Enlarged Substantia Nigra Hyperechogenicity and Risk for Parkinson Disease: A 37-Month 3-Center Study of 1847 Older Persons

Berg D, Seppi K, Behnke S, et al

Arch Neurol. 2011;68:932-937

Study Background

If patients with subclinical pathologic features of Parkinson disease (PD) could be identified before they developed symptoms, it could open a window for early neuroprotective intervention.

The substantia nigra (SN) of the midbrain is involved early in the pathogenesis and course of PD, and transcranial sonography has shown that 90% of patients with PD (but only about 10% of elderly control patients) have SN hyperechogenicity. However, it was not previously determined whether SN hyperechogenicity could predict subsequent development of PD in still-healthy persons.

Study Summary

This longitudinal, 3-center observational study prospectively evaluated the association between baseline SN echogenic status and the 3-year incidence of PD in 1847 healthy individuals who were at least 50 years of age. Participants gave a full medical history, had a neurological examination and transcranial sonography, and 1535 of them had a follow-up evaluation. The primary study endpoint was incidence of new-onset PD in relation to transcranial sonography status at baseline.

During a mean observation period of 37 months, there were 11 cases of incident PD. SN hyperechogenicity occurred in 18.7% of the total cohort in whom temporal bone window was sufficient for evaluation, in 17.1% of those who did not develop PD, and in 80% of those who did develop PD. However, only 3.1% of those with SN hyperechogenicity developed PD. Compared with participants who had SN normoechogenicity,

Viewpoint

This prospective study is the first to show a markedly increased risk for PD in elderly persons with SN hyperechogenicity. Limitations of this study include relatively short follow-up period, selection bias, and differing recruitment strategies and ultrasonographic equipment among centers. Nonetheless, transcranial sonography of the midbrain may be promising as a screening procedure to detect imminent PD in appropriate high-risk population groups, particularly because it is noninvasive, inexpensive, and quick and easy to perform by properly trained examiners.

ABSTRACT:

Enlarged substantia nigra hyperechogenicity and risk for Parkinson disease: a 37-month 3-center study of 1847 older persons.

Arch Neurol.  2011; 68(7):932-7 (ISSN: 1538-3687)

Berg D; Seppi K; Behnke S; Liepelt I; Schweitzer K; Stockner H; Wollenweber F; Gaenslen A; Mahlknecht P; Spiegel J; Godau J; Huber H; Srulijes K; Kiechl S; Bentele M; Gasperi A; Schubert T; Hiry T; Probst M; Schneider V; Klenk J; Sawires M; Willeit J; Maetzler W; Fassbender K; Gasser T; Poewe W
Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and German Center of Neurodegenerative Diseases, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany. daniela.berg@uni-tuebingen.de

OBJECTIVE: To evaluate whether enlarged substantia nigra hyperechogenicity (SN+) is associated with an increased risk for Parkinson disease (PD) in a healthy elderly population.

DESIGN: Longitudinal 3-center observational study with 37 months of prospective follow-up.

SETTING: Individuals 50 years or older without evidence of PD or any other neurodegenerative disease.

PARTICIPANTS: Of 1847 participants who underwent a full medical history, neurological assessment, and transcranial sonography at baseline, 1535 could undergo reassessment.

MAIN OUTCOME MEASURE: Incidence of new-onset PD in relation to baseline transcranial sonography status.

RESULTS: There were 11 cases of incident PD during the follow-up period. In participants with SN+ at baseline, the relative risk for incident PD was 17.37 (95% confidence interval, 3.71-81.34) times higher compared with normoechogenic participants.

CONCLUSIONS: In this prospective study, we demonstrate for the first time a highly increased risk for PD in elderly individuals with SN+. Transcranial sonography of the midbrain may therefore be a promising primary screening procedure to define a risk population for imminent PD.

