It is my privilege to welcome you to the 46th Annual Scientific Meeting of the American Academy of Neurological and Orthopaedic Surgeons. We are gathered here at the Hilton Palacio Del Rio for our annual educational program.

Our conference will provide information on a variety of Neurological, Orthopaedic and Spine related topics and I encourage you to review the information available on the meeting APP to learn all about the various speakers and their presentations. I am delighted that in this year’s program will include a number of speakers from San Antonio and the surrounding area. Joining us from UT San Antonio will be Prof. Cristian Gragnaniello, who will present Modern Management Strategies in Thoraco-Lumbar Trauma on Saturday morning. In addition, invited guest speakers, Drs. Jon-Cecil Walkes from Houston and Steven Cyr from San Antonio will contribute two fascinating lectures on Friday morning.

I am pleased that the International College of Surgeons, as our educational partner, has worked closely with our Scientific Organizing Committee to develop additional programming that is likely to be of interest to all surgical specialties. I encourage every member of the Academy to peruse the program and participate in as many sessions as possible to earn the maximum number of CME credits.

I hope you have a most enjoyable visit to the home of the Alamo during our annual meeting!

Lucia Zamorano, MD, FICS, FAANOS
Chair, American Academy of Neurological and Orthopaedic Surgeons

Welcome Letters

The center includes four operating rooms, two procedure rooms, pre-operative and post-operative recovery areas and a large reception area. It is licensed by the State of Michigan and is fully accredited by the Joint Commission for Accreditation of Healthcare Organizations. Lakes Surgery Center is affiliated with National Surgical Hospitals.

During the same period, there was no increase in advanced disease in older women, according to the researchers, led by Rebecca H. Johnson, MD, from the Seattle Children’s Hospital and the University of Washington.

In the young women, the incidence of breast cancer with distant involvement at diagnosis increased from 1.53 per 100,000 women in 1976 to 2.90 per 100,000 women in 2009. This is an absolute difference of 1.37 per 100,000, and is an average compounded increase of 2.07% per year (P < .001) over a 34-year interval.

The findings come from an analysis of incidence trends from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database.

The findings could foretell an ominous future. “The trend shows no evidence for abatement and may indicate increasing epidemiologic and clinical significance,” the researchers write.

However, experts contacted by Medscape Medical News did not sound any alarms; in fact, they suggested that the study evidence is not strong.

“These are small changes over long periods of time and without corroboration by other large population datasets. It is difficult to draw many conclusions [about the findings],” said Julie Margenthaler, MD, a surgical oncologist from the Siteman Cancer Center and the Washington University School of Medicine in St. Louis, Missouri.

Another expert said the study findings are somewhat puzzling.

It is not clear from the study “whether the overall rate of breast cancer in young women is actually increasing,” said Ann Partridge, MD, a medical oncologist from the Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts. In other words, the study does not indicate whether the increase in advanced disease means that there is an overall increase in disease in young women.

That is important because other studies using SEER data have indicated that the rate of overall disease is stable in young women, said Dr. Partridge.

She pointed out that Dr. Johnson and colleagues found that the rates of localized and regional disease held steady in young women. Therefore, because they found an increase in advanced disease, there should be an overall increase in young women, she said.

However, the researchers “did not show/discuss data on overall rates of breast cancer in young women,” Dr. Partridge wrote in an email. This omission, combined with the fact that the study findings might be in conflict with findings from other studies using SEER data, “leads me to wonder about the article,” she said.

Study statistician Franklin Chien, from Seattle Children’s Hospital, explained to Medscape Medical News how the seemingly contradictory statistics play out.

True, he said, there was no statistically significant increase in breast cancer in younger women overall, just younger women with advanced disease. “It is relatively rare for women to present with distant disease at diagnosis…. This is why we can see such a marked trend in distant-disease breast cancer, but not in breast cancer in young women as a whole,” he explained in an email.

Why the Increase?

The researchers decided to undertake this study in part because there is a “clinical impression” that more young women are being diagnosed with advanced breast cancer.

A clinician not involved with the study shares that impression.

“Anecdotally, we seem to be seeing a lot more younger women with breast cancers, many of whom are advanced. However, I have no data to support this,” Kathryn Evers, MD, told Medscape Medical News. She is a radiologist who specializes in breast cancer at the Fox Chase Cancer Center in Philadelphia, Pennsylvania.

The researchers sought proof of this clinical impression using 3 of the regional SEER registries. They culled data on incidence, incidence trends, and survival rates as a function of age and extent of disease at diagnosis for 3 periods: 1973 to 2009, 1992 to 2009, and 2000 to 2009.

In the SEER registries, localized disease is defined as being confined to the breast, regional is defined as contiguous and adjacent organ spread (lymph nodes, chest wall), and distant is defined as remote metastases (e.g., bone, brain, lung).

The researchers found that breast cancer rates, expressed by the annual percent change (APC) in incidence, were stable over the study period — except in 2 groups.

“APCs increased significantly (P < .01 and APC > 2.0) in, and only in, women aged 25 to 39 years with distant disease at diagnosis,” they write. The “one exception” to this finding is “older women, who had an increase in localized disease associated with implementation of screening mammography during the 1980s.”

Table. Increase in APC Over the 3 Study Periods in Women 25 to 39 Years of Age

The   category of distant disease as a proportion of all invasive breast cancer in younger women increased from 4.4% in the 1970s, to 4.8% in the 1980s, 5.5% in the 1990s, and 7.2% in the 2000s, the researchers report.

“Why is the increase occurring?” they ask. A possible answer is the “increased diagnostic sensitivity and scrutiny,” they say.

But if sensitivity is responsible, then there would be an “increase in detection in all patients,” Dr. Partridge pointed out.

Dr. Evers thinks that increased scrutiny is “possible” because “when breast cancer is diagnosed in younger women, there is an emotional response on the part of the physicians, so they want to ‘do everything’.” However, that “is probably a pretty small effect; most women get a pretty complete evaluation once they get the diagnosis,” she noted.

