Posted by Carla Rothaus • March 27th, 2015

Pain that extends from the buttock down the course of the sciatic nerve is common. Nearly 85% of cases are associated with a disk disorder. The causes, assessment, and management of sciatica are discussed in a new review article.

The mundane malady sciatica has been known to physicians since antiquity. It is defined as pain that radiates from the buttock downward along the course of the sciatic nerve.

Clinical Pearls

- What is the most common cause of sciatica?

Although sciatica has several causes, Mixter and Barr extended previous observations to establish in 1934 that the principal source is compression of a lumbar nerve root by disk material that has ruptured through its surrounding annulus. Neuroradiologic studies affirm that 85% of cases of sciatica are associated with disk disorder. The fourth and fifth lumbar nerve roots and the first two sacral nerve roots join in the lumbosacral plexus to form the peroneal and tibial nerves that leave the pelvis in an ensheathed single trunk as the sciatic nerve, the largest nerve in the body.

Disturbances anywhere along its course can give rise to sciatica, but the most common areas are at the sites of disk rupture and osteoarthritic change — at the L4-L5 and L5-S1 levels and, less frequently, the L3-L4 level — where there is generally compression of the root below the corresponding disk.

Table 1. Causes of Sciatica and of Conditions Simulating Sciatica.

Figure 1. Origin and Course of the Sciatic Nerve and the Main Sites of Damage.

- How do leg-raising tests help establish the cause of sciatica?

Many clinical tests have been devised to determine whether sciatic pain is caused by disk compression of a spinal nerve root; most of the tests are variations of the straight-leg-raising test. In a patient in the supine position, raising the leg with the knee extended stretches the nerve root over the protruded disk and results in a nocifensive response of muscle contraction. A positive sign consists of reproduction or marked worsening of the patient’s initial pain and firm resistance to further elevation of the leg. A diagnosis of disk compression is likely if pain radiates from the buttock to below the knee when the angle of the leg is between 30 and 70 degrees. Sensitivity of the test for disk herniation is approximately 90%, but specificity is low. Many persons without spinal abnormalities have hamstring and gluteal tightness with discomfort elicited by straight-leg raising, but the pain is more diffuse than in sciatica and the leg can be lifted higher if the maneuver is performed slowly. Increased pain on dorsiflexion of the foot or large toe increases sensitivity. The crossed straight-leg-raising test (Fajersztajn’s test) for sciatic pain involves raising the unaffected leg; this test is 90% specific for disk herniation on the contralateral side but is insensitive.

Figure 2. Straight-Leg-Raising Test.

Morning Report Questions

Q: How effective is conservative treatment?

A: The most common initial treatment is pain control by means of medication and physical therapy. Activity is usually self-limited in proportion to the degree of discomfort, and although rest is often recommended, it is not better than movement in patients who are able to remain active. Nonsteroidal antiinflammatory medications may provide short-term relief for low back and sciatic pain; however, it is difficult to determine their effect on sciatica, and many patients report little relief. Orally or systemically administered glucocorticoids have been used to ameliorate sciatica, but it is difficult to interpret their effect. Guidelines recommend restrictions on the use of opioids. Antiepileptic drugs, antidepressant agents (e.g., tricyclic agents), muscle relaxants, and pain medications that enhance the activity of gamma-aminobutyric acid have been used but with little supporting data. The benefits of physical therapy and various exercise regimens are difficult to determine, and the superiority of any one program has not been established, although most appear to be safe. Spinal manipulation for sciatica is widely used and has been studied with an assortment of designs and comparators; therefore, reviews of existing trials, most considered of low or moderate quality, draw limited conclusions.

Epidural injections of glucocorticoids are frequently administered for low back pain and related conditions. Trials have suggested an associated short-term decrease in leg pain but no decrease in the need for subsequent surgery.

Q: How does surgery compare to conservative treatment of sciatica caused by disk disease?

