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an online version of the magazine Spring/Summer 2007
Medical Rounds

> The amyloid plaque (lower left) did not impair this patient. The added microstroke (center) did.
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When Alzheimer’s Doesn’t Mean Dementia

New study to show Alzheimer’s plaques can stay silent.

 

We all know the popular sentiment: Take my hands, take my legs; just don’t ever take my mind. A Johns Hopkins study coming out soon may show more aging people how to stave off dementia even as Alzheimer’s disease invades their brains.

The secret? Reduce your risk of stroke. If we can successfully manage the effects of cerebrovascular disease, says Richard OBrien, we can reduce the rate of dementia by about a third. “It turns out that your brain can absorb an awful lot of Alzheimer’s pathology and still be normal,” adds OBrien, chief of neurology at Johns Hopkins Bayview. “But hit it with one extra stroke and it’s over.”

The findings will be detailed in a future edition of the Annals of Neurology. The paper—which bears latter-day fruits from the powerful longitudinal study on aging that was launched by geriatrics visionary Nathan Shock and about 3,000 Baltimore-area health community friends back in 1958—was conducted jointly with the National Institute on Aging.

OBrien says the new findings stem from the growing autopsy component of the study’s deceased participants. Researchers now have access to 179 of their brains, mostly from white males who died in their 80s. The tissue samples revealed that 105 of the brains showed some signs of the progression of Alzheimer’s disease, but only half of that 105 had displayed evidence of cognitive dementia while alive. What tipped the balance?

OBrien’s team found two chief distinctions among the so-called “normals”—those whose brains showed significant Alzheimer’s pathology without any cognitive decline. First, he says, the normals possessed an abundance of enlarged neurons—a finding made by Hopkins pathologist Juan Troncoso—indicating that the brains of high-functioning subjects managed to form new synapses to bypass the obstacles formed by the disease. Cognitively speaking, says OBrien, these people maintained “high plasticity” well into their 80s.

The other distinguishing trait for the normals is that they showed a very low incidence of cerebrovascular disease, chiefly demonstrated by a lack of strokes of any kind.

“It’s the combination of the two pathologies that matters most,” says OBrien. “Even a single stroke doubles your risk of dementia when combined with Alzheimer’s pathology.”

One of the surprising findings was that the majority of brains showed evidence of microscopic strokes that had caused no impairment to subjects while alive. In fact, the majority of strokes proved asymptomatic. While it is common sense that a higher number and volume of strokes would raise the risk of cognitive impairment, OBrien says the human brain can also tolerate two or even three strokes surprisingly well in the absence of Alzheimer’s pathology.

We haven’t found a way to stop Alzheimer’s yet, says OBrien, but we’re learning how to tackle its partner-in-crime—cerebrovascular disease. The chief culprit here turns out to be unmanaged hypertension. “Eliminate the strokes,” says OBrien, “and you eliminate a third of all dementias.”

 

Ramsey Flynn


In the Spotlight on Lyme

As debate swirls, Paul Auwaerter argues against overprescribing antibiotics.

Steve Desiderio, the protein prober.
> Illustration by Vladimir Rajevac

Fiery advocacy groups. Sprawling conspiracy theories. Over a thousand emotional videos on YouTube, nearly all challenging the official guidelines laid down two years ago for the treatment of Lyme disease.

The conflict? The guidelines from the 8,000-member-strong Infectious Diseases Society of America (IDSA) say Lyme disease is relatively easy to detect and treat, and that antibiotics should generally be used for no longer than one month. Not so, the opponents say, insisting there’s an emerging phenomenon they call “Chronic Lyme Disease” that causes fatigue, muscle pain, poor sleep, and memory problems requiring much longer courses of drugs that could take years.

Enter Paul Auwaerter, clinical director of infectious diseases here, who has taken to the dais at national meetings for two years in a row for live debates about Lyme. With the tick-borne illness currently afflicting nearly 20,000 people in the U.S.—and with many more claiming to have it despite the absence of its defining pathogen—we asked Auwaerter to explain the issues surrounding the controversy.

How do you currently define the Lyme condition?

The operative bug is a spirochete called Borrelia burgdorferi. It’s typically introduced by a tick’s bite, and most commonly produces the well-known rash that in some has a bull’s-eye appearance. The rash, called erythema migrans, is often accompanied by fever, malaise, headache, and musculoskeletal pains. If untreated, the infection may go on to cause heart block, chronic arthritis, and occasionally neurological complications.

How do you confirm a diagnosis?

