Neurological Complications Associated with Inflammatory Bowel Disease

Posted on June 13, 2013 by gutsandgrowth

Though I have not seen much in the way of neurological complications in our pediatric inflammatory bowel disease (IBD) population, nevertheless I worry about them. A recent article provides some insight into the incidence, the pathophysiology and approach to these complications (Inflamm Bowel Dis 2013; 19: 864-72).

Types of neurologic complications: The most common neurologic complication is peripheral neuropathy. The frequency is quite variable based on data collection method. In large administrative healthcare data, the prevalence has been reported around 2% whereas in cohort studies the range has been 8-15%. Other complications include meylopathy, cerbrovascular disease, cranial nerve palsy (eg. Melkersson-Rosenthal syndrome), seizures, and demyelinating diseases.

With regard to demyelinating diseases, this has gained additional attention in the setting of biologic agents which have been associated with this complication. However, the authors note that a pre-biologic treatment study from Olmstead County, observed a prevalence of multiple sclerosis of 1% which was 3.7 times higher than expected. In addition, similar studies have confirmed this finding.

Potential mechanisms vary greatly depending on the neurologic complication. With regard to cerebrovascular disorders, “venous thromboembolism (VTE) has been shown to occur 3 times more frequently in patients with IBD (the risk increases to 8-10-fold in patients with active colitis) than the general population.” Hence, VTE prophylaxis is recommended by the authors in hospitalized IBD patients, especially if they are experiencing a disease exacerbation.

In addition to the underlying disease, vitamin deficiencies (eg. Vitamin B12) and medications can trigger neurologic complications.

Natalizumab: progress multifocal leukoencephalopathy (PML)
Metronidazole: peripheral neuropathy (typically reversible with drug discontinuation)
Anti-TNF-α agents (infliximab, adalimumab, certolizumab): demyelination, rarely seizures, and rarely PML
Cyclosporine: various neurotoxicity in ~25%

Related blog entries:

Gluten-related Disorders

Posted on June 12, 2013 by gutsandgrowth

For those who missed a recent NASPGHAN Foundation webinar, I’ve attached two links (with permission from NASPGHAN foundation):

1. The PDF of the slides –these are very useful:

NASPGHAN GlutenWebinar 6_5_13 Final v34

2. Link to webinar, including CME:

http://limelightdc.com/clientarea/naspghan_gluten_webinar_06_13/landing_page.html

The experts provide a useful review of celiac, wheat allergy, and wheat intolerance. For celiac screening, the webinar recommends avoiding a panel of serology tests in favor of isolated Tissue Transglutaminase IgA Antibody (possibly with serum IgA level.

Related blog links:

If I have diarrhea after vacation…

Posted on June 10, 2013 by gutsandgrowth

I may want to remember this reference: “Enteropathogens and Chronic Illness in Returning Travelers” NEJM 2013; 368: 1817-25.

Some “fun facts:”

In 2007, more than 30 million Americans traveled to developing regions. ~8% traveling to these regions needed medical care during or after travel. Gastrointestinal symptoms were present in more than 25% who sought medical care.
According to the GeoSentinel Surveillance Network (42 travel medicine sites), between 1996-2005, 65% of enteric infections were due to parasites, 31% bacteria, and 3% viral. (J Infect 2009; 59: 19-27) (Parasites typically have more long-lasting infections which should be considered in interpreting this data; in addition, some pathogens are more difficult to isolate.)
Six pathogens were most prevalent: Giardia, Campylobacter, Entamoeba histolytica, Shigella, Stronglyoides, and Salmonella.

In addition to an enteric pathogen color-coded prevalence map, the article has a useful table identifying areas at high risk, mode of transmission, incubation period, common symptoms, recommended diagnostic tests and treatments.

To minimize the impact of these enteropathogens, physicians can help prepare travelers with appropriate vaccinations, malaria chemoprophylaxis (if needed), and effective anti-bacterial drugs for self-treatment should symptoms develop.

Related blog posts:

Quantifying the Heart Risks of Azithromycin

Posted on June 8, 2013 by gutsandgrowth

As noted previously in this blog (New FDA warning for azithromycin (Zithromax) | gutsandgrowth), there have been concerns raised about the risk of cardiovascular death due to the use of azithromycin. An editorial and new study indicate that this risk is mainly confined to patients at high cardiovascular risk (NEJM 2013; 1665-67 [editorial], 1704-12 [study]).

Background: in 2011, “approximately 40.3 million people in the United States (roughly one eighth of the population) received an outpatient prescription for the macrolide azithromycin.”