It is also possible that diagnosis is “delayed more frequently than in older women,” she added.

Dr. Margenthaler also believes delayed diagnosis could play a role in the findings. “The typical scenario is that a young woman feels a lump, which prompts her presentation. [However], by the time a lump is felt, it is already on average much larger than a cancer found by screening mammogram,” she explained.

Dr. Partridge said that it is “possible that something is going on biologically,” but she also said that there is “limited biologic rationale for this.”

Dr. Johnson and colleagues offer no biologically based theories about their findings.

However, the researchers and all of the experts interviewed by Medscape Medical News agree that younger women tend to be diagnosed with more aggressive and advanced disease than their older counterparts.

Last year, Dr. Partridge and colleagues published a retrospective study of 22,000 women with breast cancer to elucidate the relation between age and disease stage (Oncologist. 2012;17:775-782).

They found that being younger than 40 years is “only modestly associated with higher stage disease.” They also found that presenting with “symptoms” strongly predicted higher stage, which was more common in the younger women. “Most breast cancer in young women is picked up by a sign or symptom — usually a breast symptom, such as a mass,” said Dr. Partridge. If medical practitioners want to see fewer young women present with advance disease, research is needed to learn how practitioners and women can better recognize early symptoms of breast cancer, they conclude.

Dr. Johnson reports being on the board of the Young Adult Cancer Alliance. Coauthor Archie Bleyer, MD, from the Oregon Health and Sciences University in Portland, reports having financial ties to Sigma-Tau Pharmaceuticals. Dr. Margenthaler, Dr. Partridge, and Dr. Evers have disclosed no relevant financial relationships.

The mutation, in an immunoregulatory gene known as TREM2, was more common in Alzheimer’s disease patients than in the general 85-and-older population in Iceland with an odds ratio of 2.91 (95% CI 2.09 to 4.09, P=3.42×10^-10), reported Kari Stefansson, MD, PhD, of deCode Genetics in Reykjavik, Iceland, and colleagues.

Because of the gene’s function within the central nervous system, the mutation “may lead to an increased predisposition to Alzheimer’s disease through impaired containment of inflammatory processes,” the researchers wrote online in the New England Journal of Medicine.

Such processes have been implicated in Alzheimer’s disease previously, they noted. In fact, the so-called amyloid theory of the disease holds that brain inflammation is the “downstream effect” of the accumulation of beta-amyloid protein plaques, Stefansson and colleagues wrote.

On the other hand, the TREM2 mutation’s rarity, and the fact that many carriers in the study remained free of Alzheimer’s disease into extreme old age, suggested that it is neither necessary nor sufficient to trigger the disease.

In the study, Stefansson and colleagues first analyzed genome sequences from 2,261 Icelanders to identify variants considered likely to produce gain- or loss-of-function mutations in expressed proteins.

They then compared frequencies of such variants in 3,550 individuals with Alzheimer’s disease versus 110,050 individuals from the general Icelandic population. Included in the latter group were 8,888 who had reached the age of 85 without a diagnosis of Alzheimer’s disease and 1,236 who were that old and showed no sign of cognitive impairment.

A mutation in TREM2 causing an amino acid substitution at position 47 was the only one significantly associated with Alzheimer’s disease in the analysis. Compared with the sample drawn from the all-ages general population, the odds ratio was 2.26 95% CI 1.71 to 2.98) for increased frequency of the mutation in Alzheimer’s disease patients.

And, compared with the 1,236 controls older than 85 with no cognitive impairment, the odds ratio in patients was 4.66 (95% CI 2.38 to 9.14).

Nevertheless, the mutation was present in all three control groups at low frequencies, ranging from 0.62% in the general population sample to 0.31% in the cognitively intact older controls.

Older control members carrying the mutation — even those without Alzheimer’s disease — had poorer cognitive performance according to test results obtained periodically in Icelandic nursing home residents.

Mean scores in 3,699 noncarriers trended slowly upward by age, indicating progressively poorer cognitive function, from about 2.2 at age 81 to 2.7 at age 99.

The upward slope was noticeably steeper in 53 mutation carriers, increasing from a mean of about 2.3 at age 81 to 4 at age 97 (P=0.003 for trend).

Stefansson and colleagues also sought to replicate the frequency comparison in Alzheimer’s disease patients versus controls in other cohorts. They were able to test the frequency of the TREM2 mutation in groups of patients and controls assembled in the U.S., Germany, the Netherlands, and Norway — a total of 2,037 patients and 9,727 controls.

The mutation was less common in the control groups in those cohorts, ranging in frequency from 0.12% to 0.19%. But the approximately threefold increase in frequency in Alzheimer’s disease patients was preserved in pooled data from all four groups (OR 2.83, 95% CI 1.45 to 5.40, P=0.002).

On the other hand, among the individual cohorts, the association was significant in only one, from Munich (OR 3.15, 95% CI 1.06 to 10.40, P=0.04).

In an accompanying editorial, two other researchers commented that the study was important for its clear implication of inflammatory processes in at least a subset of Alzheimer’s disease cases.

The findings “may generate new insights into the pathogenesis of late-onset Alzheimer’s disease,” wrote Harald Neumann, MD, of the University of Bonn in Germany, and Mark J. Daly, MD, of Massachusetts General Hospital in Boston.

They also pointed out that the risk of Alzheimer’s disease associated with the TREM2 variant was in the same range as for the much more common APOE epsilon 4 variant.

Severe loss of function in TREM2 from homozygous mutation is already a recognized human disorder known as Nasu-Hakola disease, Neumann and Daly added. In this condition, a number of organ systems are affected, with severe dementia a late-stage symptom. Most patients die by age 50.

Previous research has indicated that heterozygous carriers of the Nasu-Hakola mutation are at increased risk for late-onset Alzheimer’s disease.

