CNN.COM, November 16, 2008 — Peppermint oil, soluble fiber, and antispasmodic drugs can indeed help people with irritable bowel syndrome, according to an analysis of 25 years of research on the condition, which is characterized by bouts of diarrhea and constipation.

Your browser may not support display of this image.About 10 to 15 percent of people in North America have IBS, and it’s twice as common in women. However, only about one-third of people with the intestinal disorder seek treatment.

The exact cause of IBS remains unknown, and that lack of knowledge has led to the use of a variety of treatments, including fiber supplements, probiotics, antidepressants, behavioral-based therapies, psychotherapy, food modification, acupuncture, and laxatives. However, many treatments are controversial because study results have been mixed.

Newer and more expensive medications have been introduced to the public, but some were ineffective or withdrawn from the market due to side effects. The recent study sheds light on the cheap and readily available treatments that can help patients, says study coauthor Eamonn M. Quigley, M.D., a professor of medicine and physiology at University College Cork in Ireland.

“Medical science has tended to ignore IBS; it wasn’t appreciated how much of an impact it can have on a patient’s quality of life,” he says.

In the new analysis, researchers systematically reviewed 38 studies from the last 25 years; more than 2,500 volunteers were involved. That research compared therapies — all relatively cheap, safe, and readily available — with a placebo or with no treatment at all.

The team looked at three treatments — soluble fiber, peppermint oil, and antispasmodics, which are drugs that relax the smooth muscle in the gut and relieve cramping — and found that they were all more effective than a placebo, according to the report in the British Medical Journal.

But not all fiber is the same. The soluble fiber ispaghula husk, which is also known as psyllium and found in some bulk laxatives, significantly reduced symptoms of IBS, particularly constipation; insoluble fiber, such as bran, did not relieve symptoms.

Several antispasmodic drugs helped prevent IBS symptoms, particularly diarrhea. The most effective one was hyoscine, which is sold without a prescription in the United States.

Although peppermint oil was found to be the most effective of the three therapies, more data are needed, cautions Quigley. The peppermint-oil therapy was analyzed in only four trials involving 392 patients.

Because past research has been mixed, doctors’ treatment guidelines mention the remedies, but don’t necessarily give them a ringing endorsement, says author Alex Ford, M.D., a registrar of gastroenterology at McMaster University in Hamilton, Ontario.

“I suspect that filters down to the practitioners who don’t believe they work, so they try something that’s newer or a bit sexier,” Dr. Ford says. “The problem with IBS is that it’s a chronic medical condition and no drug has been shown to alter its natural history.”

The study results are not surprising, says Joanne A.P. Wilson, M.D., a professor of medicine in the gastroenterology department at Duke University Medical Center in Durham, North Carolina.

Dr. Wilson adds that such treatments are best for patients with mild or moderate IBS. However, in her practice, she’s found that prescription medications need to be used for severe cases that don’t respond to these treatments.

Prescription drugs that have been used to treat IBS include Amitiza, a drug for chronic constipation; Zelnorm, which was pulled from the market in 2007; and Lotronex, which was removed from the market because of potentially life-threatening side effects (although exceptions are now made for women with severe, diarrhea-prominent IBS who don’t respond to other treatments).

BMJ 2008;337:a2313, November 13, 2008

Objective To determine the effect of fiber, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome.

Design Systematic review and meta-analysis of randomized controlled trials.

Data sources Medline, Embase, and the Cochrane controlled trials register up to April 2008.

Review methods Randomized controlled trials comparing fiber, antispasmodics, and peppermint oil with placebo or no treatment in adults with irritable bowel syndrome were eligible for inclusion. The minimum duration of therapy considered was one week, and studies had to report either a global assessment of cure or improvement in symptoms, or cure of or improvement in abdominal pain, after treatment. A random effects model was used to pool data on symptoms, and the effect of therapy compared with placebo or no treatment was reported as the relative risk (95% confidence interval) of symptoms persisting.

Results 12 studies compared fiber with placebo or no treatment in 591 patients (relative risk of persistent symptoms 0.87, 95% confidence interval 0.76 to 1.00). This effect was limited to ispaghula (0.78, 0.63 to 0.96). Twenty two trials compared antispasmodics with placebo in 1778 patients (0.68, 0.57 to 0.81). Various antispasmodics were studied, but otilonium (four trials, 435 patients, relative risk of persistent symptoms 0.55, 0.31 to 0.97) and hyoscine (three trials, 426 patients, 0.63, 0.51 to 0.78) showed consistent evidence of efficacy. Four trials compared peppermint oil with placebo in 392 patients (0.43, 0.32 to 0.59).

Conclusion Fiber, antispasmodics, and peppermint oil were all more effective than placebo in the treatment of irritable bowel syndrome.

Irritable bowel syndrome is a functional gastrointestinal disorder characterized by abdominal pain or discomfort and accompanied by a change in bowel habit.1 The condition has a population prevalence of between 5% and 20% in community surveys. No known structural or anatomical explanation accounts for the pathophysiology of irritable bowel syndrome, and the exact cause remains unknown, although several mechanisms have been proposed. Altered gastrointestinal motility may contribute to the change in bowel habit reported by some patients,5 and a combination of smooth muscle spasm, visceral hypersensitivity, and abnormalities of central pain processing may explain the abdominal pain that is an essential part of the symptom complex.