A: Most trials comparing surgical treatment and conservative treatment of sciatica due to lumbar disk disease favor surgery, because it results in earlier relief of pain. A review of major trials with adequate data for analysis concluded that there was conflicting evidence on long-term benefit but that surgery relieved pain more rapidly and to a greater degree than did conservative therapy. North

American Spine Society guidelines state that diskectomy provides more effective and more rapid symptom relief than do other treatments for symptoms that warrant surgery, although less severe symptoms can be managed conservatively. Complications of surgery are infrequent but include dural tears with leakage of cerebrospinal fluid, as well as damage to the root or cauda equina.

A Girl with Graves’ Disease

Posted by Carla Rothaus • March 27th, 2015

In the latest Case Record of the Massachusetts General Hospital, a 15-year-old girl with Graves’ disease was admitted to the hospital because of psychotic symptoms — including depression, hallucination, and suicidal thoughts — that began approximately 2 months after treatment with methimazole had been initiated.

Before a diagnosis of primary mood disorder can be made, organic causes of the symptoms must be ruled out.

Clinical Pearls

- What kind of psychiatric symptoms are associated with Graves’ disease?

The majority of patients with Graves’ disease report some degree of psychiatric symptoms, including irritability, anxiety, anger, or sadness, which may precede other manifestations of the illness by weeks to months. While these psychiatric symptoms usually do not reach the level of impairment necessary to make a psychiatric diagnosis, a substantial minority of patients have symptoms of sufficient severity to warrant psychiatric diagnosis. In a study involving recently diagnosed, untreated adults with Graves’ disease, 45% met criteria for an anxiety disorder and 30% met criteria for major depressive disorder.

- What are some considerations when treating Graves’ disease with associated psychiatric symptoms?

Treatment of the underlying condition is sufficient to address most psychiatric disorders secondary to hyperthyroidism. However, a more assertive approach should be considered when a patient’s psychiatric symptoms are severe, concerns about the patient’s safety emerge, or treatment of the underlying condition alone does not lead to rapid improvement in the patient’s mental state. Psychiatric medications with the potential to exacerbate known physiological complications of hyperthyroidism should be used with caution or avoided altogether. For instance, low potency antipsychotics have the potential to worsen tachycardia and medications with significant risk of QTc prolongation, such as ziprasidone, may put a patient with hyperthyroidism at particularly high risk of arrhythmia.

Morning Report Questions

Q: How is Graves’ disease in children treated?

A: Antithyroid medication is typically the first line of therapy for pediatric patients. The use of methimazole is preferred to propylthiouracil; the latter has recently been given a black-box warning in pediatrics by the U.S. Food and Drug Administration due to the unacceptably high risk of liver failure in children. Antithyroid medications act by inhibiting oxidization and organification of iodide. Normalization of thyroid hormone levels takes about 8 to 12 weeks. More definitive therapy is required as second-line therapy if there is no remission within a few years. Radioactive iodine and surgical thyroidectomy are both safe and effective in this age group.

Q: What are some of the risks of total thyroidectomy for Graves’ disease?

A: Total thyroidectomy can be done safely by an experienced surgeon.

Ultrasonography may be used to assess the size of the gland, the extent of inflammatory changes, and the presence of nodules. Computed tomographic scanning and fiberoptic laryngoscopy are not necessary. Unilateral recurrent laryngeal nerve (RLN) injury occurs in 1 to 2% of the cases, and can result in a paralyzed vocal cord on the side of the injury and permanent hoarseness, a whispery voice, and sometimes aspiration. Bilateral nerve injury, though very rare, can result in immobility of both vocal cords and the need for a tracheostomy. Temporary RLN palsies due to stretching or bruising can occur in up to 5% of patients, but the nerves often recover within 6 months. Minor voice change, including difficulty with projection and reaching the highest pitches, can be seen in some patients, especially if the external branch of the superior laryngeal nerve is injured. Permanent hypoparathyroidism occurs in 2% of patients. Temporary hypoparathyroidism occurs in up to 20% of patients and is more common in children, women, and patients with Graves’ disease. Neck hematoma can occur in approximately 1 of 300 patients who undergo total thyroidectomy and always requires reoperation; high vascularity in

Graves’ disease may contribute to a slightly higher risk.

