Images Physicians Should Know

Posted by Karen Buckley • February 24th, 2012

Are you a fan of the NEJM Images in Clinical Medicine?  If so, there’s a striking new page on the NEJM 200th anniversary website that you might enjoy.  We’ve gathered a selection of images from this popular weekly series, and put them into a gallery. Browse classic representations of common, visually appealing, and important medical conditions, and click on each image to learn more.

Images play an important role in what we do and how we learn, and this feature is intended to capture the sense of visual discovery and variety that physicians experience. Check it out and let us know what you think!

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Lichen Planus

Posted by Sara Fazio • February 23rd, 2012

The various clinical presentations and treatment options of Lichen Planus are reviewed in the latest article in our Clinical Practice series, including available data to guide management.

Lichen planus is a mucocutaneous inflammatory disease of unknown origin. The skin and oral mucosa are the most frequently involved areas. Other mucous membranes (including the genitalia, esophagus, and conjunctiva) and skin appendages (e.g., scalp hair and nails) can also be affected. One or several areas can be involved, either concomitantly or sequentially. The clinical presentation of lichen planus varies depending on the area involved.

Clinical Pearls

• What is the typical presentation of lichen planus?

Cutaneous lichen planus is characterized by flat-topped, violaceous papules, which in some cases can be intensely itchy (the so-called “purple, polygonal, pruritic papules”). The lesions may result in long-standing residual hyperpigmentation, especially in dark-skinned patients. Oral lichen planus is characterized by symmetric reticular lesions that resemble a white, lacelike network, as well as by papules, plaques, erythematous lesions, and erosions; it is a chronic disease, and its erosive form is painful. The clinical characteristics of anogenital lichen planus are typically similar to those of both the cutaneous and the oral forms. The erosive form of mucosal lichen planus may result in fibrosis, with vulvar scarring, vaginal stenosis, phimosis, esophageal stricture, blindness, or obstruction of the lachrymal canal. Progressive scarring can also affect the nails and scalp.

• What other conditions have been associated with lichen planus?

Oral lichen planus is generally considered a potentially premalignant condition; a 1% incidence of squamous-cell carcinoma has been reported among patients with this condition in both retrospective and prospective cohort studies. The true risk remains controversial. Case reports have also described squamous-cell carcinomas arising from chronic anogenital, esophageal, or hypertrophic cutaneous lichen planus lesions. Several autoimmune disorders, particularly alopecia areata and ulcerative colitis, have been reported to occur more frequently in patients with lichen planus than in control populations. There is also a significant association between lichen planus and infection with hepatitis C virus (HCV). In two meta-analyses, patients with lichen planus were reported to be approximately five times as likely as controls to be HCV-seropositive.

Morning Report Questions

Q: What diagnostic evaluation is necessary when lichen planus is suspected?

A: Lichen planus is usually diagnosed clinically. If a patient has lichen planus at any site, the clinician should examine all potentially involved sites, such as the muscosa, skin, and skin appendages (nails and hair). Specialized otorhinolaryngologic and endoscopic examinations should be considered when related symptoms such as odynophagia or dysphagia are present. A careful drug history is routinely warranted, as drug-induced lichen planus, also known as a lichenoid drug eruption, though uncommon, may be indistinguishable from the idiopathic sub-type. Histologic examination of skin or mucosal biopsy specimens is useful to confirm the diagnosis in atypical cases, as well as in cases of severe disease, and to avoid inappropriate treatment. For persistent lesions that do not disappear with treatment, biopsy should be performed to rule out early dysplasia or squamous-cell carcinoma. Given the recognized associations between lichen planus and HCV infection, screening for anti-HCV antibodies with the use of an enzyme-linked immunosorbent assay (ELISA) is recommended.

Q: How is lichen planus treated?