The rash remains the best marker for Lyme disease and standard Lyme blood tests are frequently negative in this stage of the infection. Physicians must therefore suspect Lyme disease and consider the diagnosis based on the rash. If there is uncertainty, checking a Lyme blood test four to six weeks after the rash is a good idea. For problems occurring weeks or months after the initial infection, we depend on serological tests that analyze blood samples looking for evidence that the patient’s immune system has reacted to Borrelia burgdorferi. These tests work well to diagnose Lyme disease in most patients. Those who advocate for “Chronic Lyme Disease” often use “specialty Lyme research laboratories” that diagnose the infection using unvalidated methods. This is confusing for patients.

How do you treat the Lyme?

Antibiotics such as doxycycline and amoxicillin have proven very effective. Depending on the stage, treatment can be as little as 10 days, but may extend to three weeks. For arthritis cases not responding to oral antibiotics—or for certain Lyme-related neurological problems—a course of IV antibiotics could be recommended for two or four weeks.

Why is there a debate?

Up to a quarter or more of patients experience some fatigue or muscle aches even after antibiotic therapy for the first few months after treatment. Over time, most return to normal. For unknown reasons, perhaps 5 percent continue to suffer problems long after the infection has cleared—typically things like “brain fog,” fatigue, poor sleep, and muscle and joint pains. The trouble is that these are common complaints throughout the general population. So far, no good studies help separate pre-existing conditions such as depression, fibromyalgia, or chronic fatigue syndrome from those actually brought about by the Lyme infection. Although I believe some patients continue to have problems, the key thing I tell them is that the spirochete bacteria can no longer be found despite rigorous testing. Alternative practitioners believe that B. burgdorferi evade detection through a stealth mechanism. They treat this so-called Chronic Lyme Disease with very long courses of antibiotics. They have no controlled studies that show patients durably benefit. In fact, the opposite is true. For patients with persisting symptoms after initial treatment for Lyme disease, long-term antibiotics were no better than placebo.

Does this alternative therapy cause any harm?

Yes. Excessive courses of antibiotics may contribute to drug-resistant superbugs. They tax other organ systems and may cause complications, especially intravenous antibiotic therapies. This alternative approach also consumes many resources throughout the entire health system. Other problems include some practitioners who use very unconventional strategies (chelation therapy for heavy metals, hyperbaric oxygen therapy, colloidal silver) for these “chronic Lyme” patients. These odd ideas are being used to offer hope, I believe, but it is likely a false and unproven hope.

So what can physicians here do?

Some academics and clinicians have gotten gun-shy around this whole issue. If we decline to evaluate something that others call “chronic Lyme disease,” I feel that we are not being responsive to these patients. I find it rewarding to see these patients and try to explain the differing opinions as well as outline why treatments may or may not work. I do believe that there might be something we can call “post-treatment Lyme disease syndrome”—instead of “Chronic Lyme Disease,” which suggests an active infection—but it doesn’t respond to antibiotics. What we need is more work on this problem. RF

 


A One-Day Pancreatic
Cancer Clinic

Patients leave with a consensus—and sometimes a different treatment plan.

 

  David Kass looking at pacemaker
      > Herman with Nurse Practitioner Joann Coleman.

Every Tuesday morning, six patients are seen at the pancreatic cancer clinic here. At the end of the day, they go home with a comprehensive treatment plan in hand—and for about one-quarter of participants, the clinic’s findings have been different from the patients’ outside institutions’.

Most of the discrepancies result from reviews of pathology and CT imaging, says clinic director Joseph Herman, an assistant professor of radiation oncology.

So, for example, some who believed their tumors were unresectable discovered they were actually surgical candidates. Others were found
to have previously unsuspected metastases. “While that’s unfortunate, we saved a lot of morbidity from unnecessary treatment like surgery, chemo, or radiation,” Herman says.

He conceived of the clinic at the Kimmel Cancer Center as a way to harness the expertise that exists at a high-volume pancreatic center like Johns Hopkins. “It can take patients weeks to see any one of our specialists,” he says. “Now we come to them, all on the same day.”

When patients arrive they have lab blood work and CT scans done, then assemble for an overview of support services delivered by social workers, nutritionists, genetics counselors, and others. Next, they are examined by clinicians from surgery, medical oncology, and radiation oncology who prepare a one-page summary report.

At noon, the reports are distributed at a case conference to the multidisciplinary team—about 50 people in all. A surgeon, medical oncologist, radiation oncologist, pathologist, and radiologist review patient information, imaging, and pathology and reach a consensus on a treatment plan. Finally, the plans are discussed with each patient, and when appropriate, patients are offered access to innovative clinical trials.

“We actually come to the patient with one consensus,” says Herman. “If they saw each one of us individually, it would be very confusing.”