Enjoying the life of a physician

Greg Hood, MD, Internal Medicine, 09:51AM Aug 28, 2011

Delayed gratification is the mantra physicians maintain from their time as medical students for years on end. Delayed gratification has its rewards, and its pitfalls. Holding of on the excitements and fun in life can become so ingrained that it becomes second nature, perhaps even first nature. So, how does one enjoy the life of a physician? This is not the issue of what to do with a comparatively high income. This is a question of how to enjoy life. Once the heat on one's life thermostat has been reset for so long it is common to lose a degree of perspective on life. Are others living life this way? Are you missing out on excitement in life? Will you even enjoy the things that you aren't doing in life if you attempt them? Furthermore, are you even able to get motivated to start something new? With its myriad of problems the world can seem to be a disenchanting place. Given the stresses within healthcare as a whole and the lives of physicians (reference the previous two blog entries via the blog's front page) in particular, it is unsurprising that physicians consistently rate at least double the burn out and depression rates of the general population. Some of this is due to cause, such as the personality traits of physicians. As noted in the (unscientific) poll responses for "Marriage and the Business of Medicine" a substantial percentage of responders indicated that "I expend too much effort controlling my emotions rather than sharing them" and "It has always been in my nature to be more comfortably detached from other people". For others it is an issue of effect, or a combination of the two, as noted in the responses for "I commit too much time to achieving success and status to still have time to nurture my personal relationship" and "I'm too burned out to engage in the effort required". Prospective physicians tend to be among the more idealistic of their college peers. They dedicate themselves fully to the long hours and years required to become a physician in their quest to make the world a better place and help their fellow man. Mounting frustration is common in the profession as some find the realities and practicalities of life disenchanting as they pursue what they thought were their dreams. In a sense this should not come as a surprise. If one asks any adult in their 30s, 40s, 50s or beyond what it felt like to be a teenager or how they arrived at decisions and goals as a teen and they will struggle to recall or to relate to themselves as a teen. And yet, the ideals and goals of becoming a physician are the dreams set by teenagers for their adult selves. Perhaps this is one reason for the higher percentage of physicians who are the children of physicians. In spite of a strong domination of physicians discouraging their children to enter medicine in the poll for the blog post "Doctors' children and the business of medicine" the children of physicians understandably have a more realistic worldview of what is entailed in living the life of a physician. Those who do not grow up in a physician household may be more easily dissuaded from pursuing the unfamiliar, rigorous path. It is unfortunately common for physicians, though grateful for what they have and receive, to feel unexcited and unfulfilled. Living a life of service without feeling an inner joy is a damned existence and a tragedy which society as a whole and the physician community in particular must strive to overcome. When the personal and patient care achievements do not gratify one of our colleagues then the very credibility of the dream upon which they have built their professional and personal life comes into question. Physicians are trained to understand many things, and anticipate even more. It is not good as a physician to get a "surprise". We work very hard to keep surprises out of our patients' lives. However, this can bleed over into the rest of life, where nothing is exciting to the emotions any longer, nothing surprising. This tepid existence is an abhorrence to nature, and to those living such lives. How then does one get excited about life? The most difficult questions in life are often the ones that can be so simply and succinctly asked. Of course there is no one answer, no simple answer. There are a number of avenues and steps one may take in life to try to address this fundamental question of the human existence. 1. Make incremental positive changes. At Annual Session the American College of Physicians offers sessions called "Multiple Small Feedings of the Mind". This concept, that small steps for positive change can be effective, is an important one. In order to make dramatic changes in one's life the paradox is that it is the small changes that will often lead the greatest overall change. The steps of eating just a little healthier, exercising a bit more, and others, nourish productive habits, which may grow into ways to get excited about life. Ironically, this approach again smacks of deferred gratification, but it is a familiar approach for physicians and can turn the opponent into a new opportunity. It does take some energy and motivation to get started with these small changes, but not very much. Indeed, if you are reading this article you likely have enough motivation to get started. Just getting started and doing something will give some momentum. Soon those wheels which have been grinding you down will begin turning in the other direction and a positive turn of changes can ensue. 