A: Because the cutaneous form of lichen planus may resolve spontaneously, the goals of therapy are to shorten the time between onset and resolution of the lesions and to reduce itching. Topical glucocorticoids are used as the first-line treatment; topical retinoids are not prescribed for this condition because of the risk of irritation. When topical glucocorticoids are ineffective, oral glucocorticoid therapy is sometimes used. Oral aromatic retinoids are also used, as well as phototherapy, but the latter option should be used cautiously in dark-skinned patients, who have an increased risk of residual hyperpigmentation. For erosive oral lichen planus, topical glucocorticoids are the first-line therapy. Oral glucocorticoids are generally used for erosive lesions that do not respond sufficiently to topical glucocorticoids and as first-line therapy for severe erosive oral lichen planus associated with eating difficulties. For non-erosive oral lesions, either topical corticosteroids or topical retinoids can be used as first-line treatment. For erosive genital lesions, the major therapeutic aim is to prevent or limit scarring. Topical glucocorticoids are most often used. Synechiae formation may be prevented with the use of vaginal dilators and, for uncircumcised men, foreskin retraction.

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Toxoplasmosis

Posted by Sara Fazio • February 23rd, 2012

In this week’s Case Record of the Massachusetts General Hospital, a 45-year-old man with a history of alcoholism was admitted to the hospital because of cognitive decline and jaundice. He had a 3-month history of cough, blood-tinged sputum, and vomiting. Imaging showed a peripherally enhancing brain lesion. A diagnostic procedure was performed.

Somnolence may result from abnormalities in either cerebral cortex, the reticular activating system (rostral brain stem), or both sides of the medial thalamus. The findings of somnolence (in the absence of signs of aphasia or amnesia), slow speech, difficulty putting words together, conversational repetition, and slurred speech suggest global hemispheric dysfunction.

Clinical Pearls

• What neoplastic processes are part of the differential diagnosis of a peripherally enhancing brain lesion?

The differential diagnosis of a peripherally enhancing brain lesion should always include the following neoplastic processes: metastatic tumors, primary glial tumors, and primary lymphoma of the central nervous system. Although tumor metastases may cause a solitary peripherally enhancing lesion, such lesions are more commonly multifocal. High-grade glioma may cause a solitary, rim-enhancing lesion as the relatively rapid tumor growth outstrips the blood supply, leading to central necrosis. However, both anaplastic astrocytoma and glioblastoma are more typically heterogeneously enhancing and often cross the midline. Primary lymphoma of the central nervous system, usually diffuse large B-cell lymphoma, may occur in otherwise healthy persons. Alternatively, it may occur as part of advanced infection with human immunodeficiency virus (HIV), in which case it is characteristically associated with detectable Epstein-Barr virus (EBV) DNA in the cerebrospinal fluid. It is usually homogeneously enhancing, although cases involving patients who are HIV positive may be heterogeneous or peripherally enhancing.

• What is the differential diagnosis of a subacute confusional state in a patient with liver disease?

The differential diagnosis includes five major syndromes: hepatic encephalopathy, Wernicke’s encephalopathy, alcohol withdrawal, occult seizures, and infection. Hepatic encephalopathy refers to an alternation in cognitive function that is secondary to a metabolic process caused by liver failure. Wernicke’s encephalopathy refers to the triad of gait ataxia, opthalmoplegia and confusion caused by thiamine deficiency, commonly seen in chronic alcoholics. Alcohol withdrawal, occult seizures, and underlying infection may also cause a subacute confusional state in a patient with chronic liver disease.

Morning Report Questions

Q: What is the typical presentation of CNS toxoplasmosis?

A: Toxoplasma is a protozoon that rarely causes serious illness in normal hosts. In patients with advanced HIV infection, however, it is the most common cause of focal brain mass lesions. Patients with toxoplasma infection typically present subacutely with headache, fever, changes in mental status, and focal neurologic deficits. Imaging studies of the brain reveal characteristic rim-enhancing lesions that are usually multifocal but may be solitary in up to 30% of cases. Lesions are typically less than 4 cm in diameter. Serologic testing for toxoplasma IgG would be helpful, since this test has high sensitivity for toxoplasma exposure. However, antibodies may be lost in patients with profound immunosuppression, and seroprevalence is higher in Europe than in the United States. These lesions characteristically improve rapidly with appropriate treatment. Therefore, if the clinical scenario allows observation, a trial of specific antimicrobial agents may be both therapeutic and diagnostic.

