV infection presented with cloudy vision, decreased hearing, and gait instability. Two months earlier, the patient had begun taking antiretroviral medications. A diagnostic test result was received. A new Case Record of the Massachusetts General Hospital summarizes.

Clinical Pearl

• What is the most common retinal infection in patients with human immunodeficiency virus (HIV) infection?

Cytomegalovirus retinitis is the most common retinal infection in patients with HIV infection and is manifested by hemorrhagic or granular areas of retinitis with very slow progression.

Clinical Pearl

• What type of uveitis is associated with psoriatic arthritis?

Uveitis is a common finding in patients with psoriatic arthritis; such patients typically have nongranulomatous anterior uveitis (confined to the anterior chamber). Posterior-segment findings occasionally occur and include macular edema.

Morning Report Questions

Q: Describe some of the features of ocular syphilis.

A: Syphilis can affect every part of the eye and can result in a multitude of findings. It can cause retinal vasculitis, serous retinal detachment, posterior placoid chorioretinopathy, neuroretinitis, multifocal retinitis, and other findings, including ground-glass retinitis. Superficial retinal precipitates can also be present; they are presumed to be focal inflammatory accumulations on the retinal surface. In fact, superficial retinal precipitates are strongly suggestive of syphilis.

Figure 2. Imaging Studies of the Right Eye.

Q: How is ocular syphilis managed? 

A: In patients with ocular syphilis, especially those who present with an acute onset of symptoms, prompt initiation of antibiotic treatment is essential to prevent irreversible vision loss. A lumbar puncture is recommended for all patients with ocular syphilis or otosyphilis to determine whether there is concomitant involvement of the central nervous system, but antibiotic treatment should not be delayed if the patient declines to undergo a lumbar puncture or if the procedure cannot be performed promptly. Normal results of a cerebrospinal fluid analysis do not rule out ocular syphilis, because Treponema pallidum may infect the eye without infecting the brain or meninges. Immediate treatment for ocular syphilis should be given regardless of the results of cerebrospinal fluid analysis. Ocular syphilis, otosyphilis, and neurosyphilis (i.e., syphilis with brain or meningeal involvement) all require treatment with a 10-to-14-day course of high-dose intravenous penicillin. Glucocorticoids, such as prednisone, are often given concurrently with intravenous penicillin in patients with acute ocular syphilis or otosyphilis to reduce inflammation. After the course of intravenous penicillin is completed, some clinicians also give intramuscular penicillin G benzathine. Patients whose initial results of cerebrospinal fluid analysis are consistent with neurosyphilis should undergo a repeat lumbar puncture 6 months later to assess the response to treatment; some cases of neurosyphilis require retreatment.

Extending Aromatase-Inhibitor Treatment in Breast Cancer

Posted by • June 29th, 2016

2016-06-27_9-52-07I am approaching the end of my general surgery residency and trying to decide on a sub-specialty going forward.  Over the past 2 years I have found myself drawn to the field of breast surgery, in large part due to the large breadth of research being done in the field.  Research in breast cancer has pioneered many of the current oncologic concepts and therapy that exist today for many cancers beyond breast cancer.  However, we are far from having all the answers and are constantly trying to further our understanding of the disease.  Additionally, patient desires, emotions, and fears play a large factor, oftentimes making treatment decisions more of an art than a science.  A common theme that seems to emerge from much of the breast cancer research is the balance of risks and benefits, coupled with the patient’s concerns and preferences.  Decisions are required at almost every stage of breast cancer treatment: Lumpectomy or mastectomy…or even bilateral mastectomies? Radiation or no radiation?  Chemotherapy or no chemotherapy?  Adjuvant endocrine therapy or no endocrine therapy?  And now, another big question to be answered- how long should we continue that endocrine therapy?

While several previous studies have examined prolonged effects of extended adjuvant endocrine therapy, no study had specifically looked at extended aromatase-inhibitor therapy or duration of adjuvant endocrine therapy of more than 10 years.  An recent article in NEJM by Goss et al. addresses this question with a double-blind, randomized, placebo-controlled trial.  This study, the MA.17R trial, enrolled postmenopausal women with primary breast cancer who had previously received about 5 years of an adjuvant aromatase inhibitor, preceded by tamoxifen in the majority of women, and assigned them to either daily letrozole or placebo for 5 years.  Randomization was stratified based on several potential confounding factors: lymph-node status, prior receipt of adjuvant chemotherapy, the interval between the last dose of aromatase inhibitor and randomization, and the duration of prior receipt of tamoxifen.  The primary end point was disease-free survival, including any recurrence of breast cancer (local, regional, or metastatic) or the development of a new primary breast cancer.

