Jose M. Villalon-Gomez, MD, MPH

Irritable bowel syndrome (IBS) continues to pose a diagnostic and therapeutic challenge to clinicians and patients—a challenge that arises from the varying manifestations of the condition, its complex pathophysiology, lack of effective treatment, and psychological consequences for patients. In this article, I explore new findings related to the pathophysiology, diagnosis, and management of IBS subtypes.

Start with the Rome IV classification of IBS

The Rome Foundation published its latest IBS classification and diagnostic criteria (known as Rome IV) in 2016.¹ IBS is defined as abdominal pain that (1) has recurred, on average, ≥ 1 time per week during the past 3 months and (2) is associated with ≥ 2 of these criteria¹:

• related to defecation
• associated with a change in stool frequency
• associated with a change in the appearance of stool.

Onset of symptoms should be present for 6 months before a diagnosis of IBS is made.¹

IBS subtypes—constipation-predominant (IBS-C), diarrhea-predominant (IBS-D), mixed (IBS-M), and unclassified (IBS-U) (TABLE 1)¹—are based on the frequency of specific stool forms, as described and illustrated in the Bristol Stool Scale (www.webmd.com/digestive-disorders/poop-chart-bristol-stool-scale).²

A widespread, costly, potentially debilitating disorder

IBS affects 10% to 12% of adults worldwide. The condition is more common among women and people younger than 50 years.^1,3 Women with IBS tend to have more constipation ­symptoms (IBS-C); men with IBS, more diarrhea symptoms (IBS-D).⁴

The financial burden of IBS on the health care system and patients is significant. In a 2013 appraisal of 35 studies, the authors note that estimates of the direct cost of IBS care in the United States vary considerably—from $1562 to $7547 for a patient annually.⁵

A recent study found that almost 25% of IBS patients report absenteeism from work due to IBS symptoms.⁶ A Danish study that followed 7278 patients for 5 years found that IBS patients utilized more health care, sick days, and disability pension benefits than non-IBS patients, and had increased utilization of medical resources because of psychiatric conditions.⁷

Continue to: IBS patients also have comorbidities

IBS patients also have comorbidities:

• More than 20% of IBS patients have functional dyspepsia, gastroesophageal reflux disease, incontinence, or pelvic floor dyssynergia.⁴
• The frequency of fibromyalgia syndrome in IBS patients is reported to be 20% to 65%.⁸
• 14% of IBS patients meet criteria for chronic fatigue syndrome.⁸
• Interstitial cystitis and dyspareunia are common among IBS patients.⁹

Pathophysiology is complex

Models describing the pathophysiology of IBS have evolved through the years. Recent models describe it as a combination of altered gastrointestinal motility, visceral hyperalgesia, increased intestinal permeability, immune activation, altered intestinal microbiota, and dysfunction in the brain–gut axis. Certain environmental and psychological variables (eg, previous gastroenteritis, food intolerance, chronic stress, diverticulitis, and surgery) increase the risk of IBS.^1,10,11

In the past several years, considerable attention has been paid to the roles played by the immune system, brain–gut axis function, and intestinal microbiota in IBS manifestations. Research focus in these areas might assist in the development of specific treatment modalities targeting IBS subtypes.

Immune system. A recent meta-­analysis of the records of 706 IBS patients found an increased number of mast cells and CD3 T cells in biopsy specimens from the rectosigmoid and descending colon of IBS patients.¹² Another study found a significant increase in mast cells in the ileum of IBS patients¹³; this increase is evident not only on intestinal biopsy but also at the serologic level. IBS-D patients have a higher plasma interleukin (IL)-6 level than the general population.¹⁴ Another meta-analysis found an imbalance in the serum level of tumor necrosis factor-α and IL-10 in IBS patients.¹⁵

Brain–gut axis. A 2016 meta-analysis showed that patients with anxiety and depression have a 2-fold increased risk of IBS.¹⁶ A more recent study, using data from the National Health Insurance Research Database that included 22,356 patients with IBS, found a 3.6-fold increased risk of psychiatric disorders in IBS.¹⁷ These findings reflect the complex interaction between the brain and the intestinal tract in IBS.