Irritable bowel syndrome is a chronic relapsing and remitting condition, and a significant proportion of patients will consult their general practitioner with symptoms. Current guidelines for the management of irritable bowel syndrome in the United Kingdom recommend that the diagnosis should be made on clinical grounds alone, without the need for invasive investigations, unless alarm symptoms such as rectal bleeding or weight loss are present. As a result general practitioners are increasingly responsible for the initial management of patients with irritable bowel syndrome and are expected to refer only a minority to secondary care.

If they are to fulfill this role effectively, general practitioners need efficacious treatments that do not require monitoring and are cheap, safe, and readily available. This is particularly relevant at the present time as newer and more expensive drugs have either failed to show efficacy or been withdrawn from the market owing to concerns about serious adverse events. Traditionally, people with irritable bowel syndrome were instructed to increase their daily intake of dietary fiber, because of its potentially beneficial effects on intestinal transit time.13 When this failed, various types of smooth muscle relaxants and antispasmodics were used in an attempt to ameliorate symptoms, particularly pain and bloating.12 More recently, peppermint oil, which has been shown to have antispasmodic properties,14 has been available over the counter and has been used in the treatment of irritable bowel syndrome.

Whether any of these agents are effective in the treatment of irritable bowel syndrome is controversial. Results of randomized controlled trials are conflicting, and many have been underpowered to detect a difference between active treatment and control intervention. Systematic reviews have also come to different conclusions about the efficacy of the three treatments in irritable bowel syndrome. As a result confusion exists as to the roles of these agents, with current management guidelines for irritable bowel syndrome making varying recommendations.

We carried out a systematic review and meta-analysis to determine the effect of fiber, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome.

We searched the medical literature using Medline (1950 to April 2008), Embase (1980 to April 2008), and the Cochrane controlled trials register (2007). We considered randomized controlled trials of adults (>16 years) with a diagnosis of irritable bowel syndrome based on a clinician’s opinion or that met specific diagnostic criteria (Manning, Kruis score, Rome I, II, or III), combined with the results of investigations to exclude organic disease if trial investigators thought this necessary. The studies had to compare fiber, antispasmodics, and peppermint oil with placebo or no treatment. Participants were required to be followed up for at least one week, and studies had to report either a global assessment of cure or improvement of symptoms, or cure or improvement of abdominal pain, after treatment. This was preferably as reported by the patient, but could be documented by a doctor. If studies included patients with other functional gastrointestinal disorders, then we excluded these patients from our analyses if trial reporting allowed this, but if this was not possible we excluded the studies from the meta-analysis. We also considered as eligible for inclusion the first period of cross over randomized controlled trials. To allow steady state plasma concentrations of the agents to be achieved we considered one week as the minimum duration of treatment.

We identified studies on irritable bowel syndrome using the terms “irritable bowel syndrome” and “functional diseases, colon” (both as medical subject heading and free text terms), and “IBS, spastic colon, irritable colon”, and “functional adj5 bowel” (as free text terms). These were combined using the set operator AND with studies identified with the terms: “dietary fiber”, “cereals”, “psyllium”, “sterculia”, “karaya gum”, “parasympatholytics”, “scopolamine”, “trimebutine”, “muscarinic antagonists”, “butylscopolammonium bromide” (both as medical subject headings and free text terms), and the following free text terms: “bulking agent”, “psyllium fiber”, “fiber”, “husk”, “bran”, “ispaghula”, “wheat bran”, “spasmolytics”, “spasmolytic agents”, “antispasmodics”, “mebeverine”, “alverine”, “pinaverium bromide”, “otilonium bromide”, “cimetropium bromide”, “hyoscine butyl bromide”, “butylscopolamine”, “peppermint oil”, and “colpermin”.

No language restrictions were applied. The lead reviewer evaluated the abstracts of papers identified by the initial search for appropriateness to the study question. Potentially relevant papers were obtained and evaluated in detail. Foreign language papers were translated when required. We hand searched abstract books of conference proceedings between 2001 and 2007 to identify potentially eligible studies. The reference lists of all identified relevant studies were used to carry out a recursive search of the literature. Two reviewers independently assessed articles using predesigned eligibility forms, according to eligibility criteria defined prospectively. Any disagreement between investigators was resolved by consensus.

Outcome assessment
The primary outcomes assessed were the efficacy of fiber, antispasmodics, and peppermint oil compared with placebo or no treatment on global symptoms of irritable bowel syndrome or abdominal pain after treatment. Secondary outcomes included efficacy according to specific type of fiber or antispasmodic, and adverse events as a result of treatment.

Discussion

This systematic review and meta-analysis has shown that fiber, antispasmodics, and peppermint oil are all more effective than placebo in the treatment of irritable bowel syndrome. The number needed to treat to prevent one patient having persistent symptoms was 11 for fiber, 5 for antispasmodics, and 2.5 for peppermint oil. Adverse events were significantly more frequent in those receiving antispasmodics than in those receiving placebo, but none of these was serious. As several different treatments were studied in the included randomized controlled trials, we carried out subgroup analyses.

When type of fiber was examined, wheat bran was no more effective at treating irritable bowel syndrome than placebo or a low fiber diet. The beneficial effect of fiber seemed to be limited to ispaghula husk, with a number needed to treat of 6 compared with placebo. However, significant heterogeneity was detected between trials. When only high quality studies were considered in the analysis this heterogeneity was diminished, but the difference in effect on symptoms in favor of ispaghula husk only reached marginal statistical significance.

