45-Year-Old Man with a Rash

Posted by Sara Fazio • March 28th, 2014

In the latest Case Record of the Massachusetts General Hospital, a 45-year-old man was admitted to the hospital because of diffuse, purple, blanching livedo over his arms and legs and signs of severe sepsis. Three days before presentation, the patient was bitten on his hands and forearms while bathing his dog. A diagnostic test result was received.

With respect to infections related to dog bites, one needs to consider organisms that colonize human skin and can be inoculated into the soft tissue through a dog bite. Staphylococcal and streptococcal species are common infecting organisms that can cause sepsis. Pasteurella multocida and Capnocytophaga canimorsus are considered normal oral flora in dogs.

Clinical Pearls

What are the characteristics of infection with Pasteurella multocida after a dog bite?

Infection with P. multocida, a gram-negative coccobacillus, can resemble the rapidly progressive soft-tissue infections caused by Streptococcus pyogenes, and there can be evidence of a wound infection hours after injury. P. multocida infection commonly causes cellulitis or abscesses; it can cause bacteremia, pneumonia, meningitis, and endocarditis, although these infections are less common. The organism is easy to culture and relatively sensitive to antibiotic agents.

What are the manifestations of Capnocytophaga canimorsus infection?

C. canimorsus is a fastidious gram-negative bacillus that can cause overwhelming infection after a dog or cat bite. Patients with C. canimorsus infection present with symptoms ranging from cellulitis and local infection to meningitis, endocarditis, sepsis, and shock. Many cases of severe systemic C. canimorsus infection are associated with such underlying risk factors as splenectomy, alcoholism, cirrhosis, or immunosuppression, although in approximately 40% of cases, no identifiable risk factor is found. The end of the incubation period for C. canimorsus is typically marked by the abrupt onset of symptoms. Physical examination usually reveals a purpuric rash that can evolve to purpura fulminans and frank gangrene. The clinical manifestations of sepsis are caused by a profound inflammatory response that leads to microvascular injury and endothelial damage; if hypoperfusion and inflammation persist, then disseminated intravascular coagulation, gangrene, multiorgan failure, and death can occur. A patient’s clinical history is the key to the diagnosis of C. canimorsus infection, because the organism is difficult to culture and may take up to 14 days to identify.

Morning Report Questions

Q: What are the tenets of treating patients with sepsis?

A: The guidelines of the 2008 Surviving Sepsis Campaign include fluid resuscitation for intravascular volume expansion, with crystalloids for urine output (goal, >0.5 ml per kilogram per hour), optimization of mean arterial pressure at more than 65 mm Hg, maintaining central venous pressure at a goal of 8 to 12 mm Hg and central venous oxygen saturation at >70%. Lactic acid clearance should be monitored closely, because it indicates the success of the resuscitation in improving tissue perfusion. Patients should be pancultured and soon after arrival receive broad-spectrum antibiotics in addition to circulatory support.

Q: What is purpura fulminans?

A: Purpura fulminans is a syndrome most commonly related to an acute infectious process that is characterized by intravascular thrombosis and hemorrhagic skin infarction. It is rapidly progressive, and accompanied by disseminated intravascular coagulation and overall vascular collapse. The hallmark findings in acute infectious purpura fulminans are fever, hypotension, large purpuric skin lesions, and disseminated intravascular coagulation. Meningococcus infection is commonly associated with this condition, but it may also present in the setting of infection with varicella zoster virus, gram-negative bacilli, staphylococci, Rickettsia species, streptococci, and measles virus. Pathologic examination often reveals diffuse arterial and venous thrombosis. Microscopic foci of acute inflammation may be present in the vascular adventitia.