Continue to: Intestinal microbiota

Intestinal microbiota. Research evaluating the role of altered intestinal microbiota in IBS has yielded mixed results. A meta-­analysis of 777 IBS patients showed an increase in Firmicutes spp, a decrease in Bacteroidetes spp, and an increase in the ratio of Firmicutes spp to Bacteroidetes spp in subjects’ fecal specimens.¹⁸ Another study, of 1340 patients, found no difference in Bacteroides spp and Enterococcus spp between healthy controls and IBS patients, but did find (1) lower fecal counts of Lactobacillus spp and Bifidobacterium spp and (2) higher fecal counts of Escherichia coli and Enterobacter spp in IBS patients.¹⁹

Postinfectious IBS. The Rome Foundation introduced the diagnosis of postinfectious IBS (PI-IBS) in 2019. PI-IBS develops in 10% of patients who have had infectious enteritis. Female gender, younger age, psychological distress during or before the enteritis episode, and severity of the acute episode are risk factors for this IBS variant.²⁰ A study of 21,421 enteritis patients found that 42% with protozoal or parasitic infection and 14% with bacterial infection developed IBS.

To identify possible "red flags" or other disorders, take a history that includes the course of symptoms, triggers, and alleviating factors.

Patients with nonviral enteritis often have a more severe course of enteritis, typically requiring antibiotics. It is believed that the resulting irregularities in the intestinal microbiota make these patients more likely to develop PI-IBS.²¹ PI-IBS patients are likely to improve or fully recover over time. Symptoms of PI-IBS are managed in a manner similar to how non-PI-IBS patients are managed.²⁰

Challenges in making the IBS diagnosis

Historically, the diagnosis of IBS has been made clinically after excluding red flags (ie, signs or symptoms that might reflect other underlying medical problems) in the clinical presentation. For this reason, obtain a thorough clinical history that includes the course of symptoms, triggers, and alleviating factors. Any of the following are considered red flags^1,22,23:

• age > 50 years at onset of symptoms
• new-onset constipation in the elderly
• rectal bleeding
• unexplained weight loss or anemia
• family history of organic gastrointestinal disease
• palpable abdominal or rectal mass
• nocturnal symptoms.

New studies demonstrate that several inflammatory markers can help exclude inflammatory bowel disease from the differential diagnosis in patients in whom IBS is suspected and being investigated.²⁴ In 2019, the American Gastroenterological Association published a clinical practice guideline updating the laboratory evaluation of functional diarrhea and IBS-D in adults,²⁵ and made several recommendations:

• Obtain the level of fecal calprotectin (normal level, ≤ 50 mcg/g) or fecal lactoferrin (≤ 4.0-7.25 mcg/g); if these tests are not available or results are not accessible, the C-reactive protein level is a reasonable option.
• Do not routinely use the erythrocyte sedimentation rate or C-reactive protein level to screen for inflammatory bowel disease.
• Test for Giardia lamblia with an antigen or polymerase chain reaction test.
• Do not test for ova and parasites (other than Giardia) in patients who do not have a history of travel or who have not emigrated from a high-risk area recently.
• Obtain testing for celiac disease with immunoglobulin A (IgA) tissue transglutaminase and with a second test, of immunoglobulin G (IgG) tissue transglutaminase and IgG or IgA deaminated gliadin peptides, to detect celiac disease in IgA-deficient patients.
• Order testing for bile-acid diarrhea with selenium homotaurocholic acid nuclear medicine scanning (if available in your region; the test is available in Europe); measurement of bile acid from a 48-hour stool collection; or an assay of fibroblast growth factor 19, which measures defective feedback of bile-acid synthesis. If these tests are unavailable, consider an empiric trial of a bile-acid binder.
• Do not use available serologic IBS testing.

Continue to: Continue to obtain a...

Continue to obtain a complete blood count for the evaluation of anemia. Endoscopic procedures are indicated in patients with a red flag.¹

Treat based on subtype

The first step in the treatment of all IBS patients (TABLE 2^{1,3,4,9,26,27}) is for you to develop a strong relationship with the patient: You must acknowledge the disease and empower the patient to manage their symptoms. A strong physician–patient relationship leads to more effective outcomes.⁴

Low cost and low risk of adverse effects makes exercise worth recommending to all IBS patients.

IBS treatment modalities target abdominal pain, bloating, abdominal distention, and altered bowel function—described in the literature as global symptoms. IBS-M patients should direct their treatment to the predominant symptom (constipation or diarrhea). The following sections describe available treatment options. The FIGURE^1,3,4,9,25 shows a treatment workflow based on IBS subtype and symptom severity.