Antispasmodics were of benefit, but again heterogeneity between study results was significant, and there was evidence of publication bias. Data were limited for many of the drugs licensed for use in the United Kingdom, such as mebeverine, dicycloverine, and alverine. It is difficult to know whether this is a true class effect of antispasmodics. Of all the drugs studied, most data were available for otilonium, trimebutine, cimetropium, hyoscine, and pinaverium. Trimebutine seemed to have no benefit over placebo in treating irritable bowel syndrome, whereas the other four drugs all significantly reduced the risk of persistent symptoms after treatment. Considerable heterogeneity was, however, detected between individual trials using otilonium and cimetropium and, although this was not the case when studies of pinaverium were pooled, the number of included patients was small. The best evidence for an individual compound seems to be for hyoscine, the efficacy of which was studied in over 400 patients. No statistically significant heterogeneity was detected, and 3.5 patients would need to be treated to prevent symptoms persisting in one patient. It would seem reasonable for general practitioners who want to begin a trial of antispasmodics to use hyoscine as first line treatment, but to consider other antispasmodics when this strategy fails.

Peppermint oil was also superior to placebo, although statistically significant heterogeneity was detected between study results, and only four randomized controlled trials were identified including fewer than 400 patients, so data were more limited than for fiber and antispasmodics. Three of these trials scored more than 4 on the Jadad scale, but the treatment effect was similar when only these studies were included in the meta-analysis, and the heterogeneity observed between studies was no longer detected.

The reporting in this systematic review adheres to the quality of reporting of meta-analyses statement. We have also specified the search strategy used, as well as our data extraction criteria. We believe that stating the criteria for data extraction should be standard in all systematic reviews that pool dichotomous data. The combination of our comprehensive search strategy and the translation of foreign language articles enabled us to identify studies with data from over 2500 people with irritable bowel syndrome.

Limitations of the current study arise from the quality of the studies eligible for inclusion, which in most cases was moderate to good, according to the Jadad scale. None of the included randomized controlled trials reported the method of allocation concealment, however, and as this has been shown to exaggerate treatment effect the numbers needed to treat with these treatments may have been overestimated. Most trials were done before the Rome committee published their recommendations for the design of randomized controlled trials of therapies in functional gastrointestinal disorders. Only five of the included studies used the Rome criteria to define the presence of irritable bowel syndrome, although only nine were published after the first Rome classification was proposed in 1990, and only two used a validated outcome measure to define improvement in symptoms after treatment. However, many of the included trials met some of the other suggested methodological criteria, such as presence of double blinding and a minimum duration of therapy of 8 to 12 weeks. We preferentially extracted patient reported improvement in symptoms of irritable bowel syndrome or abdominal pain whenever trial reporting allowed this, which is also in line with these recommendations. Blinding of patients in these studies may not have been entirely successful owing to differences in consistency and texture between fiber and placebo, adverse events experienced with antispasmodics and, in the case of peppermint oil, the smell and taste of active treatment. The pooling of data from trials to give an overall treatment effect, and a number needed to treat, could be criticized by some as a result of differences in the methodology of individual included studies. We carried out sensitivity analyses to explore reasons for heterogeneity between studies and in all cases identified potential reasons for this, while still showing a significant treatment effect for most of the treatments we assessed.

Several previous systematic reviews have examined the role of these three treatments in irritable bowel syndrome. All of these, however, have limitations. Three reviews did not synthesize data, so no summary effect of individual treatments was reported. Of the five that extracted and pooled data in a meta-analysis all have numerous methodological errors, which render their findings potentially inaccurate. These include errors in the extraction of dichotomous data in a large proportion of included randomized controlled trials, inclusion of non-eligible studies (according to the investigators prespecified inclusion criteria) in four meta-analyses, incorrect handling of data from cross over studies, failure to carry out an intention to treat analysis when trial reporting allowed, incorporating studies that included patients with other functional gastrointestinal diseases in the analysis, and failure to identify eligible studies published at the time of the literature search,18 leading to data on truly eligible patients being excluded from the analysis. These errors led to either an overestimation or underestimation of the pooled treatment effect in many of these meta-analyses. In addition, since these reviews were carried out further randomized controlled trials of all these treatments have been published.

Current guidelines for the management of irritable bowel syndrome are equivocal or conflicting in their recommendations for the use of these treatments, but most of these have been informed by previous systematic reviews, which are potentially methodologically flawed for the reasons discussed, and this has implications for the statements made in them. In the UK, guidelines from both the National Institute for Health and Clinical Excellence and the British Society of Gastroenterology provide similar advice. Antispasmodics are recommended as first line treatment, particularly when pain and bloating are the predominant symptoms, although which of these drugs should be preferred is not stated. The use of insoluble fiber is discouraged because of concerns that it may exacerbate symptoms, an observation not borne out by our findings. Both organizations recommend that if fiber supplementation is required then this should be in the form of soluble fibers such as ispaghula. Finally, neither of these guidelines provides any statement on the role of peppermint oil in the management of irritable bowel syndrome.

The biological rationale for the efficacy of antispasmodics is unclear, but recent research using magnetic resonance imaging has shown that patients with irritable bowel syndrome and predominant diarrhea, have a reduced colon diameter as well as accelerated small bowel transit, so antispasmodics may act by reducing colonic contraction and transit time and therefore pain and stool frequency. Ispaghula husk may increase transit time in those with irritable bowel syndrome and predominant constipation. The efficacy of peppermint oil may arise from effects on smooth muscle, again reducing colonic contractility and pain owing to its calcium channel blocking activity. We were unable to examine the effect of different treatments according to predominant stool pattern reported by the patients, however, because few of the eligible trials reported these data as many predate the use of these subgroups, making it difficult to assign people to these categories retrospectively.