In an observational study published last year (NEJM 2012; 366: 1881-90), azithromycin resulted in one death for every 21,000 outpatient prescriptions in comparison to amoxicillin. Among those with high cardiovascular risk factors, this number was much higher: one in 4100; whereas in those with no risk factors, it was less than one per 100,000. The risks also corresponded to peak drug levels as the increase in events took place during the 5-day course and an increased risk was not evident subsequently.

The newest study, referenced above. used data from a Danish national health care registry (18-64 year olds). These patients had a lower cardiovascular risk profile. More than one million prescriptions were studied. They found no difference in cardiovascular deaths between azithromycin and penicillin. In a subgroup analysis of patients with a history of cardiovascular disease, the risk ratio was 1.35 though this did not reach statistical significance.

The editorial notes that azithromycin has been shown to reduce deaths in patients treated for community-acquired pneumonia. However, the two most common indications for treatment remain bronchitis and sinusitis.

Bottom-line: The risks of azithromycin in young and middle-aged persons is exceedingly low or nonexistent. In individuals with cardiovascular risk factors, azithromycin, other macrolides and fluoroquinolones could trigger a lethal arrhythmia.

FMT -not quite the new Laser

Posted on June 6, 2013 by gutsandgrowth

I distinctly remember one of my high school teachers saying that if you asked someone if they were willing to have a serious operation like a brain lobe removal, that most would be unwilling unless there was no other choice. However, if you told them that you were going to do it with a laser, people would want to get it done right away. Such was the mesmerizing appeal of the word “laser.”

Fecal microbiota transfer (FMT) certainly does not sound as enticing as a laser treatment. Nevertheless, the authors of a recent report state that “we received interest from patients all over the world to participate.” That being said, this recent report reintroduces the concept of FMT for ulcerative colitis (UC) (JPGN 2013; 56: 597-601).

In the introduction, the authors note that probiotics, in particular VSL#3, have shown usefulness in the treatment of UC and have noted previous sporadic reports of FMT for inflammatory bowel disease. This led to their pilot study of 10 subjects (7 to 21 years); this was a single-center, uncontrolled study. Due to financial constraints, there was no correlation with fecal microbial profiling, histologic/colonoscopic activity, or stool inflammatory markers.

The authors extensively describe their protocol of FMT (240 mL [in four aliquots] daily for five days) including donor exclusion criteria and donor screening. Participants did not receive any bowel preparation prior to FMT. The majority of participants had pancolitis; only one patient had disease limited to proctitis. One of the ten patients could not retain FMT enemas.

Results:

Short-term improvement was noted with 7 of 9 (78%) achieving a clinical response within one week and 3 of 9 (33%) achieving a clinical remission.
The authors note that 6 of 9 (67%) maintained a clinical response at 1 month. Although if one examines the study’s figure 2, this graphically demonstrates a fairly meager response in about half of these patients based on their PUCAI score.
The authors do not overstate their interpretation of their results. “This unique biologic is potentially efficacious.”
Adverse effects appeared to be mild and self-limiting.

Ultimately if FMT proves efficacious for inflammatory bowel disease, feces with the right microbial mix would be quite valuable. For now, this study indicates that further research is needed in this area.

Related blog entries:

What really causes Celiac disease?

Posted on June 5, 2013 by gutsandgrowth

A fascinating article in the NY Times delves into a number of environmental factors that are likely playing a role in the increasing incidence of celiac disease. Here’s the link (thanks to Kayla Lewis for this reference):

http://www.nytimes.com/2013/02/24/opinion/sunday/what-really-causes-celiac-disease.html?pagewanted=all

Some excerpts:

“Scientists are pursuing some intriguing possibilities. One is that breast-feeding may protect against the disease. Another is that we have neglected the teeming ecosystem of microbes in the gut — bacteria that may determine whether the immune system treats gluten as food or as a deadly invader.Celiac disease is generally considered an autoimmune disorder. The name celiac derives from the Greek word for “hollow,” as in bowels. Gluten proteins in wheat, barley and rye prompt the body to turn on itself and attack the small intestine. Complications range from diarrhea and anemia to osteoporosis and, in extreme cases, lymphoma. Some important exceptions notwithstanding, the prevalence of celiac disease is estimated to range between 0.6 and 1 percent of the world’s population….Yet the more scientists study celiac disease, the more some crucial component appears in need of identification. Roughly 30 percent of people with European ancestry carry predisposing genes, for example. Yet more than 95 percent of the carriers tolerate gluten just fine. So while these genes (plus gluten) are necessary to produce the disease, they’re evidently insufficient to cause it….

A recent study, which analyzed blood serum from more than 3,500 Americans who were followed since 1974, suggested that such a trigger could strike adults at any time. By 1989, the prevalence of celiac disease in this cohort had doubled.

“You’re talking about an autoimmune disease in which we thought we had all the dots connected,” says Alessio Fasano, head of the Center for Celiac Research and Treatment at the Massachusetts General Hospital for Children in Boston, and the senior author of the study. “Then we start to accumulate evidence that there was something else.”