Treatments for all IBS subtypes

Lifestyle modification. Exercise provides overall positive health benefits. With such a variety of exercise forms, however, it is difficult to identify specific exercises that are better for IBS patients.²⁸ A study of 305 IBS patients found that exercise alleviated constipation but not other IBS symptoms, and did not improve quality of life.³ Based on low cost and low risk of adverse effects, exercise should be recommended to all IBS patients.

Dietary restriction therapies have become an area of focus for patients, clinicians, and researchers. Modification of the diet is thought to improve global symptoms and intestinal health through modification of gut microbiota, immune activation, and a decrease in levels of fecal short-chain fatty acids.²⁹

Continue to: The 2 main diets...

The 2 main diets studied for the treatment of IBS are a diet low in fermentable oligo-, di- and monosaccharides and polyols—the so-called low-FODMAP diet (TABLE 3³⁰)—and a gluten-free diet. Evidence behind the benefits of both diets conflicts; trials of the low-FODMAP diet are more favorable.

A small study with 20 patients with IBS-D and IBS-M who followed a low-FODMAP diet found improvement in IBS symptoms and a reduction in serum levels of proinflammatory cytokines, fecal bacteria, and total fecal short-chain fatty acid levels.²⁹ Several meta-analyses have shown improvement in overall IBS symptoms for patients who follow a low-FODMAP diet. Because of the heterogeneity of the studies, however, the quality of the data is low.^31-34

Data supporting the use of a gluten-free diet for IBS patients are insufficient.³¹

The American College of Gastroenterology (ACG) gave a weak recommendation for the low-FODMAP diet and recommended against the gluten-free diet in IBS patients.³ More data are needed regarding the safety profile of using a low-FODMAP diet for an extended period: There is concern about the risk of nutritional deficiencies associated with long-term use of this diet.³

Supplementation with poorly fermentable soluble fiber has been shown to alleviate global IBS symptoms; insoluble fiber does not yield improvement of symptoms. Psyllium fiber is recommended over wheat bran.^3,35

Continue to: Consider a low-FODMAP diet...

Consider a low-FODMAP diet and soluble fiber as initial treatment for all IBS patients.

Modification of intestinal microbiota. Understanding the difference between prebiotics and probiotics is important when considering treatment for IBS. Prebiotics are foods or dietary supplements that generate changes in the composition and activity of intestinal microbiota. Probiotics are live microorganisms that can improve intestinal health.³

A meta-analysis of 729 IBS patients found that prebiotics do not reduce gastrointestinal symptoms or improve the quality of life of IBS patients.³⁶ Evidence supporting the benefit of probiotics is favorable; however, data in these studies have significant heterogeneity. Several meta-analyses studied the benefits of Lactobacillus spp and Bifidobacterium spp in alleviating IBS symptoms. The studies found improvement in abdominal pain, bloating and distention, and flatulence.^3,37-40 Consider recommending probiotics for all IBS patients; for some, however, the high cost of some of these products might be an obstacle.

Consider recommending probiotics for all IBS patients, although high cost might be an obstacle for some.

Researchers are also studying the use of fecal microbiota transplantation (FMT) to treat IBS. Studies have evaluated the delivery of FMT orally (as capsules) and endoscopically. Evidence does not show improvement in global IBS symptoms with FMT. More studies, with larger sample populations, are needed.^41-43

Antispasmodic medications and peppermint oil. Antispasmodic medications have been considered a mainstay therapy for IBS because of their effect on intestinal dysmotility. Hyoscine and dicyclomine are commonly used. Meta-analyses have shown improvement in global symptoms and abdominal pain, but effects were modest.^3,44 Use this class of drugs as first-line treatment for mild IBS symptoms.

Continue to: Peppermint oil has been...

Peppermint oil has been found useful in improving IBS global symptoms and abdominal pain in several studies.^44-46 A common adverse effect of peppermint oil is heartburn, resulting from relaxation of esophageal muscle.³ Peppermint oil can be considered an adjuvant agent in treating IBS.