In summary, this systematic review and meta-analysis shows that ispaghula husk, antispasmodics (particularly hyoscine), and peppermint oil are all effective treatments for irritable bowel syndrome. Many of these are safe and available over the counter but, with the advent of newer more expensive drugs, are often overlooked as potentially effective treatments. Further large trials of these three agents in patients with irritable bowel syndrome, defined according to the Rome criteria, and using validated outcome measures are warranted. In the interim, current national guidelines for the management of the condition should be updated to include these data.

What is already known on this topic

Irritable bowel syndrome is a chronic, relapsing and remitting disorder, which can be difficult to treat

Safe, effective treatments are required, as newer more expensive therapies have been withdrawn because of concerns about safety

Fiber, antispasmodics, and peppermint oil may fulfill this role, but evidence for their use is conflicting owing to methodological errors in previous systematic reviews

What this study adds

Fiber, antispasmodics (particularly hyoscine and otilonium), and peppermint oil were all more effective than placebo for treating irritable bowel syndrome

Doctors should consider ispaghula, antispasmodics (preferably hyoscine as first line treatment), and peppermint oil to treat irritable bowel syndrome

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Dr. Gero Hütter isn’t an AIDS specialist, but he ‘functionally cured’ a patient, who shows no sign of the disease.

A Bone Marrow Transplant to Treat a Leukemia Patient Also Gives Him Virus-Resistant Cells

The Wall Street Journal, November 7, 2008, by Mark Schoofs — The startling case of an AIDS patient who underwent a bone marrow transplant to treat leukemia is stirring new hope that gene-therapy strategies on the far edges of AIDS research might someday cure the disease.

The patient, a 42-year-old American living in Berlin, is still recovering from his leukemia therapy, but he appears to have won his battle with AIDS. Doctors have not been able to detect the virus in his blood for more than 600 days, despite his having ceased all conventional AIDS medication. Normally when a patient stops taking AIDS drugs, the virus stampedes through the body within weeks, or days.

“I was very surprised,” said the doctor, Gero Hütter.

The breakthrough appears to be that Dr. Hütter, a soft-spoken hematologist who isn’t an AIDS specialist, deliberately replaced the patient’s bone marrow cells with those from a donor who has a naturally occurring genetic mutation that renders his cells immune to almost all strains of HIV, the virus that causes AIDS.

The development suggests a potential new therapeutic avenue and comes as the search for a cure has adopted new urgency. Many fear that current AIDS drugs aren’t sustainable. Known as antiretrovirals, the medications prevent the virus from replicating but must be taken every day for life and are expensive for poor countries where the disease runs rampant. Last year, AIDS killed two million people; 2.7 million more contracted the virus, so treatment costs will keep ballooning.

While cautioning that the Berlin case could be a fluke, David Baltimore, who won a Nobel prize for his research on tumor viruses, deemed it “a very good sign” and a virtual “proof of principle” for gene-therapy approaches. Dr. Baltimore and his colleague, University of California at Los Angeles researcher Irvin Chen, have developed a gene therapy strategy against HIV that works in a similar way to the Berlin case. Drs. Baltimore and Chen have formed a private company to develop the therapy.

Back in 1996, when “cocktails” of antiretroviral drugs were proved effective, some researchers proposed that all cells harboring HIV might eventually die off, leading to eradication of HIV from the body — in short, a cure. Those hopes foundered on the discovery that HIV, which integrates itself into a patient’s own DNA, hides in so-called “sanctuary cells,” where it lies dormant yet remains capable of reigniting an infection.

But that same year, researchers discovered that some gay men astonishingly remained uninfected despite engaging in very risky sex with as many as hundreds of partners. These men had inherited a mutation from both their parents that made them virtually immune to HIV.

The mutation prevents a molecule called CCR5 from appearing on the surface of cells. CCR5 acts as a kind of door for the virus. Since most HIV strains must bind to CCR5 to enter cells, the mutation bars the virus from entering. A new AIDS drug, Selzentry, made by Pfizer Inc., doesn’t attack HIV itself but works by blocking CCR5.

About 1% of Europeans, and even more in northern Europe, inherit the CCR5 mutation from both parents. People of African, Asian and South American descent almost never carry it.

Dr. Hütter, 39, remembered this research when his American leukemia patient failed first-line chemotherapy in 2006. He was treating the patient at Berlin’s Charité Medical University, the same institution where German physician Robert Koch performed some of his groundbreaking research on infectious diseases in the 19th century. Dr. Hütter scoured research on CCR5 and consulted with his superiors.

Finally, he recommended standard second-line treatment: a bone marrow transplant — but from a donor who had inherited the CCR5 mutation from both parents. Bone marrow is where immune-system cells are generated, so transplanting mutant bone-marrow cells would render the patient immune to HIV into perpetuity, at least in theory.

There were a total of 80 compatible blood donors living in Germany. Luckily, on the 61st sample he tested, Dr. Hütter’s colleague Daniel Nowak found one with the mutation from both parents.

To prepare for the transplant, Dr. Hütter first administered a standard regimen of powerful drugs and radiation to kill the patient’s own bone marrow cells and many immune-system cells. This procedure, lethal to many cells that harbor HIV, may have helped the treatment succeed.

The transplant specialists ordered the patient to stop taking his AIDS drugs when they transfused the donor cells, because they feared the powerful drugs might undermine the cells’ ability to survive in their new host. They planned to resume the drugs once HIV re-emerged in the blood.

But it never did. Nearly two years later, standard tests haven’t detected virus in his blood, or in the brain and rectal tissues where it often hides.