VANCOUVER—The quality and quantity of sleep may be associated with the risk for cognitive decline, according to four studies presented at the 2012 Alzheimer’s Association International Conference. Treatments for insomnia or circadian rhythm delay might reduce or prevent cognitive decline, investigators reported.

Sleep Duration and Cognition
Compared with a sleep duration of seven hours per day, sleep durations of five or fewer hours per day and of nine or more hours per day were associated with worse average memory at older ages, according to Elizabeth Devore, ScD, Associate Epidemiologist at Brigham and Women’s Hospital in Boston. Short and long sleep durations at midlife and in later life were both associated with worse memory in later life.

Dr. Devore and her colleagues examined 15,263 women age 70 or older who had participated in the Nurses’ Health Study. The researchers performed one initial cognitive assessment and three biennial follow-up assessments of each participant. At baseline, the subjects reported sleep duration in midlife and in later life. The investigators used multivariable-adjusted mixed linear regression models to estimate mean differences in slopes of cognitive decline in several categories of sleep duration. Multivariable-adjusted linear regression was used to estimate mean differences in overall cognitive status at older age.

Women with sleep durations that changed two hours per day or more between midlife and later life had worse average memory at older ages, compared with those whose sleep duration did not change. “Regardless of where women started out in midlife, in terms of their sleep duration, the big changes seemed to be a problem for memory,” said Dr. Devore. “These findings indicate that extreme sleep durations or greater changes in sleep duration over time may contribute to cognitive decrements in older adults.”

In performing noncardiac surgery on patients on anticoagulation, the major concern is when it is safe to perform surgery without increasing the risk of hemorrhage or increasing the risk of thromboembolism (eg, venous, arterial) after discontinuing treatment. In treating patients on long-term Coumadin perioperatively, consider the risks of hemorrhage or thromboembolism versus the benefit from the operation. When considering noncardiac surgery, these factors and the need to weigh the risk of hemorrhage against that of thromboembolism must analyzed on an individual patient basis. Certain procedures (eg, oncologic procedures, threats to limb or life) are easy analyses. More complex discussions must be had for such cases as hernia repair of other elective nonurgent operations.

The approach options for these patients can be one of the following: continue warfarin therapy, withhold warfarin therapy for a period of time before and after the procedure, or temporarily withhold warfarin therapy and also provide a “heparin bridge” during the perioperative period. Which management option to follow is primarily determined by the characteristics of the patient and by the nature of the procedure. The American College of Chest Physicians proposed guidelines for antithrombotic prophylaxis in patients with different risk factors, and it recommends that if the annual risk for thromboembolism is low, warfarin therapy can be withheld for 4-5 days before the procedure without bridging.

Patients with prosthetic heart valves pose a particular problem. Arterial thromboembolism from the heart often results in death (40% of events) or major disability (20% of events). The greatest problem encountered is that no consensus exists regarding the optimal perioperative management of anticoagulation for patients who have been receiving long-term warfarin therapy. Some prospective studies have suggested that patients on long-term warfarin therapy who undergo minor invasive procedures and are taken off their oral anticoagulation for up to 5 days have a less than 1% risk of experiencing a thromboembolic event.

It has been suggested that patients on long-term warfarin therapy (including those with mechanical heart valves or atrial fibrillation) who are undergoing minor elective invasive outpatient procedures (eg, colonoscopy, dental procedures) may have a slightly increased risk of perioperative bleeding if placed in some form of heparin therapy (eg, heparinbridge) than those who have their oral anticoagulation withheld for 4-5 days (major hemorrhage 3.7% vs 0.2% and significant nonmajor hemorrhage 9% vs 0.6%, respectively). The perioperative risk of bleeding when using a heparin bridge appears to be higher and the risk of thromboembolic events appears to be lower when Coumadin is stopped than what is reported elsewhere in the literature.

Recent studies

N-acetylcysteine is known to impair hemostasis when used for the prevention of perioperative inflammation and ischemia-reperfusion injury. Wijeysundera et al sought to determine whether N-acetylcysteine is associated with
increased blood loss and blood product transfusion in 89 patients with preexisting moderate renal insufficiency undergoing cardiac surgery.[1] Another 88 patients received placebo. The investigators found patients in the N-acetylcysteine group had a 261-mL greater mean 24-hour chest-tube blood loss and received 1.6 units more of red blood cell transfusions than the placebo group.[1] In addition, there was a significantly higher risk of receiving 5 or more units of red blood cells within 24 hours of surgery in the patients receiving N-acetylcysteine compared with the placebo group (P = 0.005). Wijeysundera et al therefore recommended clinicians and researchers consider the potential of impaired hemostasis in using N-acetylcysteine in the perioperative setting.[1]

Indications for Perioperative Management

Any patient who is on long-term anticoagulation and is to undergo a major surgery needs proactive management.[4] Some authors believe that patients can be maintained on oral anticoagulation for minor procedures, such as dental extractions, biopsies, ureterorenoscopy, Ho:YAG lithotripsy, and ophthalmic operations, as long as the therapeutic range of the prothrombin time (PT) value is not greater than 2.5.[5] A recently published study revealed a higher rate of hemorrhagic complications after glaucoma surgery in patients on anticoagulation or antiplatelet therapy. Patients who continued anticoagulation during glaucoma surgery had a hemorrhagic complication rate of 31.8% compared to 3.7% of patients with no anticoagulation or antiplatelet therapy.[6] Local bleeding with dental surgery may be controlled with tranexamic acid mouthwash or epsilon amino caproic acid mouthwash. The American Society of Gastrointestinal Endoscopy divided endoscopic procedures into low and high risk for bleeding in its 2002 guidelines on anticoagulation. Low bleeding-risk endoscopic procedures do not require a change in anticoagulation.