Prevalence of Health Care–Associated Infections

Posted by Joann Schulte • March 26th, 2014

Over 30 years ago, Dr. Robert Haley, now a professor of medicine at UT Southwestern in Dallas, led the CDC in pioneering work to apply epidemiology methods to hospital infection control.  The Study on the Efficacy of Nosocomial Infection Control Project (SENIC), published in 1985, found that hospitals with active infection control programs had 32% lower incidence of nosocomial infections.   SENIC was the cornerstone of efforts to monitor, control and prevent infections in health care settings.  A study published this week in NEJM shows the work is still vital and needed.

The article by Dr. Shelley MacGill and colleagues in 10 geographically diverse states is a prevalence study estimating 4% of patients had a hospital-acquired infection (HAI) during 2011.  Such prevalence surveys have been used in other countries to describe the scope of HAIs.   The current work by CDC and 183 U.S. hospitals included 11,282 patients and found the Clostridium difficile was the most common pathogen, causing 12.1% of HAIs.  The No. 2 pathogen was Staph aureus.  The most common types of infections were pneumonia (21.8%), surgical site infections (21.8%) and gastrointestinal infections (17.1%).

The investigators also reported device-related infections caused by central lines, catheters and ventilators and other devices, caused 25.6% of HAIs.   However, infections not associated with devices or operative procedures caused about half of all HAIs reported in the study.  The authors suggested that more work is needed to define the risks for those HAIs and development of effective prevention measures.  Currently most hospitals limit their reporting to device-related HAIs, surgical site infections and infections caused by C. difficile and methicillin-resistant S. aureus.  The current study is important because it provides a more complete modern picture on the overall HAI burden and its distribution across a spectrum of patient types.

A limitation of the study is that it focused on hospitals, not other health care facilities such as skilled-nursing facilities and other long-term care facilities.  Further work is needed in those areas since hospital stays have become shorter and many patients are now cared for in rehabilitation and chronic facilities.

Clearly the work that Dr. Haley started in health-care infections has taken root and may need expansion beyond the acute-care setting.

Global Health Author Q&A: Anne Mills of the London School of Hygiene and Tropical Medicine

Posted by Jennifer Zeis • March 24th, 2014

In a feature for Now@NEJM, we ask the authors of the Global Health review article series — all with different backgrounds, experiences, and perspectives — the same set of questions.

Answers from Anne Mills, D.H.S.A., Ph.D., of the London School of Hygiene and Tropical Medicine, London

Professor Mills is the author of the February 6, 2014, article, “Health Care Systems in Low- and Middle-Income Countries.”

What do you regard as the most significant triumph in global health within the past decade?

I don’t think it is yet a triumph, but at least there is virtually universal recognition that a health care system exists and is critical for delivering effective preventive and curative health care for the population in low and middle income countries.

Though I don’t think we have done a good enough job of describing what a health care system is and its importance. Anyone growing up in a high-income country appreciates the benefits of a health care system every day. They go to their primary care practitioner; they use their hospitals. They understand the relationship between their hospital and the broader management and regulatory system within which it is located. I struggle to understand how donors in the rich world can be blind to the importance of a health care system in supporting the delivery of specific interventions.

I don’t think we have done a good enough job of describing what a health care system is and its importance.

In the coming decade, which arena of global health do you feel warrants increased attention and awareness?

Of course the health care system! Low- and middle-income countries need to build or strengthen an efficient and effective health care system. We need better knowledge on the best design features for health care systems in differing country contexts. For this we need much greater funding for health system research. This is an important area of scientific enquiry but not yet sufficiently recognised as such.

How can we best harness the revolution in IT to improve health outcomes in the developing world?

IT has a critical role to play in supporting the delivery of health care. It can connect remote practitioners to central sources of advice. It can provide information to patients on how best to manage their condition and it is the basis of management information systems which can help monitor and improve health care delivery.

When American physicians think of global health, many are dissuaded from a global health career because they cannot spend a majority of their time abroad.  What are other ways for physicians to contribute to this discipline?

It is critical that global health be “everyone’s business.” To improve health outcomes in the world we need much greater awareness of health disparities across the world, and especially of what can be done to reduce them. Physicians, as highly educated professionals, have a critical role to play in spreading information and encouraging informed debate.