Q: What is the appropriate treatment for CNS toxoplasmosis?

A: First-line treatment for cerebral toxoplasmosis includes pyrimethamine and sulfadiazine, with folinic acid (leucovorin) to reduce the hematologic adverse effects from the antimicrobial agents. Second-line therapy, in patients who cannot take sulfadiazine or in whom it is not tolerated, is clindamycin, pyrimethamine, and folinic acid.

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Facing the Future of Face Transplants

Posted by Rena Xu • February 22nd, 2012

There were many reasons to believe that face transplants wouldn’t work.  The blood supply was too complex.  The nerves were too difficult to rewire.  The body’s immune system would reject a face it didn’t recognize as its own.

But at least eighteen face transplants have now been performed world wide, with apparently encouraging results.  And in recent years, full-face transplants – complicated transplants involving the forehead, eyelids, nose, lips, chin, and cheeks – have proven to be feasible.  In 2010, a team of surgeons led by Dr. Laurent Lantieri at the Henri Mondor Hospital near Paris successfully performed what many consider the first full-face transplant.  Since then, surgeons at the Brigham and Women’s Hospital have performed three full-face transplants successfully; details of these cases were published in a recent article in NEJM.

Why do a full-face transplant? The story begins with horrifying accidents that essentially ablated the faces of the three patients.  Two of the patients suffered severe electrical burns; the third was the victim of an animal attack.  All three lost major facial structures: eyes, nose, cheeks, lips.  They couldn’t breathe through the nose or close the mouth; all three had impaired speech.

To prepare for each operation, the New England Organ Bank identified and obtained consent from next of kin for facial donation from a family member who had suffered irreversible brain damage and had already been declared brain dead.  Donation of organs from deceased donors is not new, but the donation of the complex tissue that constitutes a face is novel and fraught with many concerns, both for the recipient and for the donor’s family.  For the patient, the match needs to be compatible both immunologically and cosmetically.  Thus, a “good match” means that the donor is of the same gender and skin color as the patient and also meets a number of clinical criteria, including a negative cross-match for antibodies that might trigger graft rejection.

For the donor’s family, it is crucial to take special care of the psychological aspects of this special donation and to involve ethicists.  Because the face is the body part most closely tied to a person’s identity, donating the face of a deceased loved one carries unique emotional burdens.  It can be challenging to comprehend and prepare for the full range of possible outcomes, from transplant failure to the transformation of the face into a new identity unrecognizable to the donor’s family.

Once a match is made between a donor and the patient, the surgeons must recover the necessary tissue; this involves obtaining not only the face and underlying structures, but also additional tissue, from the donor.  In the cases reported, one team took charge of obtaining the facial graft, taking care to preserve the major nerves, arteries, and veins of the face.  Another team was charged with obtaining a sentinel flap of tissue from the donor’s arm; this would serve as a “test canary” of sorts, as it could be sampled easily to warn of impending graft rejection.

At the same time, a third team of surgeons worked on preparing the recipient’s face to receive the graft by removing the skin, contouring remaining facial tissue that would lie underneath the graft, and identifying any of the patients remaining intact facial vessels and nerves.  The donor facial graft was then transplanted, connecting vessels and nerves.  The sentinel flap was transplanted to an inconspicuous area on the patient’s body.

After surgery, all three patients were placed on immunosuppressive agents and prophylactic antibiotics.  Periodic biopsies of the grafts were taken to test for rejection.  Two patients had single episodes of rejection that were managed successfully.  All three patients regained facial sensation; two had regained facial movement at the time of the report.  In all three, facial aesthetics were substantially restored.  There was consensus among the surgeons and the donors’ families that the patients did not resemble the donors.

While these near-term follow-up data are encouraging, it remains to be seen how the long-term outcomes of face transplants compare to those of more conventional reconstructive surgery approaches.  It also remains unclear how complete transplant rejection, if it occurs, should be handled.  A patients’ guide to face transplants published by the surgeons notes, “If the facial transplant is completely rejected by the patient’s immune system, the transplanted tissues will, unfortunately, have to be removed…. In that case, different treatment options will have to be discussed with our surgical team. Options include conventional reconstructive facial surgery according to an already prepared plan or another facial transplant at a later time.”  Even if additional surgery manages to limit the medical complications of transplant rejection, however, the associated psychological damage and ethical dilemmas will likely prove exquisitely difficult to address.