Take the Case Challenge: A Woman with Headache, Fever, and Rash

Posted by Jennifer Zeis • March 26th, 2015

A 28-year-old woman presented with headache, fever, and a rash, plus nausea and one episode of nonbloody, nonbilious emesis. The skin lesions were small, red, flat, nonpruritic, and nonpainful. What is the most likely diagnosis? What diagnostic tests are indicated?

Read the case description. Then vote and comment about what the diagnosis may be and what diagnostic tests will prove useful. Find the answers in the full text of the case to be published on April 9.  Follow the conversation on Facebook and Twitter with #NEJMCases.

Putting on and Removing PPE

Posted by Karen Buckley • March 25th, 2015

Personal protective equipment, or PPE, is used when there is a risk of exposure to infectious material, to protect the skin and mucous membranes from exposure to pathogens. A new Video in Clinical Medicine demonstrates putting on and removing PPE. This important information is now available on the Ebola Outbreak page, or browse all 59 Videos in Clinical Medicine.

Also new on the Ebola Outbreak page, New York physician Craig Spencer writes about his experience in returning to the U.S. after treating patients with Ebola in Guinea, in Having and Fighting Ebola.

The Final Nail in Early Goal Directed Therapy’s Coffin?

Posted by Joshua Allen-Dicker • March 24th, 2015

You are called to evaluate Ms. Smith urgently.  She reports several days of progressive malaise, weakness and a new cough. On your exam she is tachycardic, tachypneic and febrile.  You diagnose Ms. Smith with sepsis and explain the importance of quickly treating this life-threatening condition.

In the United States, situations like this—presentations leading to the diagnosis of sepsis –play out over 1.6 million times per year and are associated with a 16% mortality rate.  Since 2001 many healthcare professionals have pointed to early-goal directed therapy—a strict protocol aimed at quickly optimizing tissue perfusion and oxygen transport—as the key to beating sepsis.  However, a trial in this week’s NEJM (the last in a series of three) reinforces concerns that in the management of sepsis early goal directed therapy (EGDT) may not be more effective than non-protocolized usual care.

The Protocolized Management in Sepsis (ProMISe) study examined the potential benefits of EGDT, much like the recently published Protocolized Care for Early Septic Shock (ProCESS) and Australasian Resuscitation in Sepsis Evaluation (ARISE) trials.  ProCESS and ARISE did not detect a significant reduction in sepsis mortality with the use of EGDT compared with usual care, but were noted to have overall low mortality rates (less than 20%, compared with 45% seen in the initial 2001 trial).  ProMISe aimed to target a more critically ill septic population in order to examine the same question: can EGDT improve patient mortality in sepsis compared with usual care?

The authors conducted ProMISe at National Health Service hospitals in England where EGDT was not routinely being used.  Patients with (1) a known or presumed infection, (2) two or more SIRS criteria, and (3) elevated lactate or hypotension refractory to a 1 liter intravenous fluid bolus were randomized to receive usual care versus EGDT. The EGDT protocol required placement of a central venous catheter capable of continuous central venous oxygen saturation monitoring and adherence to a 6-hour resuscitation protocol.  This protocol called for the use of IV fluids, vasopressors and blood transfusions triggered by specific physiological measurements. Usual care was determined by on-site treating physicians. The primary outcome measured was 90-day mortality.

In an intention to treat analysis, ProMISe found that there was no significant difference in the 90-day mortality between the EGDT and usual care groups (29.5% vs 29.2%, p=0.90).  This was despite the EGDT group having a higher utilization rate of vasopressors, red blood cell transfusions, and intravenous fluids during their 6-hours following trial randomization.

What does ProMISe add to our knowledge about sepsis management? Simply put, ProMISe demonstrated that in patients who are recognized early as having sepsis and treated with intravenous fluids and antibiotics, EGDT did not provide significant improvement over patients treated with usual care.  However, ProMISe does more than just echo the findings of ProCESS and ARISE.