Benign Paroxysmal Positional Vertigo

Posted by Sara Fazio • March 21st, 2014

Benign paroxysmal positional vertigo is characterized by brief spinning sensations, which are generally induced by a change in head position with respect to gravity. Treatment involves canalith-repositioning maneuvers, which are reviewed in detail in this new Clinical Practice article.

Benign paroxysmal positional vertigo (BPPV) is by far the most common type of vertigo, with a reported prevalence between 10.7 and 64.0 cases per 100,000 population and a lifetime prevalence of 2.4%.

Clinical Pearls

• What are the typical presentation, epidemiology, and risk factors for the development of BPPV?

The condition is characterized by brief spinning sensations, usually lasting less than 1 minute, which are generally induced by a change in head position with respect to gravity. Vertigo typically develops when a patient gets in or out of bed, rolls over in bed, tilts the head back, or bends forward. Even though patients with BPPV occasionally report persistent dizziness and imbalance, a careful history taking almost always reveals that their symptoms are worse with changes in head position. Many patients also have nausea, sometimes with vomiting. Attacks of BPPV usually do not have a known cause, although cases may be associated with head trauma, a prolonged recumbent position (e.g., at a dentist’s office), or various disorders of the inner ear. Spontaneous remissions and recurrences are frequent; the annual rate of recurrence is approximately 15%. Patients with BPPV are at increased risk for falls and impairment in the performance of daily activities. The prevalence of idiopathic BPPV is increased among elderly persons and among women, with peak onset between 50 and 60 years of age and a female-to-male ratio of 2:1 to 3:1.

• What is the underlying pathophysiological process in BPPV?

The fundamental pathophysiological process in BPPV involves dislodged otoconia from the macula of the utricular otolith that enter the semicircular canals. When there is a change in the static position of the head with respect to gravity, the otolithic debris moves to a new position within the semicircular canals, leading to a false sense of rotation. BPPV usually arises from the posterior semicircular canal, which resides in the most gravity-dependent area of the labyrinth; this type of BPPV accounts for 60 to 90% of all cases.

Morning Report Questions

Q: How is the diagnosis made in patients with BPPV that involves the posterior canal?

A: In patients with BPPV that involves the posterior canal, nystagmus is typically induced with the use of the Dix-Hallpike maneuver. In this maneuver, with the head turned to one side at angle of 45 degrees, the patient is moved from a sitting position to supine position, with the head hanging below the examination table. The induced nystagmus is upbeat and ipsiversive torsional (the upper pole of the eyes beats toward the side of the affected [lower] ear). When there is movement of otolithic debris (canalolithiasis) in the posterior canal away from the cupula, the endolymph flows away from the cupula, stimulating the posterior canal. The nystagmus usually develops after a brief latency period (2 to 5 seconds), resolves within 1 minute (typically within 30 seconds), and reverses direction when the patient sits up. With repeated testing, the nystagmus diminishes, owing to fatigability. If the otoconia become attached to the cupula (cupulolithiasis), the evoked nystagmus is similar to that observed in canalolithiasis but is usually longer in duration. A positive response to the Dix-Hallpike maneuver, in which the nystagmus beats in the correct direction, is the standard for diagnosing BPPV involving the posterior canal.

Table 2. Diagnosis and Treatment of Benign Paroxysmal Positional Vertigo According to the Affected Canal.

Figure 1. Use of the Dix-Hallpike Maneuver to Induce Nystagmus in Benign Paroxysmal Positional Vertigo Involving the Right Posterior Semicircular Canal.

Video. Maneuvers to Diagnosis and Treat Benign Paroxysmal Positional Vertigo.

Q: How is BPPV treated?