Identifying that “something else” has gained some urgency. In the United States, improved diagnosis doesn’t seem to explain the rising prevalence. Scientists use the presence of certain self-directed antibodies to predict celiac disease. They have analyzed serum stored since the mid-20th century and compared it to serum from Americans today. Today’s serum is more than four times as likely to carry those antibodies…

your microbes change you, but your genes also shape your microbes — as do environment, breast milk, diet and antibiotics, among many other factors.

Such complexity both confounds notions of one-way causality and suggests different paths to the same disease. “You have the same endpoint,” Dr. Jabri says, “but how you get there may be variable.”…

In a far-flung corner of Europe, people develop celiac disease and other autoimmune diseases as infrequently as Americans and Finns did a half-century ago. The same genes exposed to the same quantity of gluten do not, in that environment, produce the same frequency of disease.

“We could probably prevent celiac disease if we just give the same environment to the Finnish children as they have in Karelia,” says Dr. Hyoty. “But there’s no way to do it now, except to move the babies there.”

Author of NY Times article:

Moises Velasquez-Manoff. Also, he is the author of “An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Diseases.”

Related blog links:

Celiac disease and less diabetes?

Posted on June 4, 2013 by gutsandgrowth

While there is a well-recognized association between Celiac disease and insulin-dependent diabetes mellitus (IDDM), a recent study shows a lower prevalence of non-insulin dependent diabetes mellitus (NIDDM) and metabolic syndrome in patients with celiac disease (Gastroenterol 2013; 144: 912-17).

You-Tube Link: Patients With Celiac Disease Have a Lower Prevalence … – YouTube..Dr. Toufic A. Kabbani discusses his manuscript “Patients WithCeliac Disease Have a Lower Prevalence of Non-Insulin-Dependent Diabetes Mellitus and Metabolic Syndrome.”

A retrospective review of 840 patients with biopsy-confirmed celiac disease were compared with 840 random matched controls. Controls were matched for age, sex, and ethnicity. Mean age was 49.4 years.

Key findings:

26 (3.1%) of celiac disease cohort and 81 (9.6%) (p <0.0001) had NIDDM.
3.5% of celiac disease cohort and 12.7% of controls had metabolic syndrome.
Though celiac disease patients had lower BMI, these findings were still present after controlling for this variable.
Prevalence of NIDDM was strongly associated with age in both groups. In celiac cohort, NIDDM occurred in 0% (n=343) of those <45, 3.1% in 45-64, and 9.3% in those >65. In contrast, the control group had NIDDM in 3.5%, 11% and 19.3% respectively.

With regard to pathophysiology, the authors did not think the protection from NIDDM was related to malabsorption. Evidence of malabsorption was more common in patients with CD and NIDDM than in those without NIDDM.

Related blog posts:

PPI Side Effects: “Dissecting the Evidence”

Posted on June 3, 2013 by gutsandgrowth

While proton pump inhibitors (PPIs) are used extensively for acid-related diseases and have been around for nearly 25 years, there have been a number of reports about potential side effects. As a drug class, PPIs have a very good safety profile. A recent article reviews some controversial adverse effects and summarizes the evidence for and against (Clin Gastroenterol Hepatol 2013; 11: 458-64).

I. Calcium/bone effects. After reviewing a number of studies, the authors conclude: “There is no good evidence to establish that PPI use has a significant risk for bone density loss or osteroporotic-related fractures….Supplemental calcium is not recommended or justified solely because of PPI use.”

II. Iron. “Although it is conceivable that PPI therapy may reduce absorption of nonheme iron and retard iron pool replenishment, this effect has not been well-studied or evident from widespread use in clinical practice.

III. Magnesium. “The FDA recommendation to consider checking magnesium levels before starting is not practical, in particular for the over-the-counter market. In patients who may be predisposed to …ongoing magnesium loss…it may be reasonable to follow…Given the rarity of the reports and no controlled studies to delineate the mechanisms, it is important for health care providers to be aware of this” (rare reports of profound hypomagnesemia).

IV. Pneumonia. “Small relative risk associated with short-term and high-dose PPI use. These relationships, however, do not offer a definitive explanation for the relative risk” due to the studies and confounding factors.

V. Clostridium difficile. “To date, there is insufficient evidence to conclude that there is a definitive relationship between PPI use and C difficile infection…clinicians should be aware of this potential relationship.”

VI. Traveler’s diarrhea. “The data…were overall supportive of no associated risk, albeit there were a few specific case reports suggesting a remote causal association.”

VII. Small intestinal bacterial overgrowth. “The relationship between PPI use and the development of SIBO is still not understood.”