Low bleeding-risk endoscopic procedures are as follows:

• Upper endoscopy with or without biopsy
• Flexible sigmoidoscopy with or without biopsy
• Colonoscopy with or without biopsy
• Endoscopic retrograde cannulation of the pancreatic duct without sphincterotomy
• Biliary stent insertion without sphincterotomy
• Endosonography without fine-needle aspiration
• Push enteroscopy of the small bowel

High bleeding-risk endoscopic procedures are as follows:

• Polypectomy
• Laser ablation and coagulation
• Endoscopic sphincterotomy
• Pneumatic or bougie dilation
• Percutaneous endoscopic gastrostomy tube placement
• Treatment of varices

In general, antithrombotic therapy is indicated for venous thromboembolic disease (ie, deep venous thrombosis [DVT]; pulmonary embolism [PE]; primary prophylaxis of DVT or PE; antithrombin III [ATIII], protein C, and protein S deficiency); arterial thromboembolic disease (ie, prosthetic heart valves, atrial fibrillation, congestive cardiomyopathies, mural cardiac thrombus, acute myocardial infarction, mitral valve disease); disseminated intravascular coagulation; and maintaining patency of vascular grafts, shunts, and bypasses.[7, 8] Currently, it is generally recommended that patients with the highest risk of arterial or venous thromboembolism, who
require interruption of oral anticoagulant therapy for surgery, should receive therapeutic-dose heparin therapy (eg, unfractionated heparin [UFH], low molecular weight heparin [LMWH]) during much of the interval when the international normalized ratio (INR) is subtherapeutic.

Usually, unless accompanied by significant cardiomyopathy or recent arterial embolus, patients with atrial fibrillation can have their Coumadin stopped 4 days prior to surgery, then resumed at the usual dose the night of surgery. Patients with prosthetic heart valves usually are treated with perioperative LMWH, although randomized controlled trials validating this method are lacking. Coumadin can be stopped 4-5 days preoperatively, with LMWH started the next day at a therapeutic dose. The last dose should be 12 hours preoperatively. LMWH and Coumadin can be retitrated the evening of the operative day. LMWH is stopped when the Coumadin reaches the target range. For patients at higher risk of valve thrombosis (ie, patients with 2 prosthetic valves or with caged-ball type of valves), whether LMWH provides adequate anticoagulant protection is unclear. For these patients, consider use of perioperative UFH instead of LMWH. Preoperatively, the heparin should be stopped 6 hours before the procedure. Postoperatively, the heparin can be restarted when the surgeon agrees that it is safe, usually 6-12 hours postoperatively.

Preoperative Treatment

Several protocols have been developed to care for patients taking oral anticoagulants. Regardless of the protocol used, the period of subtherapeutic oral anticoagulation should be kept to a minimum in patients with previous
embolism and in others who are at highest risk for embolism. Kearon formulated a preoperative and postoperative strategy divided into sites of embolic disease.[9] His recommendations are summarized below.

Arterial thromboembolism

In patients with previous arterial embolism, only 4 daily doses of warfarin should be withheld preoperatively and the INR should be measured the day before surgery to determine if a small dose of vitamin K is needed to accelerate the reversal of anticoagulation. If the INR is more than 1.7 on the day before surgery, administer 1 mg of vitamin K subcutaneously and repeat the INR the morning of the surgery. If on the day of surgery the INR is 1.3-1.7, administer 1 unit of frozen plasma; administer 2 units of frozen plasma if the INR is 1.7-2. The active reversal of oral anticoagulants should be discouraged in patients with mechanical valves, especially with the use of fresh frozen plasma. For a patient who has had an arterial thromboembolism within a month of surgery, start intravenous UFH when the INR drops to less than 2 to minimize the risk of recurrent embolism. Discontinue the intravenous heparin 6 hours before surgery.

Postoperative Management – Arterial thromboembolism

If surgery is performed within 1 month after an episode of arterial thromboembolism, intravenous heparin is warranted until the INR reaches 2 if the risk of bleeding is not very high. Administer intravenous UFH without a loading dose 12 hours after surgery at a rate of no more than 18 U/kg/h. Defer the first activated partial thromboplastin time (aPTT) for 12 hours to attain a stable anticoagulant response. Postoperative intravenous heparin is not recommended for patients who undergo major surgery and who are at high risk for anticoagulant-induced bleeding, even if an episode of arterial embolism has occurred within 1 month before surgery. Instead, administer subcutaneous UFH or LMWH (3000 U bid) until the INR reaches 1.8.

The study, published in the July 24 issue of Neurology, shows that 64% of 33 videos had correct information on how to perform the Epley maneuver, with most of the other videos having only minor deviations from the accepted approach, said lead author Kevin A. Kerber, MD, assistant professor of neurology at the University of Michigan Health System in Ann Arbor.

A relatively common condition, BPPV is caused by freely moving particles called canaliths that are trapped in the semicircular canal of the inner ear. A main symptom of BPPV is transient, positionally triggered dizziness.

The Epley maneuver involves a series of easy steps designed to move particles from the canal, including the following:

• turning the head 45 degrees toward the affected ear while in an upright position
• lying back quickly with the head extended below the shoulders
• moving the head 90 degrees toward the unaffected side
• turning the head another 90 degrees so the patient is nearly in the face-down position (usually requires rolling over on the side), and
• getting back up to a sitting position.

The maneuver has been proven effective in rigorous randomized trials and is included in guidelines on treating BPPV, said Dr. Kerber. “If you want to treat someone effectively, this is it.”

Treatment Underused

According to Dr. Kerber, however, this treatment is not widely used. “There haven’t been that many studies looking at this, but every one of them suggests that this maneuver is underutilized.” It is possible that physicians recommend the maneuver but just do not record it, he said.

After performing a systematic search and selecting videos that demonstrated the entire Epley maneuver and that were available on YouTube up to August 30, 2011, researchers abstracted information from each video, including its duration, posting date, and number of views, and related comments from viewers. They categorized the videos as demonstrating guided treatment or self-treatment, and as showing the maneuver for right-sided BPPV, left-sided BPPV, or both.