A: BPPV typically resolves without treatment. A prospective longitudinal study showed that the median interval between the onset of symptoms and spontaneous resolution in untreated patients was 7 days when the horizontal canal was affected and 17 days when the posterior canal was affected. However, canalith-repositioning maneuvers can be used to treat BPPV promptly and effectively. Medications are primarily used to relieve severe nausea or vomiting. For example, Epley’s canalith-repositioning maneuver was designed to flush mobile otolithic debris out of the posterior canal and back into the vestibule. The otoconia move around the canal with each step of the maneuver and eventually drop out into the vestibule, where they can be resorbed. Each position should be maintained until the induced nystagmus or vertigo dissipates, but always for at least 30 seconds. The success rate with Epley’s maneuver is about 80% after one session and increases to 92% with repetition up to four times. The Semont maneuver can also be used to treat BPPV involving the posterior canal.

Figure 2. Epley’s Canalith-Repositioning Maneuver for the Treatment of Benign Paroxysmal Positional Vertigo Involving the Right Posterior Semicircular Canal.

Figure 3. Semont’s Repositioning Maneuver for Benign Paroxysmal Positional Vertigo Involving the Right Posterior Semicircular Canal.

A 34-Year-Old Woman with Increasing Dyspnea

Posted by Sara Fazio • March 21st, 2014

In the latest Case Record of the Massachusetts General Hospital, a 34-year-old woman with a history of Raynaud’s phenomenon and symmetric joint pain was admitted to the hospital because of increasing dyspnea. An echocardiogram showed severe pulmonary hypertension. Diagnostic test results were received.

A diagnosis of pulmonary hypertension can be confirmed in a straightforward manner by echocardiography followed by right heart catheterization. Since there are many causes of pulmonary hypertension, defining the underlying cause is critical for choosing the most effective disease-specific therapy.

Clinical Pearls

What are the causes of pulmonary hypertension?

The causes of pulmonary hypertension are typically classified into five groups that are based on the underlying disorder. Group 1 is the pulmonary arterial hypertension group, which contains many broad categories of disease, such as idiopathic pulmonary arterial hypertension, inherited pulmonary arterial hypertension, and pulmonary arterial hypertension that is associated with any of a variety of entities (e.g., drugs and toxins, HIV infection, and connective-tissue diseases). Group 2 comprises disorders associated with pulmonary hypertension that are due to left-sided heart disease. Group 3 includes pulmonary hypertension attributed to underlying lung diseases and hypoxemia). Group 4 includes pulmonary hypertension due to chronic thromboembolic disease, and group 5 disorders include pulmonary hypertension due to hematologic, systemic, metabolic, or other disorders.

What are clinical and serologic features associated with systemic lupus erythematosus (SLE)?

SLE is a chronic inflammatory disease that can affect multiple organ systems. The cause is unknown, although autoantibodies (especially ANA and anti-double-stranded DNA [dsDNA], anti-Smith [Sm], and antiphospholipid antibodies) are associated with this disease. Approximately 80% of patients with lupus have a positive test for anti-dsDNA antibodies. Women are affected more often than men, and the incidence is greatest in the third and fourth decades of life. Pulmonary hypertension is an uncommon complication of lupus, typically occurring in patients with Raynaud’s phenomenon and serous effusions. SLE often manifests with fever, fatigue or weight loss, and patients may present with a photosensitive rash, arthralgia or arthritis, alopecia, serositis, and nephritis or nephrotic syndrome.

Morning Report Questions

Q: What are the characteristics of scleroderma and what are the associated autoantibodies?

A: Scleroderma involves collagen deposition in the skin of patients in their fourth through sixth decades of life, more often women than men. When internal organs are also involved, the disease is termed systemic sclerosis, which is further divided into limited cutaneous and diffuse cutaneous systemic sclerosis. The skin changes may progress from early pruritus to edema to sclerodactyly. Other common associations include Raynaud’s phenomenon, pulmonary hypertension, esophageal involvement, and interstitial lung disease. Scleroderma renal crisis, which may be precipitated by the use of glucocorticoids, develops in a small percentage of patients and, if present, might explain this patient’s apparently new systemic hypertension. Pulmonary hypertension is much more common in scleroderma than in lupus, with or without interstitial lung disease. Several autoantibodies are associated with scleroderma, especially ANA and antitopoisomerase I (anti-Scl-70), anticentromere, anti-RNA polymerase III, and anti-(beta)2-glycoprotein I antibodies.