Antidepressants. Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) have been studied for the treatment of IBS. Meta-analyses show that both are effective in reducing pain and overall IBS symptoms.^1,3,47 The number needed to treat (NNT) for TCAs is 4.5; for SSRIs, 5.⁴⁷ Data do not show that either drug class is superior to the other for IBS. Based on the adverse effect profile, TCAs are more suitable for IBS-D patients; SSRIs are better for IBS-C patients.⁴⁷

New data show that serotonin-­norepinephrine reuptake inhibitors, such as duloxetine and milnacipran, can alleviate IBS symptoms through their pain-modifying properties.⁴⁷

Based on the adverse effect profile and stigma associated with antidepressant medications, patients might be less likely to take them for IBS symptoms than for these drugs’ primary indications. Clinicians should still consider this drug class if other first-line treatments do not provide full resolution of symptoms.

Psychotherapy. Several psychotherapeutic modalities have been evaluated for efficacy in reducing global IBS symptoms. The approaches studied most often were provider-directed cognitive behavioral therapy, relaxation therapy, hypnotherapy, and multicomponent psychological therapy. The NNT for these modalities is 4, but studies had significant heterogeneity.³ Consider referring patients for psychotherapeutic intervention if they have not responded to medical therapy after 12 months.⁴

Continue to Treatment of IBS-C

Treatment of IBS-C

Prosecretory agents. Linaclotide and plecanatide are amino-acid peptides that act as a guanylate cyclase C agonist. Both increase gastrointestinal transit rate by increasing electrolyte and fluid transport into the intestinal lumen. They also decrease the activity of pain-sensing nerves by increasing extracellular cyclic guanosine-3'5'-monophosphate levels.^3,48 In a recent meta-analysis, both treatments produced improvement in global symptoms. However, linaclotide showed superior improvement in abdominal pain and global symptoms compared to other secretory agents.^48,49 Diarrhea was the most common adverse effect of linaclotide and plecanatide, although less so with plecanatide.⁴⁹

Lubiprostone activates the intestinal chloride channel type 2 on the small intestine, leading to an increase in chloride and water efflux into the intestinal lumen, in turn accelerating gastrointestinal transit.³ A meta-analysis with 1468 IBS patients found that lubiprostone improved constipation, stool consistency, abdominal pain, degree of straining, and abdominal bloating.⁵⁰ Diarrhea and nausea are commonly reported adverse effects of lubiprostone.^49,50

Linaclotide, plecanatide, and lubiprostone should be considered first-line therapies for patients with IBS-C. High cost is still a roadblock to the use of these agents.

Use antispasmodic medications as first-line treatment for mild IBS symptoms.

The US Food and Drug Administration (FDA) approved tenapanor in September 2019; however, the drug is not commercially available in the United States (it is available in Canada). Tenapanor is a sodium–­hydrogen exchanger 3 inhibitor that reduces sodium absorption from the intestine and colon. The drug increases water secretion into the intestinal lumen, thus accelerating gut transit time. It also inhibits active absorption of phosphate in the intestine.

Tenapanor was approved for treating both IBS-C and hyperphosphatemia in patients with chronic kidney disease on dialysis or end-stage renal disease.²⁶ In a recent meta-analysis, the drug showed benefit in alleviating global IBS symptoms, and ranked first in reducing bloating.⁴⁹ It is too soon to know if tenapanor will perform clinically better than other prosecretory agents.

Continue to: Serotonergic agents

Serotonergic agents. Serotonin (5-hydroxytryptamine [5-HT]) modulates gastrointestinal secretions, gut motility, and visceral sensation. Researchers have developed IBS treatments that target receptors involved in these functions.

Tegaserod is a partial, selective 5-HT₄ agonist indicated for the treatment of IBS-C in women. A study with 661 women with IBS-M and IBS-C showed that tegaserod increased the number of bowel movement episodes. Patients also reported higher stool consistency scores and fewer days with straining compared to placebo.²⁷ The medication was removed from the market in 2007 because of its potential for cardiovascular adverse effects³; however, it was reintroduced in 2019 for women < 65 years of age with IBS-C. Consider prescribing tegaserod if other treatment options fail to alleviate symptoms.