For now, the notion that undertakings as complicated as full-face transplantation are possible with the use of a consistent protocol is cause for excitement as well as reflection.  If a procedure that to date has remained a relative novelty becomes increasingly reproducible in the years to come, then the place of face transplants in the medical armamentarium  — and in society at large – may also need to evolve.  Who should qualify or not qualify for a face transplant?  What will be the ethical, social, and financial implications?  As surgical techniques evolve, as protocols are refined, and as outcomes improve, it will be increasingly important to face these, and many more, difficult questions.

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Cerebellar Ataxia

Posted by Sara Fazio • February 17th, 2012

Autosomal recessive cerebellar ataxia must be considered in any child or young adult with a progressive disorder of gait or balance or with hypotonia or excessive clumsiness. The latest review in our Current Concepts series presents a practical approach to these neurodegenerative diseases.

Cerebellar ataxia is characterized by an incoordination of movement and unsteadiness due to cerebellar dysfunction. Clinical examination reveals a gait disorder with imbalance, staggering, and difficulties with tandem walking, upper-limb and lower-limb dysmetria, dysdiadochokinesia (difficulty performing rapidly alternating movements), hypotonia, cerebellar dysarthria, and saccadic ocular pursuit.

Clinical Pearls

• When should one consider a diagnosis of autosomal recessive cerebellar ataxia?

Autosomal recessive cerebellar ataxia must be considered in any patient younger than 30 years of age with a persistent and gradually worsening disorder of gait and balance or with the development over months or years of hypotonia or excessive clumsiness. Autosomal recessive cerebellar ataxias are heterogeneous, complex, disabling inherited neurodegenerative diseases that manifest mostly in children and young adults. Cerebellar ataxia may be associated with the involvement of both the central and peripheral nervous systems as well as with many systemic signs. Important neurologic signs other than cerebellar ataxia include peripheral neuropathy (decreased or absent tendon reflexes and decreased ankle reflexes); movement disorders such as chorea, dystonia, and oculomotor abnormalities; pyramidal tract dysfunction such as extensor plantar responses, hyperreflexia, and spasticity; mental retardation, cognitive impairment, or both; and epilepsy.

Figure 1. Management of Cerebellar Ataxias in Clinical Practice.

Table 2. Typical Signs and Symptoms of a Cerebellar Ataxia and Mistakes to Avoid If the Diagnosis of Cerebellar Ataxia is Uncertain.

• What is the differential diagnosis of an acute onset cerebellar ataxia?

The acute onset of a cerebellar ataxia does not suggest a neurodegenerative disease, with the exception of rare inherited metabolic disorders. Instead, it is a diagnostic and therapeutic emergency. The differential diagnosis of acute ataxias in which symptoms appear suddenly or in a few days includes alcohol consumption; vitamin B1 deficiency; medication toxicity (e.g., carbamazepine, phenytoin, barbituric, lithium, fluorouracil, cytosine arabinoside, metronidazole, amiodarone); toxic agents (e.g., mercury, thallium, organic compounds — lead, toluene, solvents, pesticides); ischemic or hemorrhagic cerebellar stroke; relapse of multiple sclerosis, basilar meningitis (e.g., tuberculosis or listeria), cerebellitis (e.g., varicella-zoster virus, rubeola, influenza, JC virus, or pertussis), and cerebellar abscess. Neurodegenerative disease should be considered whenever cerebellar ataxia is progressive and unremitting, once acquired subacute or chronic cerebellar ataxias such as cerebellar tumor, paraneoplastic syndrome, Creutzfeldt-Jakob disease, Whipple’s disease, celiac disease, autoimmune thyroiditis, and anti-GAD associated cerebellar ataxia have been excluded.

Table 1. Acute Ataxias in Which Symptoms Appear Suddenly or in a Few Days.