Q: What is mixed connective tissue disease, and what are the clinical features and serologic markers?

A: Mixed connective-tissue disease is an overlap syndrome, with features of lupus, scleroderma, and polymyositis. It is much more common in women than in men, is typically diagnosed in the second or third decade of life, and is associated with substantial morbidity and mortality. Arthralgias, arthritis (with swollen hands), Raynaud’s phenomenon, and pulmonary hypertension are particularly prominent features of mixed connective-tissue disease. Pulmonary hypertension may be relatively rapid in onset and is often the cause of death. Some other possible manifestations of mixed connective-tissue disease are pericarditis and interstitial lung disease. There are several schemes for diagnostic criteria for mixed connective-tissue disease, and patients with the disease may ultimately meet criteria for lupus or scleroderma. Testing for the anti-U1-ribonucleoprotein (RNP) antibody (an extractable nuclear antigen antibody) is positive in patients with mixed connective-tissue disease, and is a prerequisite for the diagnosis.

Remove the Skull: Hemicraniectomy after Massive Strokes

Posted by Rena Xu • March 19th, 2014

Your seventy-year-old patient has just suffered a large stroke. The circumstances are not good: an extensive middle-cerebral-artery (MCA) infarction and massive brain edema, which mean an eighty-percent chance of mortality in the first week. For younger patients, a hemicraniectomy — the removal of half the skull — has been shown to help relieve pressure and prevent herniation as the brain expands. For a patient older than sixty years, though, it’s unclear whether such surgery is helpful or harmful. Time is precious, and you have to make a decision quickly.

A study by Juttler et al., reported in this week’s NEJM, sought to answer precisely this question: for patients sixty-one years of age or older, does hemicraniectomy improve outcomes? The Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery (DESTINY) II trial randomly assigned over a hundred patients who had suffered a malignant MCA infarction to either hemicraniectomy or conservative treatment in an intensive care unit. The primary outcome was survival without severe disability at six months, as measured by the modified Rankin scale (where 0 is no symptoms, and 6 is death; absence of severe disability means a score of 4 or lower).

The study found that a higher percentage of patients in the hemicraniectomy group survived without severe disability, as compared to the control group (38% vs. 18%; odds ratio 2.91, P=0.04). At one year, the survival rate was also higher for the hemicraniectomy group (57% vs. 24%). The trial was stopped early due to the demonstrated efficacy of hemicraniectomy relative to conservative management.

Although patients in the hemicraniectomy group did relatively better, it must be acknowledged that the survivors in both groups remained greatly disabled by their strokes.  No patients had a modified Rankin score of 0-2. As Allan Ropper, M.D., a neurologist at the Brigham and Women’s Hospital, points out in an accompanying editorial, half of the survivors a year later had a score of 4, meaning “unable to walk without assistance and unable to attend to own bodily needs without assistance,” while another third had a score of 5, meaning “bedridden, incontinent, and requiring constant nursing care and attention.” That was true for both groups. Hemicraniectomy helped, but the damage from the stroke was still devastating.

These findings raise broader questions about goals of care. Ropper writes: “In many ways, hemicraniectomy tests the fortitude of patients and their families who, in the moment, must make a decision about survival. Numerical values for the likelihood of severe disability have now been provided by the trial and may be discussed with the patient or a surrogate decision maker. However, the choice must be made early and quickly, just as the brain begins to swell, and advance directives typically do not cover these specific circumstances.”

NEJM Deputy Editor Mary Beth Hamel, M.D., M.P.H., states: “This trial provides valuable information for families who face difficult decisions about their loved ones who suffer these devastating events. The results also highlight the importance of advance care planning, to inform family and health care providers about patients’ preferences if they were to face this difficult choice.”