The case was presented to scientists earlier this year at the Conference on Retroviruses and Opportunistic Infections. In September, the nonprofit Foundation for AIDS Research, or amFAR, convened a small scientific meeting on the case. Most researchers there believed some HIV still lurks in the patient but that it can’t ignite a raging infection, most likely because its target cells are invulnerable mutants. The scientists agreed that the patient is “functionally cured.”

Caveats are legion. If enough time passes, the extraordinarily protean HIV might evolve to overcome the mutant cells’ invulnerability. Blocking CCR5 might have side effects: A study suggests that people with the mutation are more likely to die from West Nile virus. Most worrisome: The transplant treatment itself, given only to late-stage cancer patients, kills up to 30% of patients. While scientists are drawing up research protocols to try this approach on other leukemia and lymphoma patients, they know it will never be widely used to treat AIDS because of the mortality risk.

There is a potentially safer alternative: Re-engineering a patient’s own cells through gene therapy. Due to some disastrous failures, gene therapy now “has a bad name,” says Dr. Baltimore. In 1999, an 18-year-old patient died in a gene therapy trial. Even one of gene therapy’s greatest successes — curing children of the inherited “bubble boy” disease — came at the high price of causing some patients to develop leukemia.

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Gene therapy also faces daunting technical challenges. For example, the therapeutic genes are carried to cells by re-engineered viruses, and they must be made perfectly safe. Also, most gene therapy currently works by removing cells, genetically modifying them out of the body, then transfusing them back in — a complicated procedure that would prove too expensive for the developing world. Dr. Baltimore and others are working on therapeutic viruses they could inject into a patient as easily as a flu vaccine. But, he says, “we’re a long way from that.”

Expecting that gene therapy will eventually play a major role in medicine, several research groups are testing different approaches for AIDS. At City of Hope cancer center in Duarte, Calif., John Rossi and colleagues actually use HIV itself, genetically engineered to be harmless, to deliver to patients’ white blood cells three genes: one that inactivates CCR5 and two others that disable HIV. He has already completed the procedure on four patients and may perform it on another.

One big hurdle: doctors can’t yet genetically modify all target cells. In theory, HIV would kill off the susceptible ones and, a victim of its own grim success, be left only with the genetically engineered cells that it can’t infect. But so far that’s just theory. All Dr. Rossi’s patients remain on standard AIDS drugs, so it isn’t yet known what would happen if they stopped taking them.

In 1989, Dr. Rossi had a case eerily similar to the one in Berlin. A 41-year-old patient with AIDS and lymphoma underwent radiation and drug therapy to ablate his bone marrow and received new cells from a donor. It is not known if those cells had the protective CCR5 mutation, because its relation to HIV hadn’t been discovered yet. But after the transplant, HIV disappeared from the patient’s blood. The patient died of his cancer 47 days after the procedure. Autopsy tests from eight organs and the tumor revealed no HIV.

False-positive high blood pressure is common in children presenting to the ED with nonurgent problems.

Hypertension in children should be identified before symptoms or end-organ effects occur, and ambulatory care visits are recommended as potential opportunities to screen for hypertension. Investigators in Montreal evaluated the accuracy of routine blood pressure (BP) screening at triage during nonurgent emergency department (ED) visits in 549 children (age range, 3–18 years).

BP was measured using an automated machine. Children with systolic or diastolic BP above the 95th percentile for age, sex, and height who agreed to further assessment underwent manual BP measurement by a study investigator. Those with an elevated manual BP were asked to return in 4 weeks and again after another 2 months if BP remained elevated. Children with three elevated manual BP measurements were classified as having true hypertension. None of the original 549 children triaged was hypotensive.

Of the 144 patients with elevated automated BP at triage, 95 underwent manual BP measurement in the ED (49 declined to participate). Only 12 of the 95 children had an elevated manual BP. Seven were evaluated 4 weeks later and were normotensive; the other five were lost to follow-up. Thus, none of the patients who completed the study was hypertensive. In a sensitivity analysis that included patients who did not complete the study and assumed an overall hypertension prevalence of 2%, the positive predictive value for triage screening for true hypertension was 7.5%, with a specificity of 75%, and a false-positive to true-positive ratio of 12:1.

Comment: BP measurement should be part of ED evaluation, especially if hypertension could be related to the child’s presenting problem or a chronic disease, or if the child is urgently ill. However, routine BP measurement in the ED is a poor screening test for hypertension, perhaps because high BP can result from pain or anxiety, even in nonurgent patients, or from inaccurate automated BP machines (high automated BPs should be rechecked manually). An editorialist reminds us about potential financial and emotional costs associated with investigating false-positive results.

— Cornelius W. Van Niel, MD

Published in Journal Watch Pediatrics and Adolescent Medicine October 22, 2008

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Ret. Army Spc. Scott Winkler, 35, was paralyzed five years ago during an accident in Iraq.

Fish Wish program allows veterans with disabilities to swim with sharks

ATLANTA, Georgia (CNN) — Retired Army Spc. Scott Winkler had many scary encounters while serving in Iraq, but they were nothing compared with his recent experience at the world’s largest aquarium: swimming alongside a massive whale shark.

The fact that Winkler, 35, of Augusta, Georgia, is a paraplegic made the once-in-a-lifetime experience even more challenging.

“It’s like you’re in space,” Winkler said. “It’s like you’re an able body again. It makes you feel so free.”

Winkler was paralyzed five years ago during an accident while unloading ammunition in Tikrit, Iraq.

He is one of more than two dozen disabled veterans who have participated in the Fish Wish program at the Georgia Aquarium in Atlanta during the past two months.

A separate swim and dive program is open to the public, but the waiting list is nearly full until the end of the year.