Morning Report Questions

Q: What is the most frequent form of autosomal recessive cerebellar ataxia, and how does it present?

A: Friedreich’s ataxia is the most frequent autosomal recessive cerebellar ataxia, and is characterized by both cerebellar and proprioceptive ataxia (with worsening on eye closure), areflexia, and extensor plantar reflexes. Scoliosis is frequent and may be the first indication of the disease. The initial signs generally occur between 7 and 25 years of age and worsen progressively, leading to imbalance, falls, and increasing difficulty in the activities of daily living, including writing, dressing, washing, and feeding. Disease progression is variable. Patients with Friedreich’s ataxia generally lose independent locomotion after they have had the disease for 10 to 15 years. Dysarthria and dysphagia both contribute to severe disability. Two features of Friedreich’s ataxia that are often misunderstood are the absence of obvious cerebellar atrophy on brain magnetic resonance imaging (MRI) during the first years of the disease and ocular “square-wave jerks.” Nystagmus is not a prominent sign of Friedreich’s ataxia, and marked cerebellar atrophy on MRI argues against the disease. Left ventricular hypertrophy, seen in approximately 60% of patients, may be accompanied by palpitations and dyspnea and can progress to end-stage cardiomyopathy. Diabetes mellitus is reported in about 15% of patients with Friedreich’s ataxia, and carbohydrate intolerance is detected in 25% because of progressive insulin deficiency and peripheral insulin resistance.

Q: When a diagnosis of autosomal recessive ataxia is suspected, what initial evaluation should take place?

A: MRI of the brain is an essential tool for the diagnosis of autosomal recessive cerebellar ataxias. The key point is whether obvious cerebellar atrophy is detected on the sagittal sections. Other important signs include cervical spinal cord atrophy (in Friedreich’s ataxia and ataxia with vitamin E deficiency) and cerebellar and cerebral white-matter changes. In a patient with ataxia, when autosomal recessive cerebellar ataxia is suspected, several steps are required, which include identification of the clinical signs, appropriate laboratory analyses (including molecular analysis to detect Friedreich’s ataxia and biomarkers such as vitamin E and alpha-fetoprotein) plus brain MRI, and electroneuromyography (EMG). This protocol should establish the diagnosis in nearly half of patients.

Figure 1.Management of Cerebellar Ataxias in Clinical Practice.

Table 3. Clinical Features, Laboratory and Brain MRI Findings, and Molecular Features of the Major Autosomal Recessive Cerebellar Ataxias.

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HIV-Associated Psychosis

Posted by Sara Fazio • February 17th, 2012

In the latest Case Record of the Massachusetts General Hospital, a 39-year-old man with a recent diagnosis of HIV infection was admitted to this hospital with fever and bizarre, nihilistic delusions, including statements that he had died. A diagnostic procedure was performed.

Psychosis is a symptom, not a diagnosis, and can be organized into primary and secondary (organic) psychoses. Unfortunately, there is no easy way to reliably differentiate primary from secondary psychoses on the basis of the characteristics of the psychosis itself, and assessment of the overall clinical situation is very important in narrowing the differential diagnosis and determining the degree of urgency.

Clinical Pearls

• How is the diagnosis of delirium made?

The clinical diagnosis of delirium hinges on the presence of two cardinal features: disruption of attention and disruption of the sleep-wake cycle, which leads to fluctuation in symptoms over the course of a day. A delirium can be easily missed if ancillary features such as psychosis overshadow the core problem of inattention. A routine electroencephalogram (EEG) showing abnormal slowing is useful if positive, but a normal EEG is not sensitive enough to reliably rule out a delirium. The sudden onset of psychosis in a patient with fluctuating mental status is a delirium until proven otherwise.

• What are the typical clinical features of HIV-associated psychosis and how is it treated?