It’s time to make a decision about how to treat your seventy-year-old patient. You discuss the options with his care proxy and loved ones. They want whatever will keep him alive.  So you call a neurosurgeon — because based on the results of the DESTINY II study, the best chance of survival means a hemicraniectomy.

In your current practice, under what circumstances do you recommend hemicraniectomy?  To what extent does patient age factor into your treatment choice?  How will the findings of the DESTINY II study change your approach?


Management of Skin Abscesses

Posted by Sara Fazio • March 14th, 2014

The incidence of abscesses is increasing, and community-acquired methicillin-resistant Staphylococcus aureus (MRSA) has become common. A new review article explains the role of ultrasonography and provides guidance on the management of skin abscesses and the use of antibiotics.

Abscesses are one of the most common skin conditions managed by general practitioners and emergency physicians. The incidence of skin abscesses has increased, and this increase has coincided with the emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA). In many parts of the world, MRSA infections are now the most common cause of skin abscesses.

Clinical Pearls

How does ultrasound enhance the diagnostic accuracy of physical exam in detection of an abscess?

Studies in adults and children suggest that soft-tissue ultrasonography enhances the diagnostic accuracy of abscess detection and alters plans for management that are based on physical examination alone. In a prospective study involving 126 adults with clinical cellulitis in whom an emergency physician believed an abscess was not obvious on physical examination but might be present, ultrasonography resulted in a change in projected management in 56% of the patients. Ultrasonographic images showed fluid collection that was consistent with an abscess in half these patients, and approximately 80% of patients who underwent additional diagnostic testing had pus or other fluid collections. Management was also altered in three quarters of patients in whom drainage had been thought to be required on the basis of physical examination alone (e.g., it was decided that drainage was not needed, that further imaging was required, or that the incision and drainage approach should be altered).

What are the general principles of incision and drainage of an abscess in the office setting?

Many abscesses can be managed in the office setting by a general practitioner. Large, complex, or recalcitrant abscesses, especially those over sensitive areas (e.g., the hands or face), should prompt consideration of referral to a specialist or an emergency department, where additional resources can be brought to bear. The primary treatment for skin abscesses is incision and drainage. A single incision is made; the incision should be long enough to ensure complete drainage, allow lysis of loculations with a blunt instrument, and follow tension lines in order to minimize scarring. A common mistake is to make an incision that is not deep enough to reach and fully drain the abscess cavity. Particular care should be taken before incising the skin over critical structures, such as major vessels and nerves. A recent small study among adults suggested that many abscesses can be adequately drained through a short incision (median length, 1 cm).

Morning Report Questions

Q: According to the authors, when should primary closure of drained abscesses be considered?

A: Primary closure of drained abscesses should be considered for large incisions (i.e., >2 cm), especially over cosmetically important areas, and may warrant referral to a specialist. Primary closure should not be performed in patients with infected sebaceous cysts or lymph nodes or similar disease processes, patients in whom the adequacy of drainage is in doubt, and patients who have systemic infection or a strong risk factor for systemic infection (e.g., diabetes).

Figure 2. New Surgical Approaches to Abscess Treatment.

Q: When is antibiotic treatment recommended in addition to incision and drainage of an abscess, and in such cases, what is the appropriate antibiotic regimen?