The experience isn’t cheap. A half-hour dive costs $290. The veterans swam for free.

Therapeutic recreational specialist Susan Oglesby helps train safety divers at the aquarium to assist swimmers with disabilities. She explained there are very few limitations in the tank.

Your browser may not support display of this image.

Your browser may not support display of this image.”The water is the great equalizer. Once you get in, you’re floating, you’re weightless, and everybody becomes equal,” Oglesby said.

Winkler was outfitted in a wet suit and snorkeling gear. He rolled his wheelchair down a long ramp to a dock floating in the 6.3 million-gallon tank of salt water.

After sliding out of the chair, he took a deep breath and pushed himself into the water.

“It is so amazing, he said. “It’s like you don’t have a disability, because you’re just floating around with everybody else. … The fish are just swimming by. It’s a total other world.”

In addition to four 23-foot-long whale sharks, Winkler gazed on a manta ray, hammerhead sharks, goliath grouper and sawfish.

He used his arms to move his body around the football-field-size tank.

Swimming next to him were two safety divers and Orlando Perez, another young veteran from Augusta.

“It’s beautiful down there!” Perez exclaimed. “It’s peaceful, and you just forget that you’re in a wheelchair. You’re one with the fish.”

Perez, 33, a retired Army private first class, suffered a spinal cord injury during basic training 13 years ago. Like Winkler, he is confined to a wheelchair.

Perez likened the swim experience to floating on air.

“I never thought being disabled would bring me to do something so amazing,” he said. “I think it’s about overcoming the disability and not letting the disability overcome you.”

Both Perez and Winkler admitted they were nervous when they first entered in the water. They settled down after being brushed by one of the passing whale sharks.

Winkler had a big grin on his face as he talked about the benefits of taking part in the program.

“Mentally, you’re actually taking a stress break from life itself,” he said. “Physically, it’s great rehabilitation. Emotionally, your spirit is lifted, and you’re able to enjoy yourself for once.”

Yale University Medical School, November 15, 2008 — Yale researchers have taken the first critical steps in unraveling the mysteries of brain aneurysms, the often fatal rupturing of blood vessels that afflicts 500,000 people worldwide each year and nearly killed Vice President-elect Joseph Biden two decades ago.

An international team — led by Murat Gunel, professor of neurosurgery and neurobiology, and Richard Lifton, Sterling Professor and chair of genetics, and a Howard Hughes Medical Institute investigator — scanned the genomes of more than 2,000 individuals suffering from intracranial aneurysms along with 8,000 healthy subjects. They discovered three chromosome segments, or loci, where common genetic variations can create significant risk for ruptured aneurysms, which in turn cause strokes. The subjects came from hospitals in Finland, the Netherlands and Japan, and the results were similar in all groups, indicating that these variations increase risk among diverse human populations.

The findings, reported online in the journal Nature Genetics, could lead to new screening tests to identify hundreds of thousands of people at risk for strokes caused by bleeding and point to new therapies that might be able to strengthen blood vessels in the brain before they burst.

“Even though we have made significant strides in treating unruptured aneurysms, until now we have not had an effective means of identifying the majority of individuals at risk of developing this deadly problem. These genetic findings provide a starting point for changing that equation,” Gunel said.

The median age when hemorrhagic stroke occurs is 50 years old, and usually there are no warning signs. In the majority of cases, the resulting strokes cause death or severe brain damage. Without an understanding of the cause of these events, physicians have been left to respond after the fact, once the damage has largely been done. Biden was one of the lucky individuals who survived a ruptured aneurysm with minimal damage — although at the time he was stricken, his condition was thought to be grave enough that a priest was summoned to confer last rites.

The Yale study showed that the risk of harboring an aneurysm increased with the number of risk variants, or alleles. Individuals with the highest number of risk alleles tripled their risk of an aneurysm, researchers found.

Based on this large collaborative study, a screening test may one day be able to identify those who are at higher risk of forming brain aneurysms or suffering a bleeding stroke as a result.

“These findings provide fundamental insights into the genetic and biochemical changes that cause this devastating brain disease, providing hope that we may also be able to provide preventive therapy before rupture occurs,” Lifton said.

For instance, the new findings implicate variations in the gene SOX17, which is known to play a crucial role in the early development and repair of endothelial cells that make up the arterial walls of blood vessels. “These variations may interfere with the ability to produce cells that repair damage to the blood vessels, suggesting a path forward for developing new approaches to prevention,” Gunel said.

Kaya Bilguvar of Yale was first author of the paper. Other Yale researchers included Shrikant Mane, Christopher E. Mason, Murim Choi, Emilia Gaal, Yasa Bayri, Luis Kobl, Zulfikar Arlier, Sudhakar Ravuri, and Matthew W. State.

The work was funded by the National Institutes of Health, the Yale Center for Human Genetics and Genomics, the Yale Program on Neurogenetics and the Howard Hughes Medical Institute.

Citation: Nature Genetics, Nov. 9, 2008

BRAIN ANEURYSM:
Types of Brain (Cerebral) Aneurysm

Center for Endovascular Surgery — Brain aneurysms are weaknesses in the walls of the blood vessels of the brain, usually occurring at a point where a blood vessel branches. This weakness causes a bulging in the wall of the blood vessel. This bulge can take two general shapes. The first is called a “saccular” brain aneurysm and is a formation of a sac or pouch on one side of the blood vessel wall. The second type is called a “fusiform” brain aneurysm and is an outward bulging of the blood vessel wall in all directions.