Treatment of IBS-D

Antibiotics. The nonabsorbable antibiotic rifaximin is approved by the FDA for IBS-D at a dosage of 550 mg tid for 2 weeks.¹ Several studies show improvement in IBS global symptoms with the recommended treatment course^51-53; benefit persisted for the 10-week follow-up study period.¹ A meta-analysis found that the NNT for rifaximin is 8-11.⁵⁴ Preliminary data indicate that the rates of Clostridioides difficile infection and microbial resistance among rifaximin users are low.³ Consider using rifaximin as a first-line treatment option for patients with IBS-D. Retreatment might be necessary because the drug’s effect gradually disappears.⁹

Antidiarrheals. Eluxadoline is a µ-opioid and κ-opioid receptor agonist and δ-opioid receptor antagonist with effects on the intestinal nervous system.³ Several meta-analyses demonstrated that eluxadoline improves abdominal pain scores and daily stool consistency in IBS-D patients.^53,54 Eluxadoline should be considered early in the management of IBS-D patients. The most common adverse effect is constipation.

The FDA issued a safety warning in 2017 regarding an increased risk of pancreatitis in patients taking eluxadoline who do not have a gallbladder. In addition, eluxadoline should be avoided in patients with a history of sphincter of Oddi dysfunction, alcohol abuse, or severe liver problems.^3,54

Continue to: The high cost of...

The high cost of eluxadoline can be a significant barrier to use.

Serotonergic agents. Alosetron is a selective 5-HT₃ antagonist developed to treat IBS-D.³ In a meta-analysis comprising 9844 patients, alosetron showed superior abdominal pain scores and improved stool consistency compared to ramosetron, rifaximin, and eluxadoline.⁵³ In 2001, the FDA withdrew alosetron, due to severe constipation and a risk of ischemic colitis; however, the medication has become commercially available again through a risk evaluation and mitigation strategy (REMS) program for women who have disabling IBS-D symptoms.^3,54 Because of this special circumstance, alosetron is not considered first-line therapy for IBS-D.

Linaclotide, plecanatide, and lubiprostone should be considered firstline therapies for IBS-C.

Ondansetron has also been used to treat IBS-D. In a meta-analysis with 294 patients, ondansetron showed improvement in stool consistency.⁵⁵ Ondansetron does not improve abdominal pain.⁴ It can be used in patients who have mild-to-moderate symptoms.⁹ Ondansetron is not FDA approved for the treatment of IBS-D.

Bile-acid sequestrants. Traditionally, bile-acid sequestrants have been used to treat bile-acid diarrhea. A meta-analysis of 6 studies of 908 patients with IBS-D found that 28.1% were affected by bile-acid malabsorption. Two small studies that evaluated the benefits of colesevelam for IBS-D found significant improvement in stool consistency.⁵⁴ Another study, which evaluated the benefits of cholestyramine, found improvement in stool consistency, but findings were not significant.⁵⁴ Many patients taking a bile-acid sequestrant stop taking the medication because of considerable adverse effects (constipation, nausea, bloating, flatulence, and abdominal pain).⁵⁴ For that reason, this class of medication is not recommended as first-line treatment for IBS-D and is not FDA approved for IBS-D.

A role for complementaryand integrative medicine?

Recently, complementary and integrative modalities for treating IBS have sparked the interest of researchers.

Continue to: Acupuncture

Acupuncture. In a meta-analysis with 3440 patients, acupuncture was more effective than Western medicine in alleviating IBS symptoms for as long as 3 months. The authors concluded that acupuncture could be used in combination with other therapies to reduce the severity of IBS symptoms.⁵⁶

Concomitant acupuncture and Chinese herbal medicine. In a systematic review and meta-analysis comprising 21 randomized controlled trials, researchers reported that acupuncture combined with Chinese herbal medicine improved IBS symptoms, compared to what was noted in matched controls who were treated with Western medicine or with Western medicine combined with Chinese herbal medicine. The authors were cautious about the results of the meta-analysis, however, because the studies examined were small and of low quality, and presented a high risk of bias.⁵⁷

Agents not to be used routinely for IBS

Loperamide. This peripheral µ-opioid receptor agonist controls diarrhea. However, recent studies showed no significant benefit to loperamide over placebo in IBS-M and IBS-D. In 2018, the FDA issued a safety alert regarding an elevated risk of serious cardiac adverse effects in patients taking loperamide. The ACG recommends against using loperamide to treat IBS symptoms.^3,54

Polyethylene glycol. An osmotic laxative that is not absorbed in the intestinal lumen, polyethylene glycol is highly efficacious for alleviating constipation, but it does not reduce pain or other IBS symptoms. For that reason, the ACG recommends against its use.³

CORRESPONDENCE
Jose M. Villalon-Gomez, MD, MPH, Emory Healthcare Family Medicine, 4500 North Shallowford Road, Dunwoody, GA 30338; [email protected]

Irritable bowel syndrome (IBS) continues to pose a diagnostic and therapeutic challenge to clinicians and patients—a challenge that arises from the varying manifestations of the condition, its complex pathophysiology, lack of effective treatment, and psychological consequences for patients. In this article, I explore new findings related to the pathophysiology, diagnosis, and management of IBS subtypes.