2. Cast out negative thought patterns. Focusing every day on death, deterioration and disease can be a real downer. However, negative thoughts are not the fuel for a fun time. One cannot maintain excitement and enjoy life if this is where the heart is. It truly is a matter of deciding. It is one way or the other. Think back to the positive patient encounters, the ones in which a patient has lost 30 pounds, or has made a meaningful and constructive change in life, based in your advice. How did that make you feel? Taking that seed of positive energy and how it made you feel and focusing your daily mental energy on feeling like that will not only help you, but help your patients as well. 3. Seek the silver lining. There is a lot to be negative about in internal medicine, for example. However, it is important with each patient to seek the positive. Finding the small victories in life can be very powerful for endurance within this profession. Heart trouble is a major killer still, yet we have ways through our advice and prescriptions that we can make the patient more comfortable, and more likely to live to see their daughter graduate. Antibiotic resistance is a terrible problem, but still every day we help people live through what would have been fatal infections a few years ago. The EMR server is down, but this is an opportunity to go for a walk with the family. 4. Exercise. Some believe exercise should be a four letter word. Nevertheless, it is something our bodies were built to have. Sitting on the Chesapeake in a sailboat with no sails is no fun. Sitting in the middle of life and not moving/exercising isn't either. Negative energy goes into peoples' thoughts about their appearance, their energy, their health problems and mortality. The number one, most effective treatment for over 85% of the health problems I see in the office is daily aerobic exercise. The most effective means to reduce or eliminate most medications I prescribe every day is daily aerobic exercise. The human body was designed for seven to twenty four hours of aerobic exercise each week. Starting with what one is capable of today, and building up to a minimum of seven hours a week is life changing, life-energy changing. 5. Value loved ones. As noted in the last two blog entries family members are integrally involved in our lives, and as such, the success of the business of medicine. Showing those in your life that you value them, investing time and energy in them will help you, both in the short and the long term. It gives them an opportunity to show you their returns to you. It also allows you to see life stages and life experiences from other points of view. 6. Rediscover your hobbies. Whether it is an income producing hobby or not there is value from doing off-career-topic hobbies that you love. If building furniture or painting is your hobby and it brings you income then that's the cherry on top. Reading, playing music or modeling for your own pleasure is a worthwhile investment of time and life energy because it injects energy into your life. If you don't have a hobby that you are passionate about then start exploring and trying new ones until you find yours. 7. Surround yourself with excited people. Working with competent but negative people is perhaps the biggest negative secret in the business of medicine. No one can destroy the energy and morale of a practice like a jaded, faded negative coworker. By contrast, when you work with excited people, and feed excited energy in yourself, the experience changes completely. 8. Make a point to recharge. Sometimes the drained unexcited feeling can't be shaken. This is an important time to take a break, even from your usual recharging or vacation activities. Use the frequent flier miles to go to Bermuda instead of selecting more free magazines for the waiting room. Go somewhere you haven't been before. There are often great places within your state to go - that you've never been before. When we were in California Sequoia National park became one of my top three favorite places on Earth. Getting somewhere new, somewhere completely different is a way to decompress one's perception of time again. Events which adults are familiar with are routinely perceived to take minutes or seconds whereas to children experiencing the same thing for the first time it feels like hours. This is called time perception compression. If you allow yourself to experience wholly new experiences then you have the opportunity to slow the pace of life down, and see it through more of a child's eye again. 9. Accept feedback. Most physicians don't like feedback, or at least have trouble accepting and believing positive feedback. They sense that there is another shoe out there that might fall... someday. Each person on this planet is mortal, so yes, one day even the patient with the most remarkable "save" you have made will still die. But positive feedback is positive energy, encouragement. It is a gift back from the patient to carry you a little farther in life. When you get negative feedback, if it is constructive, then use it to get better. If it is hateful, which is rare, then keep perspective that it is a personal tragedy in that person's life that their soul is so diminished. When you receive praise practice accepting it, letting it sink in, rather than just expressing gratitude and not letting the other person's positive energy truly touch you. 10. Help others. Many physicians ultimately find their positive energy in mission trips, overseas and otherwise. There is a lot to be negative about in such travel, the jetlag, the disease, unsanitary and distasteful conditions. Yet, one never hears those who do engage in such trips coming back drained or disheartened. Rather, the ways in which they help others, whether trivial or life-changing, infuse so much positive energy in their lives that no burdens inherent in the delivery of the service are able to detract from the experience.