1918 patients were randomized with 959 patients in each group.  Baseline characteristics of age, stage, and prior adjuvant endocrine therapy were similar between the two groups.  Overall daily adherence (assessed with questionnaires) was low, but similar between the two groups, 62.5% among those receiving letrozole and 62.3% among those receiving placebo.   5 year disease-free survival was 95% (95% confidence interval [CI], 93 to 96) in the letrozole group and 91% (95% CI, 89 to 93) in the placebo group. The hazard ratio for disease recurrence or the occurrence of contralateral breast cancer comparing letrozole to placebo was 0.66 (95% CI, 0.48 to 0.91; P=0.01).  The results remained similar when looking at the previously specified stratification groups.  There was no significant difference in overall survival between the 2 groups or when analyzing any of the prespecified subgroups.  Extended letrozole therapy significantly reduced the annual incidence rate of contralateral breast cancer with an annual incidence rate of 0.21% in the letrozole group and 0.49% in the placebo group (P =0.007),  with a hazard ratio of 0.42 (95% CI, 0.22 to 0.81).

Few women in both groups discontinued assigned treatment due to toxic effects (5.4% in the letrozole group vs. 3.7% in the placebo group) and non-bone related toxicity was low in both groups.  However, there was a higher rate of bone fracture and new onset osteoporosis in the letrozole group as well as a higher mean loss of bone mineral density in the hip.  The placebo group actually had an increase in bone mineral density in the hip and spine likely due to discontinuation of their prior endocrine therapy and concurrent use of bone-protecting medications, rates of which were high across both groups.  Overall quality of life was similar for both groups.

While results of this study appear promising, there are some limitations to the interpretation.  In the accompanying editorial, Drs. Chlebowski and Budoffoint out that the “the favorable side-effect profile in the MA.17R trial may be due to the self-selection of women who had limited side effects during previous treatment with letrozole.”  Additionally, the greatest effect seems to be in preventing contralateral breast cancers as opposed to reducing recurrences and there was no effect on overall survival which Chlebowski and Budoff  says “should not be surprising” as “the participants, who in most cases underwent randomization approximately 10 years after the time of diagnosis, have passed the peak risk of recurrence and a considerable proportion of their remaining risk as well.”  Regardless of these caveats, the results of this study have potentially large implications for changing treatment in post-menopausal breast cancer.  In the end, this will likely be another story of shared decision making as, per the editorialists, “oncologists and patients with breast cancer weigh the risks and benefits of the use of long-term adjuvant endocrine therapy.”

A Man with a Pruritic Rash

Posted by • June 24th, 2016

2016-06-17_12-33-39Although human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus, it seems to induce a precancerous state that can lead to adult T-cell leukemia–lymphoma (a subtype of cutaneous T-cell lymphoma), instead of being directly carcinogenic. HTLV-1 is associated with a long latency period, and most affected patients are exposed to the virus early in life. The four clinical variants of adult T-cell leukemia–lymphoma — acute, lymphomatous, chronic, and smoldering — affect the clinical presentation and prognosis.

A 65-year-old man with end-stage renal disease and a history of syphilis presented with a leg injury and a diffuse pruritic rash. A recent serologic test had been positive for human T-lymphotropic virus type 1. A diagnostic procedure was performed. A new Case Record of the Massachusetts General Hospital summarizes.

Clinical Pearl

• What are some general features of cutaneous T-cell lymphoma?

Cutaneous T-cell lymphoma can be manifested by pruritic scaly plaques and papules that usually occur on the buttocks and other nonphotodistributed areas and appear gradually. There are many types of cutaneous T-cell lymphoma. Mycosis fungoides accounts for the majority of cases of T-cell lymphoma with cutaneous involvement (approximately 65%), whereas adult T-cell leukemia–lymphoma accounts for less than 1% of cases. Mycosis fungoides can be manifested by a patch, plaque, or tumor and may also progress to involve the lymph nodes and viscera.

Clinical Pearl

• HTLV-1–associated adult T-cell lymphoma–leukemia occurs most commonly in patients living in what geographic regions?

HTLV-1–associated adult T-cell leukemia–lymphoma occurs most frequently in patients who live in areas where HTLV-1 is endemic, such as the Caribbean basin, southwestern Japan, and parts of South American and central Africa, but it can also be identified in the United States.

Figure 1. Clinical Photographs.

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

Morning Report Questions

Q: Is adult T-cell leukemia–lymphoma difficult to distinguish from mycosis fungoides?