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Along with occurring within the brain itself, an aneurysm can occur within the major head and neck vessels leading to the brain, called the carotid arteries with the same devastating results. The Carotid arteries are the vessels in your neck forward of the large neck muscle on the side of your neck which can be felt pulsing. The carotid arteries are extremely prone to vascular disease which can weaken their structure leading to aneurysms.

Affects of Brain (Cerebral) Aneurysm:
Brain aneurysms can cause problems in several different ways. They may rupture and cause bleeding into the fluid spaces surrounding the brain or into the brain itself. This “hemorrhage” usually causes a severe headache, which is often described by the patient as “the worst of my life.”

In addition, brain aneurysms may cause problems not related to bleeding. As an aneurysm grows, it may compress adjacent areas of the brain or specific nerves (such as the optic nerve, the nerve that transmit signals from the eye to the brain). Depending upon the location of the aneurysm, this mechanical pressure (mass effect) can result in a variety of symptoms including, but not limited to, abnormal sensations, blindness, seizures or paralysis. Additionally, some aneurysms contain blood clots that may dislodge and be carried by blood flow further into the brain, blocking smaller arteries, which can lead to a stroke.

Treatment of Brain (Cerebral) Aneurysm:
An alternative to open surgery is the minimally invasive procedure known as endovascular embolization. With this technique, a tiny incision is made in the upper portion of the thigh, where a catheter (small tube) is placed into the large artery of the leg, and with x-ray guidance is advanced through blood vessels until it reaches the aneurysm site. The aneurysm is then “packed” with tiny thread-like coils that are passed through the catheter into the aneurysm. The coils and the body’s reaction to them effectively seal off the aneurysm.

In contrast to conventional open surgery, this technique allows the aneurysm to be treated from the inside of the vessel, thus the name “endovascular” surgery. Endovascular embolization can be used to treat aneurysms in many locations and has been shown to be particularly useful in treating aneurysms that are very difficult or impossible to reach by conventional neurosurgical techniques.

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About Brain Aneurysms And Common Symptoms

Center for Endovascular Surgery — Experts at the Center for Endovascular Surgery specialize in evaluating brain aneurysm symptoms and treating patients who present with unruptured and ruptured brain aneurysms.

A brain aneurysm (sometimes called cerebral aneurysm) is an abnormal bulging or ballooning portion of a weakened blood vessel that is located in the brain. The larger the bulging becomes, the more likely the brain aneurysm will bleed into and around the brain. When brain aneurysms bleed they cause sudden death in half of the patients. Those that survive only remain functionally intact less than half of the time. Brain aneurysm bleeds cause strokes that can seriously impair speech, motor and sensory function.

Who Is At Risk For Brain Aneurysms?
Factors that increase the risk for brain aneurysms and associated symptoms include:

* Age
* Family or personal history of brain aneurysms
* Certain conditions such as polycystic kidney disease and connective tissue disorders
* Smoking

High blood pressure, high cholesterol and alcohol abuse may increase risk as well, but studies are less conclusive.

What Are Brain Aneurysm Symptoms?
Most people with unruptured brain aneurysms experience little to no brain aneurysm symptoms. In some instances, people experience brain aneurysm symptoms before rupture, including:

* A “warning” headache that may occur several days or weeks before the rupture
* A dilated pupil in one eye
* Problems with vision or eye movement
* Pain above or behind the eye, or in the temple, back of the head or neck

Brain aneurysm symptoms more typically occur when an aneurysm ruptures. This is considered an emergency situation and requires immediate emergency care. The first wave of symptoms of a ruptured brain aneurysm typically include:

* A very severe headache. Even if a patient is prone to headaches or migraines, this headache will feel very different from the normal pattern
* Neck stiffness
* Nausea
* Vomiting
* Sensitivity to light

The above brain aneurysm symptoms are often immediately followed by:

* Confusion or change in mental state or consciousness
* Coma
* In some cases, seizures

Evaluating Brain Aneurysm Symptoms
If the physicians at the Center for Endovascular Surgery suspect a brain aneurysm that is not ruptured, they will perform a thorough personal and family history and a medical examination. Based on the patient’s brain aneurysm symptoms, the Center’s physicians will also perform tests to see if they can detect the brain aneurysm or detect a low level of blood leakage in the brain, which can precede a rupture. These tests might include:

* A lumbar puncture spinal tap to see if the spinal fluid has traces of blood or is yellow (signs of bleeding in the brain)
* Cerebral angiography. X-rays are taken of the brain after a dye is injected into it through a catheter threaded through the groin. Aneurysms are often seen on this x-ray.
* Magnetic resonance angiography: This test can detect unruptured aneurysms and screen high-risk patients. Similar to cerebral angiography, images are taken of the brain after a dye is injected into it through a catheter threaded through the groin.

When patients present with brain aneurysm symptoms, the Center’s physicians work to secure the aneurysm within 24 hours of presentation so as to prevent a second bleed. Risks of re-bleed are highest in the post-bleed period. Patients undergo emergency angiography followed by endovascular coiling or surgical clipping.

The Center’s physicians work closely with the emergency departments of Beth Israel Medical Center in Manhattan, Beth Israel’s Kings Highway Division in Brooklyn, and St. Luke’s-Roosevelt Hospital Center to stabilize the patient. Patients are evaluated and transferred to Roosevelt Hospital’s Neuroscience Intensive Care Unit as rapidly as possible. Close monitoring of the patient is combined with support for the patient and their loved ones, so as to explain the plan of action.