VIII. Interstitial nephritis. Extremely rare. “Investigators…did not find enough evidence to support a causative relationship.”

IX. Methotrexate. “Coadministration of PPIs with high-dose methotrexate appears to be correlated with delayed methotrexate elimination.”

Also discussed: Vitamin B12, Clopidogrel, Spontaneous bacterial peritonitis

The authors conclude that the above reported associations have received considerable attention. “Because PPIs are overprescribed in many patients, …the clinical effects always should be reviewed and attempts should be justified to stop any therapy that may not be needed.”

Related blog entries:

Tacrolimus for Refractory Crohn’s Disease

Posted on June 2, 2013 by gutsandgrowth

While tacrolimus has been considered a potential option for refractory Crohn’s, data on its usage are sparse, mostly small retrospective studies. Another small retrospective study from the Mayo clinic provides data from their experience with 24 adult patients who were treated with tacrolimus for a median of 4 months (Inflamm Bowel Dis 2013; 19: 1107-11).

17 (71%) of study participants were female and their median age was 38 years. 18 (75%) had ileocolonic disease. All patients were either intolerant or unresponsive to at least one anti-TNFα agent. Most patients received concurrent therapy: thiopurines (58%), methotrexate (8%) and antibiotics (46%).

Results:

67% responded to tacrolimus and 21% achieved a steroid-free remission.
Patients with trough levels of 10 to 15 ng/mL had the highest response (86%) and remission (57%).
Adverse events were common (75% of patients); 8 (33%) required dose reduction and 6 (25%) led to treatment discontinuation. Frequent adverse events included acute kidney injury (29%), paresthesia (29%), headache (17%), and tremor (17%).
54% of patients in this series required surgery within a median of 10 months after starting tacrolimus.
Of the patients who achieved remission (n=5), 2 were transitioned to immunomodulator therapy to minimize long-term toxicity. 1 patient did well after stopping all therapy during a 6 month followup. 1 patient stopped treatment due to paresthesias and 1 patient continued therapy for 2.5 years.

The study does not describe the use of antibiotics for the prevention of Pneumocystis jiroveci pneumonia.

Take-home message: Tacrolimus doesn’t look too promising for refractory disease.

Related blog post:

Predictors of colectomy in pediatric UC | gutsandgrowth

Additional references:

-IBD 2008; 14: 7-12. Tacrolimus of minimal efficacy for UC and Crohn’s. Some achieve response (22/32 in UC and 7/15 in Crohn’s) only 3/32 UC with remission and 1/15 Crohn’s with remission
-Gut 2006; 55: 1255-1262. Use of prograf in refractory UC. Troughs 10-15, then 5-10 after remission; partial response in 68% at week 2 & 58% at week 10 (n=19)
-Gastroenterol 2003; 125: 380. Tacrolimus helped but did not cure fistulizing disease
-J Pediatr 2000; 137: 794-799. n=14.
-Am J Gastro 1997; 92: 876. Use in fistualizing Crohn’s.
-Am J Gastro 1998; 93: 18. Use in IBD.
-IBD 1999; 5: 239. Combined c azathioprine for perianal fistulae. response: initial 2.4weeks, 12.2weeks complete. 7/11 c complete response.
-IBD 2009; 15: 193. topical tacrolimus for proctitis. 10/12 w proctitis responded to 2 mg or 4 mg enema in 100 mL of sterile water.
-IBD 2007; 13: 245. Use for perianal disease.
-Gut 2000; 47: 436-440. Topical tacrolimus may be effective in the treatment of oral and perineal Crohn’s disease.

Breaking down lung defenses in Cystic Fibrosis

Posted on May 31, 2013 by gutsandgrowth

Cystic fibrosis patients develop chronic neutrophilic inflammation of the airways. Neutrophils which help fight off bacterial infections also release peroxidases and proteases which can damage the lung tissues. Neutrophil elastase which is one of the proteases elaborated by neutrophils can digest elastin; this is prevented by α-1-antitrypsin. However, when there is excessive free neutrophil elastase this can overwhelm this protection. A recent study has shown that neutrophil elastase activity in bronchoalveolar lavage (BAL) at 3 months of age was associated with early bronchiectasis (NEJM 2013; 368: 1963-70).

Design: 127 consecutive infants (from region of Western Australia) who were diagnosed with cystic fibrosis after newborn screening were recruited; however, 10 were too young and 3 were lost to followup due to relocation. Most were followed for 3 years; 78 remained in the study at 36 months. Chest CT scans and BAL were performed at 3 months, 1 year, 2 years, and 3 years when patients were in stable clinical condition.

Bronchiectasis was identified by CT scan findings: “defined as a bronchus-to-artery ratio of more than 1.0 or the presence of a non tapering bronchus in the transverse plane.”