Researchers also determined whether the videos included diagnostic information and were accurate in the time spent on each position of the maneuver (most should last at least 20 seconds).

The videos appeared to come from a number of different sources, said Dr. Kerber. Most seemed to have been made by healthcare providers, including physicians and physical therapists, but some were likely made by patients in their home.

The total number of hits for all videos was 2,755,607. The most widely viewed video (with 802,471 hits) was produced in 2008 by the Practice Parameter on BPPV of the American Academy of Neurology (AAN). That video, along with 4 others, accounted for 85% of hits for all videos.

The researchers rated almost two thirds of the videos (64%) as accurate demonstrations of the maneuver. Most videos (82%) provided accurate time spent on each position. However, none of the videos included complete diagnostic information about BPPV.

Reasons for inaccuracies included things such as patients turning their head more than 45 degrees, or the head not being extended back far enough. “One of the key things about the maneuver is lying all the way back with the head way back, kind of on the end of a table,” said Dr. Kerber. “Some of the videos just had the person lay back flat, which we don’t think would get the particles to move enough to be effective.”

In some videos, the movements were too slow, or the head was lifted during the rollover step. “If you do that, the particles can fall in the opposite direction to where you want them to go,” he said.

Although inaccurate movements could fail to remove particles from the canal, the maneuver is, for the most part, very safe in that it involves no more than lying down and rolling over. What could potentially be dangerous, however, is if a patient has a stroke, looks the symptoms up on YouTube, comes across one of these videos, and mistakes the symptoms for BPPV. “In that case, they waste time rolling themselves around and delaying potential treatment,” said Dr. Kerber.

Accuracy but Not Outcome

The authors rated the videos only on their accuracy and did not rank their quality in terms of outcome. That, said Dr. Kerber, can be done only through a randomized controlled trial.

Physicians do not appear to be recommending this treatment, or even learning about it. “When I talk to medical students, they may have heard of it, but they don’t know how to do it,” said Dr. Kerber.

Because dizziness bridges several specialties, including general medicine, otolaryngology, and neurology, information on the Epley maneuver may “fall through cracks,” he said.

Many physicians prescribe medicines for patients with BPPV, which can be a problem because many of these drugs are sedating, said Dr. Kerber. “Then you have someone walking around who is not only dizzy, but also sedated.”

Some patients are told just to wait it out, and that the vertigo will resolve in 6 to 8 weeks. “The condition is called benign because you’re not going to die from it, but it’s not benign in terms of symptoms,” said Dr. Kerber. “People who have it report missing work, having to stop driving and their normal routine of activities, and sometimes having to go to the emergency department.”

More than one third (39%) of the videos had at least 1 accompanying comment. Judging from the reviews, patients use the videos to self-treat. Many said that the videos were beneficial, even describing the maneuver as a “miracle,” but others said that they tried the maneuver and it did not work, which, said Dr. Kerber, suggests that they do not have BPPV.

Another theme that emerged from the comments was that healthcare providers use the videos as a prescription for patients or for educational purposes.

Pirate Video

When approached for a comment, Timothy Hain, MD, professor of neurology, otolaryngology, and physical therapy/human movement science at the Northwestern University Feinberg School of Medicine, Chicago, Illinois, raised the issue of plagiarism. He said that sharing of educational health videos on social media is a major problem. “I have noticed at least 5 of my own videos pirated on YouTube,” Dr. Hain told Medscape Medical News.

Many of his BPPV treatment protocols from copyrighted material have been uploaded illegally, and without giving proper credit, he said. This, he added, is “immensely discouraging” to content providers, who do not get paid for their very expensive content creation.

Dr. Hain also finds the quality of the videos generally rather poor, in part because of time limitations. “It’s impossible to substitute a 1-minute video for a 30-minute healthcare provider encounter,” he said.

In addition, there are the problems inherent in any “self-treatment” approach, for example, patients may not be able to determine the correct side, or they mistake a more sinister type of dizziness such as a brain tumor for BPPV, and waste time with home treatments, he said.

However, said Dr. Hain, the videos do lower healthcare costs, and the treatment they depict is “pretty benign.”

Ronald Tusa, MD, PhD, from the Departments of Neurology, Otolaryngology, Ophthalmology, and Rehabilitation Medicine at Emory University, in Atlanta, Georgia, whose research interests include causes of disequilibrium, found the study useful. He already teaches patients the Epley maneuver and includes a description of it in handouts.

“Based on this study, on the sheet I give to patients, I will probably include the YouTube site,” where they can find the correct demonstration of the maneuver, he said.

But patients tend to lose the sheet, he noted, and because it may be difficult to find an accurate video just by searching YouTube, Dr. Tusa said it would be a “great idea” if the AAN included its video on its Web site, so patients can easily access it. (By Pauline Anderson)

Dr. Kerber is funded by the National Institutes of Health/National Center for Research Resources and the Agency for Healthcare Research and Quality; has received speaker honoraria from the American Academy of Neurology, Munson Medical Center, and the University of Utah; has served as a consultant for the American Academy of Neurology; has served as a one-time consultant for Pierre Fabre and as an expert witness for Estes, Ingram, Foels & Gibbs, P.A.; and receives publishing royalties (anticipated) for Clinical Neurophysiology of the Vestibular System , 4th edition. Full disclosures are available on the journal’s Web site.

The study showed that patients with MCI who have a plasma caffeine level of 1200 ng/mL avoided progression to dementia over the following 2 to 4 years.

These patients exhibited a plasma cytokine profile that was exactly the same as that of Alzheimer’s disease (AD) transgenic mice that were given caffeinated coffee and didn’t progress to dementia. It’s therefore very likely that it’s caffeine from coffee, and not from other sources, that affords the cognitive protection, said study senior author Gary W. Arendash, PhD, research scientist, Bay Pines Veterans Affairs Hospital, St. Petersburg, Florida.