A: The diagnosis of adult T-cell leukemia–lymphoma with cutaneous involvement is challenging because it mimics other forms of T-cell lymphoma with cutaneous involvement, particularly mycosis fungoides. Skin biopsies from patients with adult T-cell leukemia–lymphoma often initially lead to a diagnosis of mycosis fungoides. Findings that suggest that cutaneous patches or plaques are caused by adult T-cell leukemia–lymphoma instead of mycosis fungoides include increased expression of CD25 and distribution of the patches or plaques in photodistributed areas. Among patients who live in areas where HTLV-1 is endemic, serologic testing for HTLV-1 may be positive both in those with adult T-cell leukemia–lymphoma and in those with mycosis fungoides. Thus, in a patient who has HTLV-1 infection, the accurate diagnosis of adult T-cell leukemia–lymphoma requires evidence of proviral DNA integration, obtained by means of direct polymerase-chain-reaction testing of skin lesions.

Figure 3. Skin-Biopsy Specimen (Immunoperoxidase).

Table 2. Features of Mycosis Fungoides and Adult T-Cell Leukemia–Lymphoma.

Q: What is the prognostic implication of cutaneous involvement in adult T-cell leukemia–lymphoma?

A: Approximately 50% of patients with adult T-cell leukemia–lymphoma have some form of cutaneous involvement, such as patches, plaques, papules, nodules, tumors, erythroderma, or purpura. The type of skin lesion is of prognostic importance, since the survival rate is lower among patients with erythroderma or tumors than among patients with only patches or plaques. Among patients with acute or lymphomatous adult T-cell leukemia–lymphoma, cutaneous involvement has been associated with a decreased survival rate.


Body-Mass Index in Adolescents

Posted by • June 24th, 2016

2016-06-17_10-36-07Overweight and obesity in adolescents have increased substantially in recent decades and affect a third of the adolescent population in some developed countries. Twig et al. assessed the risk of fatal cardiovascular events in adulthood according to the body-mass index range during adolescence, using a national database of 2.3 million Israeli adolescents in whom height and weight were measured between 1967 and 2010.

In this study, a range of values for body-mass index that were well within the accepted normal range in adolescence predicted increased cardiovascular and all-cause mortality during 40 years of follow-up. A new Original Article summarizes.

Clinical Pearl

• In developed countries, how do trends in cardiovascular mortality among young adults compare to those among older age groups?

In contrast to the steep decline in the rate of death from cardiovascular causes among older age groups, cardiovascular mortality among young adults has not decreased or the decline has slowed in several developed countries.

Clinical Pearl

• Is the association between body-mass index and increased risk of subsequent cardiovascular mortality limited to those who are overweight or obese?

Some, although not all, studies suggest that a BMI that falls within the upper-normal range in adolescence is associated with an increased risk of death from cardiovascular causes, although a determination of the BMI threshold that is associated with such an increased risk remains uncertain.

Morning Report Questions

Q: Is there evidence of an association between an adolescent BMI in the mid-normal range and an increased risk of subsequent cardiovascular mortality?

A: The large size of the study by Twig et al., which incorporated more than 42 million person-years of follow-up, provided adequate statistical power to assess the associations within the currently accepted normal range of BMI values. Excess all-cause mortality (including cardiovascular mortality) starting at the 50th percentile of adolescent BMI values confirmed the findings of an earlier study on a portion of this cohort. Thus, the classification of BMI according to the accepted normal range (i.e., the 5th to 84th percentiles and a BMI ranging from 18.5 to 25.0) may underestimate the risk associated with being overweight in adolescence. This inference is supported by findings of the current study of Twig et al. that there is a graded increase in the risk of death starting at the mid-normal range of adolescent BMI (50th to 74th percentiles) and that the high-normal BMI range (75th to 84th percentiles) was associated with hazard ratios of 2.2 for coronary heart disease and 1.8 for total cardiovascular causes.

Table 2. Duration of Follow-up and Cause of Death, According to Percentile of BMI during Adolescence.

Table 3. Hazard Ratios for Cause of Death, According to Percentile of BMI during Adolescence.

Figure 2. Body-Mass Index (BMI) during Adolescence and Subsequent Cardiovascular Mortality.

Q: Does the association between cardiovascular mortality and increased BMI in adolescence take decades to become evident?

A: Twig et al. found that, in calculations of the risk of death from total cardiovascular causes at different follow-up times and 10-year intervals, the association between cardiovascular mortality and increased BMI was evident by 10 years of follow-up (hazard ratio, 2.0; 95% CI, 1.1 to 3.9) and was more pronounced during the follow-up period from 30 to 40 years (hazard ratio, 4.1; 95% CI, 3.1 to 5.4).