Vampire Bat Causes Fatal Rabies Encephalitis in USA

Andrew Wilner, MD, Neurology, 10:46PM Sep 1, 2011

Deadly Bat Bite A flurry of fictional vampires has recently invaded American television, movie screens, and bookstores. While the Centers for Disease Control and Prevention (CDC) offers no statistics on vampire attacks, the CDC did report the first case of fatal rabies in the US from a vampire bat (August 12, 2011). Fruit Bat just hanging around...(photo AW) Clinical History According to the patient's mother, the 19 year old boy had been bitten by a bat on the left foot while sleeping in Michoacan, Mexico, before coming to Louisiana to work as a laborer on a sugar cane plantation. After one week of work, he developed generalized fatigue, left shoulder pain, and left hand numbness. Initially, his symptoms were attributed to overexertion. He then experienced hyperesthesia of his left shoulder, left hand weakness, generalized areflexia, and drooping of the left upper eyelid. A presumptive diagnosis of the Miller-Fisher variant of acute inflammatory demyelinating polyneuropathy (Guillain Barre) syndrome was made. He became febrile, had respiratory distress, and lapsed into a coma. A lumbar puncture revealed 87 WBCs (97% lymphocytes) and a protein of 233 mg/dL. Rabies virus specific immunoglobulin G and immunoglobulin M were present in the CSF. Rabies virus antigen was detected in postmortem brain tissue, and antigenic typing isolated the vampire bat rabies variant. I chatted with Brett Petersen, MD, MPH, Medical Officer, Poxvirus and Rabies Branch, CDC, who was kind enough to answer my many questions. He told me that this case is unusual because vampire bats are only found in Latin America, not in the US. Dr. Petersen explained that patients may develop hypersalivation and hydrophobia due to painful laryngeal spasms. "Even the sight of water can create pain," he stated. According to Dr. Petersen, bat rabies is uniformly fatal, even for infected bats. However, the long incubation period of the virus allows it to be transmitted from bat to bat. In human cases, the median incubation period is 85 days. In general, for a person to be infected with bat rabies, the virus must be inoculated under the skin from the bat's saliva. This requires a bite or a scratch (Hooper et al. 2011), although infection by aerosolized virus has been proposed. Rabies is caused by a Lyssavirus and has the highest case fatality of any infectious disease (Blanton et al. 2010). With rare exceptions, every patient dies. Vampire Bats Characterized by big ears and razor sharp teeth, vampire bats feed at night, quietly landing or jumping onto their prey. However, because of the bat's padded feet and wrists, the victim may be unaware of the bat's presence. Heat sensors in the bat's nose detect accessible blood vessels close to the skin's surface. The bat has an anticoagulant in its saliva that allows it to lap up blood with its tongue. After feeding for approximately 30 minutes, the bat may have ingested so much blood that it is barely able to fly. Victims may not realize they have been bitten. Bat teeth are very fine and may leave only pinpoint puncture marks <1mm that may be nearly undetectable (De Serres et al. 2008). In the past 20 years, most of the people infected with bat rabies did not report a bat bite (De Serres et al. 2008).  The number of rabies cases in the US has decreased dramatically due to the elimination of canine rabies by vaccination programs for dogs. Rabies now comes from wildlife such as raccoons, bats, skunks and foxes (Blanton et al. 2010). This is in contrast to the global situation, where rabies kills approximately 55,000 people per year, mostly due to rabid dogs (De Serres et al. 2008). Humans are not natural reservoirs for rabies virus (Hooper et al. 2011). Since the elimination of dogs as a rabies reservoir in the US, bat rabies has become the most common cause of human rabies. In 2009, only 4 cases of rabies were identified in the US. Of these, 3 were due to bats. A fourth case of rabies was in a physician who had been bitten by a rabid dog while traveling in India. Vampire bats are the leading cause of human rabies in Latin America. One concern about global warming is that it could possibly affect the range of vampire bats, introducing them into the Southern USA, resulting in an increase in bat rabies. Post-Exposure Prophylaxis Over 20,000 people receive rabies post-exposure prophylaxis in the US each year, and there are no reported failures (Hooper et al. 2011). The purpose of post-exposure prophylaxis is to prevent the virus from reaching the central nervous system. While the neurotropic virus travels through peripheral nerve axons to the central nervous system, there is no clinical evidence of infection. Post-exposure prophylaxis is 100% effective if administered before symptoms develop. However, once the rabies virus has entered the central nervous system and caused symptoms, the outcome is nearly always fatal.   The current recommendations for postexposure prophylaxis are 4 doses of rabies vaccine and 1 dose of rabies immunoglobulin. The wound should be vigorously cleaned and infiltrated with rabies immunoglobulin. The immunoglobulin provides immediate protection while the vaccination induces endogenous antibodies. While the older rabies vaccine was made from nervous tissue and was painful, the current vaccine is made from human diploid cell culture or purified chick embryo cells and is no more painful than other vaccines. In 2008, the CDC revised its vaccination guidelines from 5 shots down to 4, administered on days 0 (right away), 3, 7, and 14. Allergic reactions are infrequent (1/1000), but patients should be closely supervised (De Serres et al. 2009). Persons with altered immunocompetence should receive the older 5 dose regimen. If work or travel predispose individuals to rabies exposure, they can be vaccinated prophylactically. There is also research on an intranasal vaccine (Cruz et al. 2008). Conclusions: For those who have received excessive exposure to vampires from TV, cinema and other media, their suffering may continue, as a vaccine is still unavailable. However, if one is bitten by a bat, the CDC recommends the following: 1. If the bat is available, test it for rabies. If the test is negative, no anti-rabies prophylaxis is needed. 2. If the bat flies away, assume it was rabid and administer post-exposure prophylaxis according to the CDC guidelines. 3. Treat as soon as possible after the bite. Rabies, although rare, should be considered in the differential diagnosis of unexplained acute, progressive, encephalomyelitis. Because of the relatively long incubation period of the rabies virus, a travel history should be obtained from the patient because of the possibilty of infection outside the US. Prompt post-exposure treatment is critical-once a patient has developed symptoms, there is no established therapy (Jackson 2011).  More information on bat rabies can be found on the CDC rabies web page. References Blanton JD, Palmer D, Rupprecht CE. Rabies surveillance in the United States during 2009. JAVMA 2010;237(6):646-657. Cruz ET, Romero IAF, Mendoza JGL et al. Efficient post-exposure prophylaxis against rabies by applying a four-dose DNA vacine intranasally. Vaccine 2008;36:6936-6944. De Serres G, Skowronski DM, Mimault P et al. Bats in the bedroom, bats in the belfry: Reanalysis of the rationale for rabies postexposure prophylaxis. Clinical Infectious Diseases 2009;48:1493-9. De Serres G, Dallaire F, Cote M, Skowronski DM. Bat rabies in the United States and Canada from 1950 through 2007: Human cases with and without bat contact. Clinical Infectious Diseases 2008:46:1329-37. Hooper DC, Roy A, Barkhouse DA et al. Rabies virus clearance from the central nervous system. Chapter 4 Advances in Virus Research 2011;79:55-71. Jackson AC. Therapy of human rabies. Chapter 17 Advances in Virus Research;79:365-372.

A Misdiagnosis: Sleepiness and Severe Headache

Mark Crislip, MD

Authors and Disclosures

Posted: 09/02/2011

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Clinical Presentation

A 28-year-old Gambian man presents with progressive headache and lower-extremity weakness.

History and Physical Examination

History. The patient's progressive headache started 2 weeks prior to admission. It slowly advanced from mild to severe and constant and became global with photophobia and a stiff neck. Five days prior to admission he was seen in the emergency department where, after a lumbar puncture, he was told that he had viral meningitis (it was September, enteroviral season). For 2 days prior to admission he had had progressive lower-extremity weakness.