The research also suggests that certain cytokine patterns could signal for impending conversion to dementia among those with MCI, said Dr. Arendash.

Lower Caffeine Levels

The new case-control study included 2 cohorts of 124 participants in a Florida Alzheimer’s Disease Research Center study of persons aged 65 years and older. All participants had undergone a battery of baseline neurologic assessments and cognitive tests and were categorized as normal, MCI, or dementia. As well, researchers had access to fasting blood samples taken at baseline.

Over the next 2 to 4 years, researchers annually reassessed the cognition of the participants. They separated the participants into 5 groups: (1) initially normal and remained normal, (2) initially normal but converted to MCI, (3) initially MCI and remained so, (4) initially MCI but converted to dementia, and (5) initially dementia and remained so.

Analysis of plasma caffeine levels from the initial visit showed significantly lower caffeine levels in participants with MCI relative to the normal group (P < .03). Caffeine levels were also lower in participants with dementia than in those with normal cognition, but this association did not reach statistical significance (P < .07).

There was a 26% lower plasma level of caffeine in normal persons who converted to MCI over the course of the study compared with those who remained normal, but this was not significant because of considerable variability in caffeine levels among individuals in both of these subgroups.

However, 11 patients with MCI who progressed to dementia had plasma caffeine levels that were 51% below levels at study initiation vs those with MCI who remained MCI (P < .02).

None of the MCI participants who converted to dementia had initial caffeine levels above 1200 ng/mL while half of those with stable MCI had higher levels. Baseline plasma caffeine levels greater than 1200 ng/mL in MCI patients were associated with a 100% chance of avoiding progression to dementia during the 2- to 4-year follow-up.

Patients with MCI in both the Miami (n = 81) and the Tampa (n = 43) study cohorts independently showed the same relationship between blood caffeine levels and later risk for dementia progression.

Critical Level

That 1200-ng/mL level appears to be an important threshold, said Dr. Arendash. The amount of coffee needed to reach this critical level appears to be 3 to 5 cups of daily, with a target of 5 cups or 500 mg of caffeine. Those previous AD mouse studies showed that 1 to 2 cups, or between 100 and 200 mg of caffeine (which is what typical Americans drink daily), was not enough to ward off dementia, he said. It’s not known whether it’s necessary to spread those 5 cups throughout the day, he added.

It’s important to remember, though, that half of the patients with stable MCI in the study who had caffeine levels below 1200 ng/mL also didn’t progress to dementia. Clearly, other factors play a role. Such factors probably include the level of cognitive and physical activity, the presence of hypertension, and antioxidant intake, especially from fruits and vegetables, said Dr. Arendash.

The study also found that 3 cytokines — granulocyte colony-stimulating factors (G-CSF), interleukin-10, and interleukin-6 — were lower in the plasma of patients with MCI who were destined for AD conversion than in both the nonconverting MCI participants and the participants with dementia. None of the 8 other plasma cytokines that were measured showed any such profile when the same 2 MCI subgroups were compared.

“When that initial blood sample was taken, MCI patients that went on to convert to AD had low levels of all those cytokines,” said Dr. Arendash. “That could be diagnostic; it could be a very important plasma indicator of impending AD.”

The studies of AD transgenic mice, which produce the same abnormal human protein as the human brain, amyloid-beta, demonstrated that long-term oral administration of caffeinated coffee prevents cognitive impairment.

The cytokine profile of the participants in this current study was the same as that in these AD mice. “Their profiles matched identically to the mice given coffee but not other sources of caffeine;” said Dr. Arendash. “That’s why we strongly believe that most, if not all, of those MCI patients who did not convert were on habitual coffee intake.”

The mouse research allowed investigators to identify disease-modifying mechanisms for caffeine. The studies showed that caffeine alone suppresses brain levels of enzymes required for amyloid-beta production via targeting of specific signal transduction mechanisms. This research also suggested that something in coffee increases plasma levels of those 3 key cytokines: G-CSF, interleukin-10, and interleukin-6. G-CSF, in particular, has beneficial cognitive actions in AD mice that involve synaptogenesis and neurogenesis.

Aside from caffeine, coffee is rich in antioxidants and anti-inflammatory compounds that may also contribute to reduced risk for AD.

This study was a retrospective analysis, so a definitive relationship will have to be derived through a clinical trial in which participants consume caffeinated coffee, other caffeinated products, or decaffeinated coffee, over a period several years, said Dr. Arendash. He suggested that residents of China, where coffee consumption is very rare, would make an ideal control population for such research.

Accumulating Evidence

Reached for a comment, Karen Ritchie, PhD, Faculty of Medicine, Imperial College, London, United Kingdom and Directeur de Recherche, Institut National de la Santé et de la Recherche Médicale, Montpellier, France, said the study, which involved a direct measure of caffeine in plasma rather than just reports of caffeine consumption, adds to accumulating evidence of a beneficial effect of caffeine.

However, she told Medscape Medical News, the study’s “weak point” is that, unlike the epidemiologic studies, such as the ones she and her colleagues have carried out, alternative explanations of this observation were not taken into account.

“For example, persons drinking less coffee may also have more hypertension, more depression, more heart disease, less social activity than those with higher levels, and these factors are in themselves related to onset of dementia.”

Still, one of Dr. Ritchie’s own previous studies, published in Neurology , concluded that the psychostimulant properties of caffeine appear to reduce cognitive decline in women without dementia, especially at higher ages.

The question of whether some people are protected against dementia because they drink coffee or because they do or have something else that non–coffee drinkers don’t, remains unanswered, she said.

WASHINGTON — The FDA has approved the restless legs syndrome drug gabapentin enacarbil (Horizant) to treat postherpetic neuralgia.

The drug is administered in one 600 mg dose for the first 3 days of treatment, followed by 600 mg doses twice daily on day four and onward, a statement from makers GlaxoSmithKline and XenoPort said.