A: The Infectious Diseases Society of America (IDSA) recommends systemic antibiotic treatment, in addition to incision and drainage, for patients with severe or extensive disease (e.g., multiple sites of infection) or with rapid disease progression and associated cellulitis, signs and symptoms of systemic illness, associated coexisting conditions or immunosuppression, very young age or advanced age, an abscess in an area difficult to drain (e.g., face, hands, or genitalia), associated septic phlebitis, or an abscess that does not respond to incision and drainage alone. Empirical antibiotic therapy, if prescribed, should have in vitro activity against community-associated MRSA. Most patients who have a minor abscess can be treated as outpatients with inexpensive oral antibiotics. TMP-SMX, clindamycin, and tetracycline have been shown to have in vitro activity against 94% to nearly 100% of more than 300 MRSA isolates tested in a 2008 U.S. emergency department-based surveillance study. Other antibiotics with anti-MRSA activity that have been approved by the Food and Drug Administration for the treatment of skin and soft-tissue infection include vancomycin, linezolid, daptomycin, telavancin, tigecycline, and ceftaroline.

29-Year-Old Man with Headache and Diplopia

Posted by Sara Fazio • March 14th, 2014

In the latest Case Record of the Massachusetts General Hospital, a 29-year-old man was admitted to the hospital because of headache, vomiting, photophobia, diplopia, and stiff neck. He was born in Southeast Asia. Brain imaging showed diffuse leptomeningeal enhancement. Cultures were sterile. A diagnostic procedure was performed.

Chronic meningitis differs in important ways from acute meningitis. The symptoms of chronic meningitis are typically milder, and patients less often present with a complete meningitis syndrome. Over time, however, focal and diffuse neurologic deficits can accrue. Cases that involve prominent basal inflammation can be particularly severe, with cranial-nerve palsies, vasculopathy in the circle of Willis, and obstruction of CSF outflow leading to hydrocephalus.

Clinical Pearls

What are the most common infectious causes of chronic meningitis?

Historically, the most common infectious cause of chronic meningitis in case series has been Mycobacterium tuberculosis. Other organisms that cause chronic meningitis are Borrelia burgdorferi, Treponema pallidum, and Ehrlichia chaffeensis. Pyogenic bacteria rarely cause chronic meningitis but can do so in persons with a parameningeal focus, endocarditis, or partially treated acute bacterial meningitis. HIV is the most common viral cause of chronic meningitis, but HIV-related meningitis is rarely symptomatic. Fungal organisms are a typical cause of chronic meningitis in persons with immunocompromise. However, several fungi, especially cryptococcus, can cause meningitis in apparently normal hosts.

What are the noninfectious causes of chronic meningitis?

There is an extensive list of noninfectious causes of chronic meningitis. Several forms of vasculitis are associated with chronic meningitis, including primary central nervous system vasculitis, the Churg-Strauss syndrome, granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis), and Cogan’s syndrome. Connective-tissue diseases associated with meningitis include systemic lupus erythematosus, rheumatoid arthritis, and Sjogren’s syndrome. Several other systemic inflammatory processes have been associated with chronic meningitis, the most important of which is neurosarcoidosis. Chemical irritation can cause chronic meningitis in persons who have a dermoid cyst with intermittent release of cholesterol crystals, in those who have undergone a craniotomy, and in those who have received treatment with intravenous immunoglobulin or trimethoprim-sulfamethoxazole. Finally, neoplasms, most commonly breast carcinoma, lung carcinoma, melanoma, and leukemia, are relatively frequent causes of chronic meningitis.

Morning Report Questions

Q: What is the differential diagnosis for a low glucose level in the cerebrospinal fluid (CSF)?

A: Although there is an extensive differential diagnosis for causes of hypoglycorrhachia (a low CSF glucose level), the most prominent infectious causes are pyogenic bacteria, tuberculosis, and fungi, and the most important noninfectious causes are neoplasms, sarcoidosis, and subarachnoid blood; pyogenic bacteria and neoplasms tend to cause the lowest glucose levels.

Q: What are the characteristics of primary diffuse leptomeningeal gliomatosis?

A: Primary diffuse leptomeningeal gliomatosis is a distinct glioma syndrome, which is defined by diffuse infiltration of neoplastic glial cells in the leptomeninges without evidence of a primary intraparenchymal tumor. This is a rare diagnosis; there are approximately 50 autopsy-confirmed cases reported in the literature. This disease tends to affect relatively young people, and the prognosis is generally extremely poor, with a median survival time from diagnosis of 4 months in one review.