• Review of symptoms: no constitutional or other symptoms
• Remote medical history: none
• Medications: none
• Allergies: none
• Habits: none
• Pets: none
• Diet: regular
• Travel: born and raised in rural Gambia; has been in the United States for about a year
• Social: married; no children
• Immunizations: up to date
• Sports/water exposure: none
• Infectious disease exposure: PPD negative 3 months ago

Physical examination. On physical examination, the following were noted:

• Vital signs: temperature: 97.9º F; pulse: 89 beats/min; respirations: 20 breaths/min; blood pressure: 126/67 mm Hg
• General: sleepy but arousable
• HEENT: normal, except for stiff neck
• Lungs: clear
• Heart: normal
• Abdomen: nontender without masses or organomegaly
• Extremities: normal
• Skin: multiple scars
• Neuro: oriented to person, place, and time. Sleepy but responds appropriately. Cranial nerves intact. Upper extremities normal. Proximally in the quadriceps and iliopsoas muscle strength was 5/5, and the patient was able to bear weight and ambulate. Cerebellar examination was normal for finger-to-nose testing and he had bilateral positive Babinski (upgoing toes) sign. Reflexes were 1+ in the upper extremities, 2+ at the right knee jerk, 1+ at the left knee jerk, 2+ at the ankle, with 2-3 beats of clonus. Tone was normal without atrophy or vesiculation. Gait was wide-based. Tandem gait could not be performed.

Diagnostic Evaluation

Lab results. The following results were obtained:

• WBC: 4 x 10³/mm³
• Hgb: 10.9 g/dL
• Differential: normal
• Hemoglobin A1c: normal
• Glucose: 105 mg/dL
• Bilirubin: 0.3 mg/dL
• Calcium: 8.5 mg/dL
• Albumin: 3.2 g/dL
• Total protein: 10.4 g/dL
• Alkaline phosphatase: 78 U/L
• ALT: 25 U/L
• AST: 36 U/L
• Urinalysis: normal

Lumbar puncture

• CSF collected before admission: WBC 254 x 10³/mm³ with 9 RBCs, 42 neutrophils, 42 lymphocytes, 16 monocytes. CSF glucose: 11 mg/dL. CSF protein: 185 g/dL. Gram stain negative.
• CSF collected upon admission: WBC 112 x 10³/mm³, similar differential, CSF glucose 21 mg/dL, and CSF protein 234 g/dL.

Diagnostic Imaging

• Chest x-ray: clear
• MRI of spine; radiologist report: "Enhancement of CSF consistent with inflammatory change. No focal lesions observed. No focal enhancement. No evidence of a cord compression. When images before and after infusion of paramagnetic contrast are compared, there is fairly gross enhancement of the CSF in the thoracic and lumbar portions of the spine. This is less obvious to nonexistent at the cervical level and in the vicinity of the craniocervical junction."

What is the cause of the patient's granulomatous meningitis and weakness?

Mycobacterium tuberculosis

Meningovascular syphilis with transverse myelitis

African sleeping sickness

Histoplasma capsulatum var. duboisii, African histoplasmosis

Cryptococcus gattii

References

New Brain Death Guidelines for Children Released

Allison Gandey

Authors and Disclosures

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August 31, 2011 — New brain death guidelines for infants and children have been issued. Updated for the first time in nearly 25 years, the recommendations provide step-by-step instructions to help guide clinical decision making.

"These revised pediatric death diagnostic guidelines are intended to provide an updated framework in an effort to promote standardization of the neurologic examination and use of ancillary studies," reports the task force, led by Thomas Nakagawa, MD, from Wake Forest University School of Medicine in Winston-Salem, North Carolina.

A standardized checklist, provided to help ensure all components of the examination are carried out, is included as an appendix, the authors note, but they emphasize the importance of supporting families going through the loss of their child.

"Diagnosing brain death must never be rushed or take priority over the needs of the patient or the family," they conclude. "Physicians are obligated to provide support and guidance for families as they face difficult end-of-life decisions and attempt to understand what has happened to their child."

http://pediatrics.aappublications.org/content/early/2011/08/24/peds.2011-1511.full.pdf 

Also involved in the guidelines, published online
August 28 in Pediatrics, is the Society of Critical Care Medicine, the American Academy of Pediatrics, and the Child Neurology Society. The document was also reviewed and endorsed by a number of other societies, including the American Academy of Neurology.

Because of insufficient data in the literature, recommendations for preterm infants younger than 37 weeks' gestational age are not included in these recommendations.

2 Exams

"[B]rain death in term newborns, infants and children is a clinical diagnosis based on the absence of neurologic function with a known irreversible cause of coma," the authors write.

The guidelines state that hypotension, hypothermia, and metabolic disturbances should be treated and corrected. Medications that can interfere with the neurologic examination and apnea testing should be discontinued, allowing for adequate clearance before proceeding.

The task force calls for 2 examinations, including apnea testing, separated by an observation period. They recommend that examinations be performed by different attending physicians. However, apnea testing may be performed by the same physician.