Patients with renal impairment should have adjusted doses, the statement added.

Safety and efficacy for the new indication were evaluated in a 12-week principal efficacy trial and two supportive studies of a combined 574 patients.

Adverse events in the studies included somnolence, dizziness, headache, nausea, and fatigue.

Patients taking anti-epileptic drugs, including other gabapentin formulations, may be at increased risk for suicidal ideation and behavior, as well as potentially fatal multi-organ hypersensitivity, symptoms of which include fever, rash, and lymphadenopathy.

The drug should be tapered to once daily for a week before ceasing treatment to reduce risk of withdrawal seizure, the statement said.

The drug was initially approved for the treatment of moderate-to-severe primary restless legs syndrome in April 2011.

“The findings of this study suggest that the blood pressure lowering and lipid effects of plain dark chocolate could represent an effective and cost effective strategy for the prevention of cardiovascular disease in people with metabolic syndrome (and no diabetes),” the researchers, with senior author Christopher M. Reid, PhD, CCRE Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, The Alfred Centre, Melbourne, Victoria, Australia, conclude.

“Chocolate benefits from being by and large a pleasant and, hence sustainable, treatment option,” they write. “Evidence to date suggests that the chocolate would need to be dark and of at least 60-70% cocoa, or formulated to be enriched with polyphenols.”

Dark chocolate, derived from coca beans, is rich in polyphenols, specifically flavonoids that exhibit antihypertensive, anti-inflammatory, antithrombotic, and metabolic effects, all of which may contribute to cardio-protection.

Long-Term Effects

Previous studies have shown that dark chocolate consumption may lower blood pressure, but they have been relatively short, only up to a maximum of 18 weeks. Studies have also shown that dark chocolate may decrease total and low-density lipoprotein cholesterol and increase high-density lipoprotein cholesterol, but again, these changes have been explored only in short-term trials.

To determine potential long-term effects of consuming dark chocolate every day, as well as the cost-effectiveness of this strategy, Australian researchers used statistical modeling techniques, particularly a Markov model to which health states (“alive without cardiovascular disease,” “alive with cardiovascular disease,” “dead from cardiovascular disease,” “dead from other causes”) and decision analysis (no dark chocolate [control], or with dark chocolate [treatment]) were added.

With each annual cycle, the researchers used risk prediction algorithms and population life tables to estimate how eating dark chocolate every day for 10 years would affect patients with metabolic syndrome.

The study used data on 2013 participants from the Australian Diabetes Obesity and Lifestyles study who had metabolic syndrome, did not have a diagnosis of cardiovascular disease or frank diabetes, and who were not receiving antihypertensive medications.

The patients were relatively young (mean age, 53.6 years) and considered at high risk: They had a mean systolic blood pressure of 141.1 mmHg, mean total cholesterol level of 6.1 mmol/L, mean hemoglobin A1c of 34.4 mmol/mol, and mean waist circumference of 100.4 cm.

The researchers concluded that under the best-case scenario, in which all these patients ate dark chocolate daily for a decade, 70 nonfatal cardiovascular events, including nonfatal stroke and nonfatal myocardial infarction per 10,000 population, as well as 15 cardiovascular related deaths per 10,000 population, could be prevented.

The estimated incremental cost-effectiveness ratio was $52,500 per years of life saved when $42 per person per year was assumed to have been spent on a prevention strategy using dark chocolate.

Even if only 80% of individuals with metabolic syndrome adhered to daily consumption of dark chocolate over 10 years, preventing only 55 nonfatal and 10 fatal events per 10,000, it would still be considered an effective and cost-effective intervention strategy, the authors write.

Prevention Strategy

A dark chocolate prevention strategy of $42 per person per year in a high-risk population would be cost-effective “based on the commonly accepted, albeit arbitrary, threshold of $50,000 per years of life saved,” said the authors.

The $42 per person per year could be devoted to advertising, education campaigns, or, potentially, subsidization of dark chocolate in this high-risk population, they said.

The authors point out that they did not assess the potential effectiveness of dark chocolate consumption on cardiovascular events other than nonfatal stroke and nonfatal myocardial infarction, such as heart failure.

They also stressed that the effects of dark chocolate consumption on blood pressure and total cholesterol, although beneficial, are not as profound as those of drug interventions.

The authors have disclosed no relevant financial relationships.

BMJ. Published online May 31, 2012.

The double-blind, placebo-controlled study will test the drug crenezumab, an antibody that targets beta-amyloid, in a large extended family in Colombia, many of whom carry genetic risk mutations. Typically, cognitive impairment begins at around age 45 in affected individuals.

This trial is an important step in testing the amyloid hypothesis of the disease and could have wide-reaching implications, said Ronald Petersen, MD, PhD, director, Alzheimer’s Disease Research Center, Mayo Clinic, Rochester, Minnesota. Dr. Petersen chaired the Advisory Council on Alzheimer’s Research, Care and Services that was charged with developing the National Alzheimer’s Project Act (NAPA) signed into law by President Barack Obama in 2011. The National Alzheimer’s Plan was called for in NAPA.

“It’s going to be relatively pure test of the amyloid hypothesis,” said Dr. Petersen, because the drug targets amyloid. “This is something that needs to be done, but whether it’s going to be applicable to the general population of patients with AD is another question.”

The government will also contribute to a $7.9-million effort to investigate an insulin nasal spray as a treatment for AD. A recent small study showed memory improvements in adults with amnestic mild cognitive impairment or AD who used the spray.

The funding for both trials is included in the $50 million in research support announced for fiscal 2012 as part of the Alzheimer’s Plan. Another $80 million was announced for fiscal 2013. The plan has a stated aim of finding an effective AD treatment or preventive strategy by the year 2025.

The plan, said Dr. Petersen, signals a real commitment to the cause.