First of all, the ProMISe study aimed to enroll a more critically ill study population than those examined by the two preceding studies.  They were successful in this respect, with an overall trial mortality of 29%.  However, the observed mortality rate remained significantly below that of the original EGDT trial.  While the results from ProMISe allow an expansion of conclusions from ProCESS and ARISE to include more sick populations, some might argue that they fail to allow for translation to those who carry even higher expected mortality rates, such as those in the original EGDT trial.

Secondly the authors of ProMISe, acknowledging that valuable outcomes in sepsis may be more than just the most immediate and health-related ones, also defined a set of interesting long-term outcomes relating to quality of life and costs.  The study did not find a significant difference between EGDT and usual care groups with respect to reported quality of life and healthcare costs at 90 days and 1 year.  Additionally, ProMISe calculated a low probability that EGDT was cost effective in comparison to usual care. At a time when the conversations about healthcare value and the patient experience are of increasing relevance to actual bedside care, these results add weight to the arguments against EGDT.

So is ProMISe the end for early goal directed therapy? The results of ProMISe imply that one can stray from the strict EGDT protocol and still achieve equivalent results in sepsis care.  However, it would be misleading to depict the results of ProMISe as pushing us towards some kind of post-EGDT world where sepsis interventions are neither early nor goal-directed.  As the study authors note, by the time of their randomization into the study every patient in ProMISe had received antibiotics and an average of 2 liters of intravenous fluids.  Patients in the usual care group were still given transfusions, vasopressors and intravenous fluids, suggesting physicians must have been following some goals (no doubt they were aware of the results of the hallmark 2001 trial), albeit ones less formalized than those promoted by EGDT. 

In the aftermath of the ProCESS-ARISE-ProMISe trilogy, it should come as no surprise that the Surviving Sepsis Campaign—a champion of EGDT—recently announced that they would be re-evaluating the sepsis literature and their EGDT protocols.  Instead of ending EGDT, ProMISe likely marks the beginning of a new chapter in sepsis care, where interventions remain early and goals remain present, but the rules governing the clinical approach put more emphasis on clinician intuition than strict targets.

Have questions or comments about the ProMISe trial? Please join the NEJM Group Open Forum from March 24 to April 2 for a fascinating online discussion with authors, experts and your peers. 

Take the Fluids and Electrolytes Challenge

Posted by Karen Buckley • March 23rd, 2015

A 53-year-old woman with chronic kidney disease, hypertension, and a mood disorder presented with irritability and pressured speech. Lab data include: blood pressure 130/85 mm Hg, plasma sodium 155 mmol/L, potassium 4.5 mmol/L, blood urea nitrogen 67 mg/dL, creatinine 1.99 mg/dL, glucose 90 mg/dL, and plasma osmolality 339 mOsm/L. What is the best strategy to support this patient?

Take the poll and comment now.

The answers will be published on April 2 alongside the next article in the Disorders of Fluids and Electrolytes series, “The Molecular Physiology of Water Balance.”


Uncomplicated Skin Infections

Posted by Carla Rothaus • March 20th, 2015

Uncomplicated skin infections are a common outpatient clinical problem. In a randomized, controlled trial, clindamycin and trimethoprim–sulfamethoxazole (TMP-SMX) were compared as outpatient therapy for uncomplicated cellulitis or abscess.

Results of cultures of skin-infection lesions in the United States have shown that most of the infections are caused by methicillin-resistant Staphylococcus aureus (MRSA), but the most effective approach to therapy in areas where community-associated MRSA is endemic has not been defined. A randomized clinical trial was performed comparing clindamycin and TMP-SMX [trimethoprim-sulfamethoxazole] for the treatment of uncomplicated skin infections at four U.S. centers located in areas where community-associated MRSA is endemic.

Clinical Pearls

- How do clindamycin and TMP-SMX compare for the treatment of uncomplicated skin infections in areas where MRSA is endemic?