The guidelines recommend an observation period of 24 hours for term newborns to children aged 30 days. For infants and children up to age 18 years, the guidelines call for a 12-hour observation period.

The first examination determines whether the child has met the accepted neurologic examination criteria for brain death, the authors write. The second confirms brain death based on an unchanged and irreversible condition.

The task force suggests that assessment of neurologic function after cardiopulmonary resuscitation or other severe acute brain injuries be deferred for 24 hours or longer if there are concerns or inconsistencies in the examination.

Apnea testing to support the diagnosis of brain death must be performed safely and requires documentation of an arterial PaCO₂ level 20 mm Hg above the baseline and 60 mm Hg or higher, with no respiratory effort, during the testing period. If the apnea test cannot be safely completed, an ancillary study should be performed.

The guidelines state that "[a]ncillary studies (electroencephalogram and radionuclide cerebral blood flow) are not required to establish brain death and are not a substitute for the neurologic examination."

The task force says these studies may be used when components of the examination or apnea testing cannot be completed safely because of the underlying medical condition. They can also be considered if there is uncertainty about the results of the neurologic examination, if a medication effect may be present, or to reduce the interexamination observation period.

When ancillary studies are used, a second clinical examination and apnea test should be performed, and components that can be completed must remain consistent with brain death.

The complete guidelines are available online.

Last June, new brain death guidelines for adults were issued. Unlike these recommendations, the guidelines call for only 1 exam. "The original guideline did not require this either," Gary Gronseth, MD, from the University of Kansas, Kansas City, told Medscape Medical News at the time. "Some people may object, but we found that 1 exam was sufficient."

The guideline authors have disclosed no relevant financial relationships.

Real-World Predictors of Success of Rituximab in RA: Viewpoint

Authors and Disclosures

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Highest Clinical Efficacy of Rituximab in Autoantibody-Positive Patients With Rheumatoid Arthritis and in Those for Whom No More Than One Previous TNF Antagonist Has Failed: Pooled Data From 10 European Registries

Chatzidionysiou K, Lie E, Nasonov E, et al
Ann Rheum Dis. 2011;70:1575-1580.

Background

Rituximab is a B-cell-depleting therapy that has been widely used over the past several years for the treatment of rheumatoid arthritis (RA). Typically, rituximab is used for RA after another biologic disease-modifying antirheumatic drug (DMARD) such as an anti-tumor necrosis factor agent has failed to control RA; however, it is still not clear what the optimal treatment strategy for rituximab should be. These authors used a large-scale pooled database of patients with RA in Europe that were treated with rituximab to investigate the real-world predictors of efficacy of this agent.

Study Summary

The authors identified 2019 patients from 10 European countries treated with rituximab at a dose of 2 1000 mg infusions given 2 weeks apart. They evaluated the 3- and 6-month efficacies of this treatment measured by the 28-joint count Disease Activity Score (DAS28).

The mean age of these subjects at the time of rituximab treatment was 54-years-old, 80% were female, the mean duration of RA was approximately 12 years, approximately 86% were rheumatoid factor positive, and approximately 77% were cyclic citrullinated peptide antibody (CCP) positive (although not all patients had CCP assessed). At the time of first use of rituximab, the mean DAS28 at baseline was 5.8, approximately 77% were on concomitant DMARDs, and from data on 1844 patients, 63% had failed at least 1 biologic agent.

Overall, the DAS28 improved in most patients after they received rituximab, and by 6 months, the number of patients with high disease activity (DAS28 > 5.1) had decreased from 73% to 26% (but there were substantial numbers of subjects without available data at the 6-month mark). In multivariate analyses, the predictors of a good EULAR response (DAS improved by > 1.2, and an overall score of ≤ 3.2^[1]) before initiation of rituximab were: (a) use of ≤ 1 biologic DMARD, (b) lower baseline DAS28 level, and (c) and anti-CCP positivity. The authors also found that there was a trend for patients using concomitant oral DMARDs to have improved DAS28 scores at 3 and 6 months when compared with those not taking DMARDs.

The authors conclude that rituximab was most effective in seropositive patients when used as the first biologic agent, or before the failure of > 1 anti-tumor necrosis factor agent.

Viewpoint

Controlled clinical trials can provide only limited amounts of information about drug efficacy; therefore, the approach these authors used to evaluate the "real-world" efficacy of rituximab for RA is to be applauded. Take-home points from their study are that certain patient groups may have better responses to rituximab therapy, including those treated with rituximab as a first-line biologic or before the use of multiple anti-tumor necrosis factor agents, those taking concomitant DMARDs, and those with CCP positivity (supporting findings of other studies^[2,3]; although the improvement seen in this study in patients that were sero-negative suggests that rituximab is still effective even in absence of rheumatoid factor/CCP positivity). However, because this is not a controlled trial, these findings should be interpreted with some caution because there may other factors not accounted for that influence these findings, although this study should help set the stage for additional studies that can provide more specific guidance for the use of rituximab in RA.

Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries.