What Are The Treatment Options For Brain Aneurysms?
Physicians at the Center for Endovascular Surgery strive to treat patients in the safest and least invasive way. The treatment of choice, if possible, is to treat the aneurysm without “opening the head.” In fact, greater than 70% of all aneurysms treated at the Center are treated without open surgery, using minimally invasive approaches such as endovascular coiling. The Center has one of the highest percentages in the nation for use of endovascular coiling and has significant experience with this technique. When aneurysms and brain aneurysm symptoms cannot be treated using endovascular techniques, the surgical team performs open surgery to secure the aneurysm to prevent re-rupture.

Patients with ruptured brain aneurysms often require placement of a ventricular drain to divert spinal fluid, which can build up in the brain following brain aneurysm hemorrhage. Patients are additionally treated with a combination of medical therapies including calcium channel blockers to prevent vasospasm, a narrowing of cerebral blood vessels, which can occur after a brain aneurysm bleed. Vasospasm can lead to stroke. Blood volume therapy is also used to increase the circulating blood volume, which can also act to prevent these types of strokes. Infrequently, patients are additionally managed with medications to elevate blood pressure following aneurysm treatment, to overcome vasospasm in patients manifesting stroke signs and symptoms of vasospasm-related stroke.

Every effort is also made to treat patients with unruptured aneurysms and their symptoms without “opening the head.” Patients with unruptured aneurysms do not require prolonged stays in the Neuroscience Intensive Care Unit and are not treated with the medical modalities mentioned above. These patients often return to home within a few days after treatment.

Prochlorperazine might provide relief sooner and with less drowsiness.

JournalWatch.org, November 14, 2008 — Prochlorperazine has been shown to be more effective than metoclopramide for acute migraine, but prochlorperazine is associated with akathisia in about one third of patients (JW Nov 14 1995 and JW Emerg Med Jan 2 2002). In a randomized, double-blind study, researchers compared efficacy and side effects of intravenous prochlorperazine (10 mg) and IV promethazine (25 mg) in patients who presented to a single emergency department with benign headache. Patients with fever, trauma, or neurological deficit or who reported the “worst headache of their lives” were excluded; 70 patients were enrolled. Diphenhydramine (25 mg) was administered for symptoms of dystonia or akathisia.

Thirty minutes after drug administration, significantly more patients in the prochlorperazine group than in the promethazine group (69% vs. 39%) had a clinically meaningful decrease in headache intensity (defined as a reduction of Your browser may not support display of this image.25 mm on a 100-mm visual analog scale). However, the magnitude of the change (mean reduction, 36.4 vs. 23.7 mm, respectively) did not differ significantly between groups. Rates of akathisia, use of rescue medications, patient satisfaction, and recurrence of pain within 5 days after discharge were similar between groups. Drowsiness within 1 day after ED discharge was significantly more common in the promethazine group (71% vs. 40%). One third of patients in each group required rescue treatment with diphenhydramine for dystonic reactions or akathisia; rescue treatment was successful in all patients.

Comment: Promethazine is known to cause severe necrosis with inadvertent arterial injection (recently the subject of a multimillion-dollar award), and this study certainly does not support its use. Prochlorperazine is a first-line agent for acute migraine treatment, provided that patients are educated about akathisia and given oral diphenhydramine to take if symptoms develop.

— Aaron E. Bair, MD, MSc, FAAEM, FACEP

Published in Journal Watch Emergency Medicine November 14, 2008
Citation(s):

Callan JE et al. Prochlorperazine vs. promethazine for headache treatment in the emergency department: A randomized controlled trial. J Emerg Med 2008 Oct; 35:247.

JournalWatch.com, Massachusetts Medical Society — In a cohort study with long-term follow-up, none of the 344 patients suffered a relapse after achieving sustained virologic response.

Hepatitis C virus (HCV)-positive patients who achieve sustained virologic response (SVR) after undergoing interferon-based therapy generally are believed to have cleared the virus permanently. However, some studies have suggested that HCV RNA can persist in liver tissue and peripheral blood mononuclear cells (PBMCs). Now, researchers in France have reexamined this issue.

The investigators assessed the presence of HCV RNA in serum, liver tissue, and PBMCs in 344 HCV-infected patients who, between January 1988 and January 2005, achieved SVR after undergoing interferon-based therapy. SVR was defined as an undetectable serum HCV RNA level 6 months posttreatment, using transcription-mediated amplification (sensitivity, <9.6 IU/mL). Median follow-up duration was 3.3 years (range, 0.5–18.0 years).

During follow-up, none of the 344 participants developed detectable serum HCV RNA levels. PBMC specimens, collected from 156 participants (median, 3 years posttreatment), had no detectable HCV RNA. Among 114 available frozen liver specimens collected 1 and 6 years posttreatment, HCV RNA was detectable in 2 (1.7%). Paired liver-biopsy specimens (pretreatment and a median of 0.5 years posttreatment), available for 126 patients, showed fibrosis-stage improvement in 70 (55.6%), stability in 41 (32.5%), and deterioration in 15 (11.9%).

Comment: This cohort study with long-term follow-up verifies that once an HCV-infected patient achieves SVR, as determined by transcription-mediated amplification, the risk for virologic relapse is very low. Furthermore, after SVR is achieved, HCV RNA is not present in PBMCs, and many patients show improvement in hepatic fibrosis. In a minority of patients, HCV RNA persists in liver tissue; the clinical significance of this finding is unknown. Clinicians should be confident that their HCV-infected patients who achieve SVR truly have cleared the virus.

— Atif Zaman, MD, MPH

Published in Journal Watch Gastroenterology November 14, 2008

Citation(s):

Maylin S et al. Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C. Gastroenterology 2008 Sep; 135:821.