The common clinical features of HIV-associated psychosis include sudden onset without prodrome, delusions (87% of patients), hallucinations (61%), and mood symptoms (81%). In HIV-associated psychosis, neurologic findings are typically limited and CT findings are nonspecific; however, EEGs are abnormal in 50% of cases. Cognitive impairment has consistently been described as a feature of HIV-associated psychosis, although it cannot be distinguished from a first episode of schizophrenia. Since substance abuse is a common coexisting disorder in HIV-infected patients and can further impair cognition, it is important to rule out the use of alcohol or other drugs as a contributing cause. When psychosis occurs in patients with HIV-associated dementia, it is characterized by prominent agitation, irritability, and delusions and is often part of a manic syndrome that has been called “AIDS mania.” Olanzapine is an antipsychotic agent often chosen for treatment because of its proven efficacy and relatively low risk of causing extrapyramidal symptoms and tardive dyskinesia, which are highly prevalent among patients with HIV.

Morning Report Questions

Q: What is the differential diagnosis of sudden change of mental status in a patient with advanced HIV-1 infection?

A: The differential diagnosis includes processes that cause central nervous system disease in immunosuppressed hosts. Cerebral toxoplasmosis should be considered, particularly in the setting of serologic evidence of past infection. Magnetic resonance imaging (MRI) typically demonstrates ring-enhancing lesions. Cryptococcal meningitis is another possibility. Results of cerebrospinal fluid (CSF) analysis are often bland in cryptococcal meningitis, since the organism may not elicit a robust inflammatory response. Detection of cryptococcal antigen in the CSF helps to establish this diagnosis. Infection with Mycobacterium tuberculosis may cause chronic central nervous system disease, which may manifest as tuberculous meningitis or a tuberculoma. Although MRI may reveal gross disease, it is not particularly sensitive for the detection of invasion of the central nervous system; therefore, tuberculosis affecting the central nervous system cannot be ruled out. Cytomegalovirus (CMV) infection should also be considered, especially if abnormalities are seen on retinal examination. Testing for CMV in the blood and CSF is used to make this diagnosis; negative results make CMV encephalitis unlikely although not impossible. These patients are also at risk for progressive multifocal leukoencephalopathy or lymphoma associated with Epstein-Barr virus.

Q: What is the immune reconstitution inflammatory syndrome (IRIS)?

A: Immune reconstitution inflammatory syndrome (IRIS) is a paradoxical worsening of inflammation caused by the reconstitution of immune function while on antiretroviral therapy. As immune function starts to recover, patients often mount an exuberant inflammatory response to an underlying infectious agent. IRIS is typically treated with prednisone, in addition to treatment of the underlying infection.

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Read the Latest 200th Anniversary Articles

Posted by Karen Buckley • February 16th, 2012

During the 2012 anniversary year, we are publishing a series of engaging Review and Perspective articles from established authors who are preeminent in their fields. Each article explores a story of progress in medicine over the past 200 years. These articles will appear every other week.

The relationship between patients and doctors is at the core of medical ethics, serving as an anchor for many important debates in the field. Dr. Robert Truog delves into the topic in a 200th anniversary Perspective article, new this week, and talks more about it in an audio interview, available online now.

In the first article in our anniversary review series, Drs. Eugene Braunwald and Elizabeth Nabel explore the evolution of the understanding and treatment of coronary artery disease and myocardial infarction since angina pectoris was described in the first issue of NEJM in 1812. Read the review and take a look back at the original report from January 1812.

In the second article in our anniversary review series, Drs. Anthony Fauci and David Morens of the National Institute of Allergy and Infectious Diseases highlight the tremendous advances that have been made in the field of infectious disease over 200 years, from the identification of microbes, to defining their genetic structure, to the development of focused antimicrobial therapies, to the realization of vector biology.

Other anniversary articles now available include a Perspective article in which Dr. Allan Brandt reflects on the seismic change in medical knowledge and practice covered in NEJM over the past two centuries, including an audio interview with the author, and an editorial from current NEJM editors.

On March 1st, look for a new review from Drs. Jeffrey Drazen and Erika von Mutius, “An Asthma Patient Seeks Medical Advice in 1828, 1928 and 2012.”

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Prehospital Control of Status Epilepticus

Posted by Lisa Rosenbaum • February 15th, 2012

Anyone who has ever been challenged to start an IV in a patient having a seizure knows why depending upon intravenous lorazepam to terminate status epilepticus is not ideal. Terminating a seizure as quickly as possible is imperative, as the longer a patient seizes, the more difficult it becomes to terminate with pharmacotherapy. The knowledge that the longer the patient seizes, the worse the clinical outcomes, only makes those seconds struggling to gain access seem more interminable.