Ann Rheum Dis.  2011; 70(9):1575-80 (ISSN: 1468-2060)

Chatzidionysiou K; Lie E; Nasonov E; Lukina G; Hetland ML; Tarp U; Gabay C; van Riel PL; Nordström DC; Gomez-Reino J; Pavelka K; Tomsic M; Kvien TK; van Vollenhoven RF
Correspondence to Katerina Chatzidionysiou, Arbetargatan 28A, 1tr, c/o Gunilla Johansson, 11245 Stockholm, Sweden; aikaterini.chatzidionysiou@karolinska.se.

OBJECTIVE: To assess the 6-month effectiveness of the first rituximab (RTX) course in rheumatoid arthritis (RA) and to identify possible predictors of response.

METHOD: 10 European registries submitted anonymised datasets (baseline, 3- and 6-month follow-up) from patients with RA who had started RTX, and datasets were pooled and analysed. Heterogeneity between countries was analysed by analysis of variance. Predictors of response were identified by logistic regression.

RESULTS: 2019 patients were included (mean age/disease duration 53.8/12.1 years, 80.3% female, 85.6% rheumatoid factor (RF) positive and 76.8% (456/594 patients) anti-cyclic citrullinated peptide antibodies (anti-CCP) positive). For these patients an average of 2.7 disease-modifying antirheumatic drugs (DMARDs) (range 0-10) had failed, and RTX was given as the first biological agent in 36.6% of patients. There was significant heterogeneity between countries for several baseline characteristics, including the number of previous biological agents. Disease Activity Score based on 28 joint counts (DAS28) decreased from 5.8±1.4 at baseline to 4.2±1.4 at 6 months (p<0.0001) and 22.2%/42.5% achieved European League Against Rheumatism (EULAR) good/moderate response. Larger 6-month improvement in DAS28 was observed in RF-positive and anti-CCP-positive versus seronegative patients. The following predictors of EULAR good response at 6 months were identified in a multivariate analysis: anti-CCP positivity (OR=2.86, p=0.003), number of previous DMARDs (OR=0.84, p=0.06), ≤1 previous biological agents (OR=1.89, p=0.04), baseline DAS28 level (OR=0.74, p=0.003).

CONCLUSION: In this large observational cohort of patients with RA treated with RTX, seropositive patients achieved significantly greater reductions in DAS28 at 6 months than seronegative patients. Effectiveness was best when RTX was used as the first biological agent or after failure of no more than one anti-tumour necrosis factor agent.

EHRs Improve Care, Outcomes for Patients With Diabetes

Robert Lowes

Authors and Disclosures

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August 31, 2011 — Patients with diabetes were more likely to meet care standards, such as annual eye exams, and outcome standards, such as blood glucose control, if their physician used an electronic health record (EHR) instead of a paper chart, according to a study published today in the New England Journal of Medicine.

Such good news about EHR usage has been scarce, comments lead author Randall Cebul, MD, a professor of medicine, epidemiology and biostatistics at Case Western Reserve University, Cleveland, Ohio, and coauthors.

Government efforts to promote EHRs anticipate "a quality-related financial return," they write. However, "available studies have shown few quality-related advantages of [EHRs] over traditional paper records."

To put the question to the test, the authors studied how 46 medical practices in and around Cleveland cared for 27,207 adults with diabetes. The practices, 33 of which relied on EHRs, publicly report their clinical performance in managing chronic illnesses as members of a group called Better Health Greater Cleveland (Dr. Cebul serves as its president). All 13 of the paper-based practices were so-called safety-net providers that serve a high proportion of patients considered vulnerable on account of lower income, lower education, lack of insurance, and other factors. Thirteen of the 33 EHR-based practices also qualified as safety-net providers, although the risk factors for their patients were less pronounced than for those in the paper-based practices.

The different categories of practices were compared on the basis of 4 standards of care and 5 clinical outcomes. The 4 standards of care were:

• Receipt of a glycated hemoglobin value;
• Kidney management, defined as testing for urinary microalbumin or prescription of an angiotensin-converting enzyme inhibitor or an angiotension-receptor inhibitor;
• An eye exam to screen for diabetic retinopathy; and
• Administration of a pneumococcal vaccine.

For the 5 clinical outcomes, the authors chose:

• A glycated hemoglobin value below 8%;
• Blood pressure below 140/80 mm Hg;
• A low-density lipoprotein cholesterol value below 100 mg/dL or documented prescription for a statin medication;
• A body mass index below 30 kg/m²; and
• Nonsmoking status.

EHRs May Not Fully Account for Performance Gap

When the authors looked at composite results, patients in the EHR-based practices scored 35.1 percentage points higher on care standards and 15.2 percentage points higher on outcome standards after an adjustment for income, education, insurance status, ethnic group, and other factors. The digital practices were ahead of the paper ones 25 percentage points on eye exams and nearly 11 percentage points for blood glucose control.

When the paper-based practices were compared to safety-net counterparts equipped with EHRs, the latter still came out on top in terms of composite care and outcome scores, although by smaller margins than when all EHR-based practices were studied.