The trial by Miller et al. enrolled outpatients with uncomplicated skin infections who had cellulitis, abscesses 5 cm or larger in the greatest diameter (smaller for younger children), or both. All abscesses underwent incision and drainage. Patients were randomly assigned in a 1:1 ratio to receive either clindamycin or TMP-SMX for 10 days. The cure rates with TMP-SMX and clindamycin did not differ significantly. The rate of cure in the intention-to-treat population (524 patients) at the test-of-cure visit was 80.3% (95% confidence interval [CI], 75.2 to 85.4) in the clindamycin group and 77.7% (95% CI, 72.3 to 83.1) in the TMP-SMX group (difference, −2.6 percentage points; 95% CI, −10.2 to 4.9; P=0.52). In the population that could be evaluated (466 patients), the rate of cure was 89.5% (95% CI, 85.2 to 93.7) in the clindamycin group and 88.2% (95% CI, 83.7 to 92.7) in the TMP-SMX group. There were no significant differences between treatment groups, in either the intention-to-treat population or the population that could be evaluated, in subgroups consisting of children, adults, or patients with cellulitis, abscesses, or mixed abscess and cellulitis lesions.

Figure 2. Comparison of the Efficacy of Clindamycin and TMP-SMX in Patients with Uncomplicated Skin Infection.

Table 3. Cure Rate at Test-of-Cure Visit in the Overall Population Relevant Subgroups.

- What pathogen is thought to be the most common cause of cellulitis?

The cause of cellulitis is incompletely understood, because a causative pathogen is not identified in most cases; this was true in the Miller study, in which 80% of cellulitis lesions could not be cultured because skin was intact. Expert opinion and empirical data suggest that cellulitis is most commonly caused by Streptococcus pyogenes.

Table 2. Wound Culture Results at Baseline.

Morning Report Questions

Q: What is the contribution of antibiotic therapy to the cure of abscesses that undergo incision and drainage?

A: Among all the patients in this study, 46% had one or more abscesses larger than 5 cm in diameter (proportionally smaller in young children), all of which underwent incision and drainage. Although incision and drainage alone may be sufficient for treatment in many cases, there are likely to be subgroups in which antibiotic therapy is needed. Outcomes in antibiotic-treated patients with abscesses in this study’s relatively low-risk population could reflect either similar true efficacies or the adequacy of incision and drainage alone. Large placebo-controlled trials are needed to further understand the role of active therapy in the treatment of patients with abscesses.

Q: Are there differences in the rates and types of adverse events associated with clindamycin and TMP-SMX?:

A: Overall rates of adverse events were similar in the clindamycin and TMP-SMX groups (18.9% and 18.6%, respectively). The most common adverse events in the clindamycin and TMP-SMX groups were diarrhea (9.7% and 10.1%), nausea (2.3% and 2.7%), vomiting (2.3% and 1.6%), pruritis (1.5% and 1.2%), and rash (1.2% and 0.8%). Most adverse events were mild or moderate and resolved without sequelae. There were no treatment-associated serious adverse events. Overall adverse-event rates were similar in the pediatric and adult subgroups.

A Man with Progressive Neurologic Decline

Posted by Carla Rothaus • March 20th, 2015

In the latest Case Record of the Massachusetts General Hospital, a 31-year-old man was seen in the neurology clinic because of personality changes and neurologic decline of 3 years’ duration. Previous imaging studies showed mild atrophy in the frontal lobes. He could not speak or follow commands. Additional diagnostic testing was performed.

Frontotemporal dementia is the most common cause of dementia in adults younger than 60 years of age; onset of symptoms typically occurs in the sixth decade.

Clinical Pearls

- What is frontotemporal dementia?

Frontotemporal dementia was first described by Arnold Pick in 1892. Frontotemporal lobar degeneration, the cause of frontotemporal dementia, targets circuits of the bilateral frontoinsular cortexes. The three subtypes of frontotemporal dementia are based on the types of inclusions present in the brain: tau, TDP43 (transactive response DNA-binding protein 43), and FUS (RNA-binding protein fused in sarcoma). Pick’s disease, the prototypical form of frontotemporal dementia, is associated with cytoplasmic and glial aggregates of tau-3R. Most cases of frontotemporal dementia are sporadic, but 10 to 15% of cases are associated with an autosomal dominant genetic mutation.