Start with the Rome IV classification of IBS

The Rome Foundation published its latest IBS classification and diagnostic criteria (known as Rome IV) in 2016.¹ IBS is defined as abdominal pain that (1) has recurred, on average, ≥ 1 time per week during the past 3 months and (2) is associated with ≥ 2 of these criteria¹:

• related to defecation
• associated with a change in stool frequency
• associated with a change in the appearance of stool.

Onset of symptoms should be present for 6 months before a diagnosis of IBS is made.¹

IBS subtypes—constipation-predominant (IBS-C), diarrhea-predominant (IBS-D), mixed (IBS-M), and unclassified (IBS-U) (TABLE 1)¹—are based on the frequency of specific stool forms, as described and illustrated in the Bristol Stool Scale (www.webmd.com/digestive-disorders/poop-chart-bristol-stool-scale).²

A widespread, costly, potentially debilitating disorder

IBS affects 10% to 12% of adults worldwide. The condition is more common among women and people younger than 50 years.^1,3 Women with IBS tend to have more constipation ­symptoms (IBS-C); men with IBS, more diarrhea symptoms (IBS-D).⁴

The financial burden of IBS on the health care system and patients is significant. In a 2013 appraisal of 35 studies, the authors note that estimates of the direct cost of IBS care in the United States vary considerably—from $1562 to $7547 for a patient annually.⁵

A recent study found that almost 25% of IBS patients report absenteeism from work due to IBS symptoms.⁶ A Danish study that followed 7278 patients for 5 years found that IBS patients utilized more health care, sick days, and disability pension benefits than non-IBS patients, and had increased utilization of medical resources because of psychiatric conditions.⁷

Continue to: IBS patients also have comorbidities

IBS patients also have comorbidities:

• More than 20% of IBS patients have functional dyspepsia, gastroesophageal reflux disease, incontinence, or pelvic floor dyssynergia.⁴
• The frequency of fibromyalgia syndrome in IBS patients is reported to be 20% to 65%.⁸
• 14% of IBS patients meet criteria for chronic fatigue syndrome.⁸
• Interstitial cystitis and dyspareunia are common among IBS patients.⁹

Pathophysiology is complex

Models describing the pathophysiology of IBS have evolved through the years. Recent models describe it as a combination of altered gastrointestinal motility, visceral hyperalgesia, increased intestinal permeability, immune activation, altered intestinal microbiota, and dysfunction in the brain–gut axis. Certain environmental and psychological variables (eg, previous gastroenteritis, food intolerance, chronic stress, diverticulitis, and surgery) increase the risk of IBS.^1,10,11

In the past several years, considerable attention has been paid to the roles played by the immune system, brain–gut axis function, and intestinal microbiota in IBS manifestations. Research focus in these areas might assist in the development of specific treatment modalities targeting IBS subtypes.

Immune system. A recent meta-­analysis of the records of 706 IBS patients found an increased number of mast cells and CD3 T cells in biopsy specimens from the rectosigmoid and descending colon of IBS patients.¹² Another study found a significant increase in mast cells in the ileum of IBS patients¹³; this increase is evident not only on intestinal biopsy but also at the serologic level. IBS-D patients have a higher plasma interleukin (IL)-6 level than the general population.¹⁴ Another meta-analysis found an imbalance in the serum level of tumor necrosis factor-α and IL-10 in IBS patients.¹⁵

Brain–gut axis. A 2016 meta-analysis showed that patients with anxiety and depression have a 2-fold increased risk of IBS.¹⁶ A more recent study, using data from the National Health Insurance Research Database that included 22,356 patients with IBS, found a 3.6-fold increased risk of psychiatric disorders in IBS.¹⁷ These findings reflect the complex interaction between the brain and the intestinal tract in IBS.