The authors cautioned that they could not conclude that EHRs were the sole explanation for the quality differences. Causal wildcards include "the participation of exceptional EHR-based organizations, a nonrepresentative sample of paper-based organizations and inadequate adjustment for patient characteristics." They also noted that their study would have provided more compelling evidence for an EHR edge if they had measured before-and-after performance for groups that had switched from hard copy to software.

All authors state that they are active participants in Better Health Greater Cleveland, a regional collaborative supported by the Robert Wood Johnson Foundation and other sources. Their disclosure forms are available with the full text of this article.

  N Engl J Med. 2011;365:825-833. Published online August 31, 2011.

Shopping in Scrubs: OK or Not? Physicians Are Talking

Brandon Cohen

Authors and Disclosures

Posted: 08/26/2011

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Are scrubs only for the operating room, or are they appropriate for everyday use? Should they be worn to the supermarket or a school board meeting? A recent discussion on Medscape's Physician Connect (MPC), an all-physician discussion group, brought out some strong opinions on where scrubs are appropriate and where they are not -- and on what motivates those who wear them in public.

An emergency medicine doctor kicked things off with an eloquent rant: "Is it just me, or is anyone else upset seeing staff wearing scrubs to go shopping? Yesterday, I saw a woman at the supermarket wearing scrubs and her white lab coat on top. Won't this behavior give the public the impression that scrubs aren't clean, but just a fashion statement?"

Should staff be allowed to wear scrubs while shopping?

Yes, it's not a big deal if they carry dirt and germs

Only interns and residents who have no time to do laundry

No, it gives the wrong impression to the public

Many colleagues agreed: "I think the issue is status. You look cool and medical in scrubs," wrote a disparaging general practitioner (GP).

"Some people seem to like the attention that wearing them in public brings: I guess because wearing your stethoscope around your neck is just a bit too obvious?" added another GP.

A third GP continued in this vein: "Are you really so, so busy that you didn't have time to change into street clothes? Really? You couldn't spare that 3 minutes? Most of the time it's a desire to be recognized as a medical professional of some sort. Pretty pathetic in my opinion."

However, some who regularly shop in scrubs, particularly emergency medicine doctors, pushed back. One wrote: "This is ridiculous. I work my butt off. I put on scrubs when I go to work and take them off when I go home. I live 40 miles away "in the middle of nowhere," as my wife likes to say. When I'm coming home, I call her to see if she needs anything -- if so, I stop and buy it."

"Wearing scrubs to go shopping is attention-seeking behavior. However, swinging into the grocery store or popping into a store to get some specific thing that you need after having been at work and, oh by the way, wearing scrubs is just practicality," wrote another emergency medicine doctor.

A third emergency medicine doctor continued this defiant tone, and even expanded the field of acceptable venues for scrubs: "Get a life. I've been to all my kids' programs in scrubs, and because I'm on the school board, I go to the meetings in scrubs before doing my night shifts."

A GP quickly responded: "Alternatively, you could wear jeans and a T-shirt to work, change into scrubs at the hospital, and change back at the end of your shift. Then you don't look like a boob wearing scrubs at a school board meeting. Do the firemen on the board wear their firefighting outfits? Do the farmers wear boots covered in mud? Take an extra 5 minutes a day and just wear scrubs in the hospital, where they belong."

Another GP broke it down even further: "If urgent care is so messy that you need to wear scrubs, you should be changing out of them before you go anywhere else. If not, you might as well dress like the rest of us doing outpatient care."

However, an emergency medicine doctor fired back: "If I crack a chest and get bloody at work, I change -- otherwise, live with it."

"I am not about to go home, change into street clothes, and go back to town to grocery shop. I'm also not going to drag a change of clothes with me to the hospital on the off chance that that shift happens to be on the slow side and I get a chance to make a grocery list," argued another emergency medicine doctor.

A disapproving surgeon, noting the spread of this trend, wrote: "I was once attending my Congressman's birthday party, which was nothing more than a fundraiser. Most were wearing coat and tie, with quite a few in business attire. Next thing I know here comes a local gastroenterologist wearing scrubs. It looked ridiculous."

A pediatrician went further still: "Wearing hospital scrubs away from the hospital is theft."

An ophthalmologist tried to find some middle ground: "I don't go shopping while wearing scrubs, but I have pumped gas on my way home from work with them on."

A mildly conflicted surgeon added: "I understand that I probably make others in the grocery store upset, but they're so comfy and clean that I don't feel too bad about it."

Fifty-one percent of those responding to an accompanying poll objected to wearing scrubs outside the hospital. Fewer than 14% claimed that it was not a big deal, whereas a few crafted their own responses, such as a vote for limiting the practice to Halloween.

Finally, one physician raised a startling possibility: that not all of those wearing scrubs in public may be medical professionals. What if the primary offenders are dressing not for the time crunch of a tough job, but for the demands of fashion? "Scrubs are becoming popular as casual wear, and they are really inexpensive," wrote the physician, who even linked to a site where anyone can easily buy a variety of official-looking hospital scrubs.

The full discussion of this topic is available at: http://boards.medscape.com/forums/.2a0a8300. Note, this is open to physicians only.