- What is the clinical presentation of frontotemporal dementia?

Patients with frontotemporal dementia that starts on the left side of the brain present with primary progressive aphasia. Patients with frontotemporal dementia that starts on the right side of the brain present with psychiatric symptoms associated with the behavioral variant of frontotemporal dementia. Most affected patients are initially thought to have a primary psychiatric condition and are often being seen by marriage or addiction counselors, psychologists, human-relations officers, or legal counselors.

Morning Report Questions

Q: How is the behavioral variant of frontotemporal dementia diagnosed?

A: The six major symptoms of the behavioral variant of frontotemporal dementia are disinhibition, apathy, loss of sympathy and empathy, repetitive behaviors, hyperorality, and loss of executive function. A possible diagnosis of the behavioral variant of frontotemporal dementia can be made if three of these six symptoms are present. A probable diagnosis can be made if selective frontotemporal atrophy or hypometabolism is present or if the patient has a genetic mutation that is known to cause frontotemporal dementia.

Q: How is frontotemporal dementia managed?

A: There are no disease-modifying therapies for frontotemporal dementia. Nevertheless, the symptoms of frontotemporal dementia can be treated, ideally by a multidisciplinary team of specialists. Treatment includes pharmacologic and nonpharmacologic management of symptoms, management of coexisting conditions, psychosocial support, and education of the family and, if possible, the patient. No medications have been approved for the symptomatic treatment of frontotemporal dementia, but many have shown beneficial effects in small studies. For example, selective serotonin-reuptake inhibitors and other antidepressants can modulate disinhibition and compulsive behavior, stimulants and prodopaminergic agents can sometimes reduce apathy and attentional impairment, and mood stabilizers and antipsychotic agents can ameliorate agitation and aggression. The side effects of these medications may outweigh the benefits and should always be closely monitored. Strategies for nonpharmacologic management of symptoms can include behavioral, speech and language, occupational, and physical therapy, as well as psychotherapy (for the patient or the family). Finally, it is critical to assist patients and families with end-of-life care, facilitating access to palliative care resources.

New Topics on the NEJM Group Open Forum

Posted by Karen Buckley • March 19th, 2015

There’s a lot to talk about on the NEJM Group Open Forum. Read the discussion, like, share and comment to become a part of these active and engaging conversations.

Reviving Research to Prevent Gun Violence: If you were given a research grant to investigate some aspect of firearm violence, how would you direct those resources? How can clinicians who regularly treat patients affected by gun violence translate their experience into a research framework? This discussion, based on a recent NEJM Perspective article, is ongoing until March 24.

Women Physicians in Leadership Roles: While half of medical degrees are now being awarded to women, only a small percentage of leaders in the field are women, so how do we create change? This NEJM CareerCenter discussion is ongoing until March 26.

And, coming on March 24, @JWatch Morning Report – A Behavioral Mystery: Watch videos and see images of a challenging case as it evolves over five days, and tell us how you would manage the case at each stage. Our experts will answer your questions and discuss your diagnosis and management plan with you.

Watch the Latest NEJM Quick Takes

Posted by Karen Buckley • March 18th, 2015

There may be important new progress in the treatment of Crohn’s Disease. Watch the 1-minute Quick Take video summary of the phase 2 trial of Mongersen, an oligonucleotide that interferes with a signaling pathway involved in the pathogenesis of Crohn’s Disease. Also, read the full article and editorial.

Watch other recent video summaries, including:

CABG vs PCI w/Everolimus-eluting Stents

Improved Air Quality and Lung Development in Children

Peanut Consumption in Infants at Risk of Peanut Allergy

Mass Treatment with Single-Dose Azithromycin for Yaws  

You may also wish to browse all previous NEJM Quick Takes.