“The fact that the president, the congress, everybody, has mobilized around this at least makes us think that people at the federal government level are starting to pay attention, and realizing that we have got to do something about this; we just can’t continue with the niceties and give lip service to it,” he told Medscape Medical News.

Families at Risk

Autosomal dominant AD is caused by a mutation in 1 of 3 genes — amyloid-beta precursor protein (APP) and presenilin 1 and 2 (PSEN1, PSEN2) — and accounts for about 1% of all AD cases. “Statistically, children of an affected parent have a 50/50 chance of inheriting that mutation, across all generations,” said Dr. Petersen. Carriers have a 100% risk of developing the disease at roughly the same age as their parent, but offspring who don’t carry the mutation have the same risk as anyone else.

The government’s plan includes National Institutes of Health funding on the order of $16 million toward the $100 million cost of the study in Colombia. The trial will enroll 300 participants 30 years of age or older, 100 in each of 3 groups: participants with the mutation who will take crenezumab, those with the mutation who will take placebo, and noncarrier relatives who will receive placebo. It will also include “a handful” of Americans, perhaps 20 or 30, said Dr. Petersen.

Participants will receive placebo or the treatment drug, being developed by Genentech in collaboration with Swiss biotech company AC Immune SA, for up to 5 years. Using advanced imaging techniques, cerebrospinal fluid tests, biomarkers, and sensitive cognitive measures, researchers will assess whether the treatment reduces accumulation of amyloid and maintains brain size, and whether it preserves cognitive function.

Recruitment for the trial, set to begin early next year, should be “relatively straightforward” compared to a regular drug trial, partly because of what’s known already about the affected families and also because “these people are eager” to find a cure, said Dr. Petersen.

Investigators will work with Francisco Lopera, MD, from Grupo de Neurociencias de Antioquia at the University of Antioquia in Colombia, who first identified the family’s illness nearly 3 decades ago and helped determine its cause: a presenilin mutation. The trial will be led by Eric M. Reiman, MD, executive director, Banner Alzheimer’s Institute (BAI), in close cooperation with Dr. Lopera and Genentech’s research and clinical team.

“We are grateful for the chance to evaluate such a promising prevention treatment,” Dr. Reiman said in a statement. “We have tried to design the study in a way that might bring the field closer to ending Alzheimer’s before another generation is lost.”

In addition to government funding of the trial, BAI is committing $15 million, with Genentech contributing the remaining cost, in addition to providing the study drug and clinical and operational expertise.

Preclinical studies showed that crenezumab binds to amyloid proteins and clears them from the brain. It has been studied in both healthy individuals and people with AD and is being evaluated in a phase 2 clinical study in patients with mild to moderate symptoms. To date, no significant safety issues have been detected.

A panel of experts chose the Genentech drug among several other candidate agents for the prevention trial because it has fewer side effects. For example, it does not cause vasogenic edema.

Other similar antiamyloid drugs include bapineuzumab, being tested by Pfizer Inc and Johnson & Johnson, and solanezumab, under investigation by Eli Lilly and Co.

Best Evidence

Experts, including Dr. Petersen, believe that this trial, which involves taking a treatment when still cognitively normal, could provide the best evidence yet on the involvement of amyloid in AD. It’s possible that previous trials of other antiamyloid drugs didn’t show an effect because patients were too far along in the disease

Results of earlier trials give experts reason to believe they’re on the right track in starting a treatment well in advance of symptoms. The first results from the Dominant Inherited Alzheimer’s Disease (DIAN) study, a multicenter international study of autosomal dominant AD, reported last summer during the Alzheimer’s Association International Conference, showed that measurable biochemical and imaging markers can be detected up to 20 years before symptoms appear.

Baseline data for that study showed that cognitively normal individuals who are mutation carriers and therefore destined to develop AD in their 40s, 30s, and sometime even their 20s have lower levels of beta-amyloid 42 (Aβ-42) and elevated levels of tau and phosphorylated tau (p-tau) compared with their non–mutation-carrying siblings, as determined by imaging and cerebrospinal fluid and blood testing.

As well, DIAN investigators were able to detect cognitive changes on clinical testing among mutation carriers who were asymptomatic at baseline.

If the new study shows that crenezumab can prevent AD in people certain to develop it, other trials could be designed to test it and other antiamyloid drugs in larger populations, according to a Banner statement. If the treatment’s effects on biological measurements of the disease are shown to predict its clinical benefit, the study could establish a much faster way to test future therapies.

AD Burden

Experts predict that without an effective treatment, the number of Americans with Alzheimer’s will double by 2050 to more than 10 million, and related healthcare costs could soar to over $1 trillion a year. This is in addition to the caregiver burden, which can take a serious toll on the physical, mental, and financial well-being of family members.

Also included in next year’s $100 million effort to combat Alzheimer’s disease is $4 million earmarked for the development of high-quality, up-to-date training for doctors, nurses, and other providers. The plan will also allocate $4.2 million to improved public awareness that will include a television advertisement and a new Web site (www.alzheimers.gov), $10.5 million to caregiver support, and $1.3 million toward improved data collection.

The federal plan “is going in the right direction” but is still just a step, commented Dr. Petersen. “To make the giant leaps, we really need the major changes in funding, but I think more news is good news.”

However, it’s still encouraging, particularly in light of the current belt-tightening environment, he said.

“In the grand scheme of things, when you look at what’s happening at the federal government level, everybody is gearing up for a downturn, a reduction of up to 10%,” said Dr. Petersen. “They are battening down the hatches at NIH (National Institutes of Health), and there may be even more draconian cuts coming down the road. Here’s a little glimpse of something going in a positive direction, and that’s good.”

The Alzheimer’s Association applauded the plan. “This is a strong plan that promises important progress when implemented,” Harry Johns, president and CEO of the Alzheimer’s Association, said in a statement. “For all Americans, not just the more than 5 million living with Alzheimer’s and their 15 million caregivers today — this plan is an historic achievement.”