Intravenous lorazepam has demonstrated clinical efficacy for seizing patients in the Emergency Room. However, paramedics, treating patients in the field, often reach for intramuscular midazolam instead. Though this immediate delivery of treatment likely feels more effective than watching a patient seize as you fumble with an IV, in the absence of clinical trials, the question has remained: does intramuscular midazolam actually do the trick?

In today’s issue of NEJM, the Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) investigators provide data to suggest that, indeed, intramuscular midazolam is as safe and effective as IV lorazepam for pre-hospital treatment of patients in status. This non-inferiority trial included 79 hospitals and over 4000 paramedics. 893 patients in status were randomized to either IV lorazepam or intramuscular midazolam. Status was defined as convulsions lasting longer than five minutes, and still occurring upon EMS arrival. Both adults and children over 13 kg were included. The study was designed to be double-blind, double-dummy, meaning all patients either received either intravenous lorazepam plus intramuscular placebo, or intravenous placebo plus intramuscular midazolam. IM injection was made simple by using an auto-injector. The primary outcome was termination of the seizure prior to arrival to the Emergency Department, without the requirement for additional therapy. The results?

Intramuscular midazolam was clearly non-inferior, successfully terminating seizures in 73% of patients, as compared to a 63% termination rate in the lorazepam group. Notably, among those in the intravenous medication group who were still seizing upon ED arrival, 31 (of 445) never received the medication because of difficulty placing an IV. This was compared to 5 in the intramuscular group who did not receive medication due to malfunction of the auto-injector.

Secondary outcomes, including the need for endotracheal intubation, recurrent seizures, and safety endpoints, midazolam was also non-inferior. Though lengths of stay did not differ between the two groups for those who were eventually admitted, more patients who had received midazolam were actually discharged from the ED, (42% in the midazolam group versus 34% in the lorazepam group). Adverse events did not differ between the two groups.

Though it is at this juncture where one usually points out the study’s limitations, and suggests the opportunities for future investigation, these data are really quite definitive: intramuscular midazolam is at least as good as IV lorazepam for prehospital treatment of patients in status. Wondering how to effectively deliver therapy to seizing patients in the field may not be what keeps you up at night, but for those who face this challenging task daily, this trial is a game changer.

For more on this topic, see the editorial by Lawrence Hirsch, M.D., from Yale University School of Medicine.

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Sign Up for 200th Anniversary Email Updates

Posted by Andrea Parent • February 13th, 2012

Stay in the know about the NEJM 200th anniversary celebration with monthly email updates. The 200th anniversary email updates are designed to keep you informed about anniversary content and events.

Sign up for 200th anniversary email updates to stay informed.

After submitting, please check your email for a confirmation message from NEJM, and click the “confirm” link. Please do not reply to the email directly. Thank you!

Sign up for 200th anniversary email updates to hear about:

  • The latest publication in a series of engaging review articles that tell the story of progress in medicine over the last 200 years
  • The newest anniversary messages, stories and videos from the NEJM community
  • The upcoming release of a documentary film that narrates three groundbreaking findings that transformed practice
  • Information about the upcoming 200th symposium on June 22 at Harvard Medical School
  • The articles selected for the current month’s round of voting to determine the most important NEJM article
  • The latest images selected from the NEJM Archive for the Historical Image Challenge
  • New features on the 200th anniversary website

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New Interactive Medical Case

Posted by Karen Buckley • February 13th, 2012

Our latest Interactive Medical Case, ” A Startling Decline,” is now available.

An 89 year-old presented with changes in cognition and personality. Six months earlier, he began to require help managing his finances and operating his computer. His family observed that he had a poor memory for recent events and found it difficult to express himself.

What diagnostic and management steps do you choose? Receive feedback on your choices and learn more about his condition and optimal treatment steps at NEJM.org. You may also wish to browse previous Interactive Medical Cases and try more.

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