Have You Seen the Latest NEJM Quick Take?

Posted by Jennifer Zeis • March 13th, 2014

Our new Quick Take looks at a study on the care of children in Africa who have fever and a negative test for malaria. If a malaria test comes back negative, what might be the culprit? In less than three minutes, this Quick Take summarizes a new report on children in Tanzania.

Quick Takes are brief animations that summarize the key findings of an original research article and their broader implications, and are narrated by our Editor-in-Chief, Jeffrey Drazen.

And did you know we’ve published seven Quick Takes already? Check out all seven of the Quick Takes on this new page that collects them. Studies that received Quick Take treatment include reports on in-flight medical emergencies, radium-223 and prostate cancer, pulmonary nodules detected on CT, cesarean or vaginal delivery for twins, nut consumption and mortality, and distracted driving.

Idelalisib in Relapsed CLL and Indolent Lymphoma

Posted by Daniela Lamas • March 12th, 2014

It’s been five years since weakness and fatigue brought your patient, then seventy years old, to see his doctor. A routine blood test revealed an abnormally elevated white blood cell count. Doctors quickly diagnosed him with chronic lymphocytic leukemia. Soon afterward, he was started on his first of three treatment regimens that took him from rituximab to cyclophosphamide to fludarabine. But the leukemia had progressed. And while the drugs hadn’t suppressed his disease, they had wreaked havoc on his body. Now, he was ill and frail with platelets so low and kidney function so impaired that further chemotherapy simply wouldn’t make sense.

“Isn’t there anything else we can try?” he asks.

The answer now might be a cautious yes. Two studies in this week’s issue of NEJM describe promising results about a new oral drug called idelalisib. In one study, researchers show that idelalisib might help patients with CLL who aren’t candidates for further chemotherapy – like your patient – live longer. The other trial, published by a different team, demonstrates that the same drug might offer a benefit without a hefty side-effect profile for patients with non-Hodgkin’s lymphoma whose disease has progressed despite traditional therapies.

The results are driven by basic science studies into how signaling in B cells, the cells that go awry in both these disease, works. In the lab, scientists have learned that a specific set of cell signals becomes inappropriately hyperactive in malignancies like chronic lymphocytic leukemia. But attempts to inhibit individual pathways are often thwarted by side effects and resistance. Idelalisib represents an advance, because the drug targets a very specific pathway – the delta isoform of the phosphoinositide 3-kinase (PI3K) signal transduction pathway – and does so elegantly, without devastating adverse events.

Taken together, the two studies are striking. In one, Richard Furman and colleagues randomly assigned 220 patients with relapsed CLL to receive rituximab plus either idelalisib or placebo. These were all patients whose co-morbidities rendered them ineligible for further standard chemotherapy. The study was stopped early because the patients receiving idelalisib clearly did so much better. Those taking the study drug were less likely to see progression in their disease and more likely to be alive 12 months later.

In the other study, Ajay Gopal and his team looked at whether idelalisib could benefit a group of patients with “indolent” non-Hodgkin’s lymphoma. This term refers to slow-growing but largely incurable lymphomas that had either not responded, or had come back after a course of treatment, and could lead to death. In this study, patients were not randomly assigned to the drug, or to placebo. Instead, 125 patients were given the drug – and monitored. What the researchers found was that the study drug was just as good as, and maybe better than, the other current treatment options. Importantly, toxicity of the drug was described as “acceptable,” with most common adverse events being diarrhea and elevation in liver function tests.

While the precise target population and long-term effects of this drug remain to be seen, its success in these two studies serves as an example of how science can move from bench to bedside, write biologists and cancer researchers David Fruman and Lewis Cantley in an accompanying editorial: “The emerging success of idelalisib illustrates the clinical translation of basic research studies of signaling pathways in malignant B cells into clinical advances in treatment of patients with B-cell malignancies.”