 

Anne Bennett Swingle

 


Time to Shrug it Off?

Duo changing the game for replacing worn shoulders.

 

Baha system cochlear implant device
      > The reverse shoulder prosthesis.

Ed McFarland and Steve Petersen are making up for lost time. They specialize in shoulder replacements, and have puzzled over how too many aging Americans avoid the procedure for all the wrong reasons. Last year, they published a study showing that shoulder procedures in general are actually safer and more cost-effective than those offered for knee and hip joints. Now, they’ve mastered a novel procedure that can relieve pain and restore function in cases many had previously deemed lost causes.

The orthopedic duo is now doing 75 of these so-called “reverse shoulder prosthesis” procedures annually, with results that make a new case. “It’s kind of revolutionized the way we treat these guys,” says McFarland, who heads up adult orthopedics here. “Ninety-nine percent of our patients get pain relief and say they wish they’d done it sooner.”

The reverse shoulder prosthesis requires replacement of key shoulder structures but reverses the positions of the ball-and-socket elements at the upper end of the arm in a way that enhances the joint’s stability and range of motion.

 

RF



BACK TO NURTURE

Duo changing the game for replacing worn shoulders.

 

CGI of brains
      > Illustration by Sherrill Cooper

While the nature versus nurture debate quietly rages on, a Johns Hopkins pharmacologist is suggesting an idea that might sound positively old-school: Rather than focusing mostly on high-tech genetics in disease and pharmaceutical research, how about a return to studying simpler factors such as food, sleep, and medication interactions?

For the last decade, Charles Flexner says, researchers been caught up in trying to understand how the minute differences in each person’s genes affect the way patients process and respond to medications. However, recent studies have shown that the influence of genetics on an individual’s pharmacological response is surprisingly small—by some estimates, genes account for only about 10 percent of the differences in people’s reactions to the same medication. The real heavy hitters in pharmacology and other aspects of health? Outside influences that affect a patient’s daily life, such as whether he or she does shift work, smokes, or even consumes a diet heavy in a particular food. Researchers collectively call these influences “environmental” factors.

“I’m not a gambling man, but if I had to take a bet on whether genes or environment affect a patient more, I’m betting on the environment,” says Flexner, who made the case in an editorial in the March 2008 Clinical Pharmacology and Therapeutics. 

Though most medical fields never completely left studying environmental factors behind, funding for genetics research now dwarfs that of environmental influences. That’s easy to understand, says Flexner—since genetics is technologically “sexier.” It’s also easier to get a handle on patients’ set-in-stone genes than the multitude of changeable influences that they encounter every day.

Converting researchers to his way of thinking won’t be easy, Flexner acknowledges. The first step in his PR campaign: coming up with a catchy new moniker for this old field of study. In his recent editorial, he rechristened environmental influences in drug research with the name “pharmacoecology”—a combination of pharmacology and ecology, the study of the environment.

Flexner notes that he isn’t encouraging researchers to give up on genetics. Rather, he says, scientists shouldn’t forget nurture when they’re studying nature. “I think of pharmacoecology as ‘back to the future,’” Flexner quips. “We need to rediscover our past to move forward.”

Christen Brownlee



Nothing to Sneeze At

So-long to shots for allergy sufferers?

 

polymer fibers
     

Photo by Keith Weller

For decades, people with allergy-related conditions have been rolling up a sleeve once a week at the doctor’s office to receive injections of allergens.

Now Sandra Lin, a specialist in sinusitis and allergy here, is offering an alternative treatment that eschews injections altogether. Known as sublingual immunotherapy, the approach involves a daily regimen of placing a few drops of an allergen solution under the tongue and holding it there for several minutes. The potion, a custom blend of extracts proven through allergy skin testing to cause reactions,
is given in consecutively stronger doses for about four months and then levels off. As with injections, it must be taken for three to five years in order to maximize long-lasting effects.

“Sublingual immunotherapy has been shown to improve allergy symptoms, decrease the need for medicine, decrease asthma attacks, and decrease the chance of developing asthma in allergic children. And because patients can take it at home, they should be more compliant,” Lin says. The approach could expand access to those in rural areas, and make treating children (typically terrified of allergy shots) easier, she adds.

Widely used in Europe and endorsed by the World Health Organization, sublingual immunotherapy is not now prevalent in the United States (in part because it is not covered by insurance), nor is it approved by the FDA. What’s needed to clear that hurdle and make the approach available to millions of allergy sufferers: more research to define its molecular and cellular mechanisms, and clinical trials to determine ideal dosing strength and schedule. 

ABS

 
 
 
 
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