Continue to: Intestinal microbiota

Intestinal microbiota. Research evaluating the role of altered intestinal microbiota in IBS has yielded mixed results. A meta-­analysis of 777 IBS patients showed an increase in Firmicutes spp, a decrease in Bacteroidetes spp, and an increase in the ratio of Firmicutes spp to Bacteroidetes spp in subjects’ fecal specimens.¹⁸ Another study, of 1340 patients, found no difference in Bacteroides spp and Enterococcus spp between healthy controls and IBS patients, but did find (1) lower fecal counts of Lactobacillus spp and Bifidobacterium spp and (2) higher fecal counts of Escherichia coli and Enterobacter spp in IBS patients.¹⁹

Postinfectious IBS. The Rome Foundation introduced the diagnosis of postinfectious IBS (PI-IBS) in 2019. PI-IBS develops in 10% of patients who have had infectious enteritis. Female gender, younger age, psychological distress during or before the enteritis episode, and severity of the acute episode are risk factors for this IBS variant.²⁰ A study of 21,421 enteritis patients found that 42% with protozoal or parasitic infection and 14% with bacterial infection developed IBS.

To identify possible "red flags" or other disorders, take a history that includes the course of symptoms, triggers, and alleviating factors.

Patients with nonviral enteritis often have a more severe course of enteritis, typically requiring antibiotics. It is believed that the resulting irregularities in the intestinal microbiota make these patients more likely to develop PI-IBS.²¹ PI-IBS patients are likely to improve or fully recover over time. Symptoms of PI-IBS are managed in a manner similar to how non-PI-IBS patients are managed.²⁰

Challenges in making the IBS diagnosis

Historically, the diagnosis of IBS has been made clinically after excluding red flags (ie, signs or symptoms that might reflect other underlying medical problems) in the clinical presentation. For this reason, obtain a thorough clinical history that includes the course of symptoms, triggers, and alleviating factors. Any of the following are considered red flags^1,22,23:

• age > 50 years at onset of symptoms
• new-onset constipation in the elderly
• rectal bleeding
• unexplained weight loss or anemia
• family history of organic gastrointestinal disease
• palpable abdominal or rectal mass
• nocturnal symptoms.

New studies demonstrate that several inflammatory markers can help exclude inflammatory bowel disease from the differential diagnosis in patients in whom IBS is suspected and being investigated.²⁴ In 2019, the American Gastroenterological Association published a clinical practice guideline updating the laboratory evaluation of functional diarrhea and IBS-D in adults,²⁵ and made several recommendations:

• Obtain the level of fecal calprotectin (normal level, ≤ 50 mcg/g) or fecal lactoferrin (≤ 4.0-7.25 mcg/g); if these tests are not available or results are not accessible, the C-reactive protein level is a reasonable option.
• Do not routinely use the erythrocyte sedimentation rate or C-reactive protein level to screen for inflammatory bowel disease.
• Test for Giardia lamblia with an antigen or polymerase chain reaction test.
• Do not test for ova and parasites (other than Giardia) in patients who do not have a history of travel or who have not emigrated from a high-risk area recently.
• Obtain testing for celiac disease with immunoglobulin A (IgA) tissue transglutaminase and with a second test, of immunoglobulin G (IgG) tissue transglutaminase and IgG or IgA deaminated gliadin peptides, to detect celiac disease in IgA-deficient patients.
• Order testing for bile-acid diarrhea with selenium homotaurocholic acid nuclear medicine scanning (if available in your region; the test is available in Europe); measurement of bile acid from a 48-hour stool collection; or an assay of fibroblast growth factor 19, which measures defective feedback of bile-acid synthesis. If these tests are unavailable, consider an empiric trial of a bile-acid binder.
• Do not use available serologic IBS testing.

Continue to: Continue to obtain a...

Continue to obtain a complete blood count for the evaluation of anemia. Endoscopic procedures are indicated in patients with a red flag.¹

Treat based on subtype

The first step in the treatment of all IBS patients (TABLE 2^{1,3,4,9,26,27}) is for you to develop a strong relationship with the patient: You must acknowledge the disease and empower the patient to manage their symptoms. A strong physician–patient relationship leads to more effective outcomes.⁴

Low cost and low risk of adverse effects makes exercise worth recommending to all IBS patients.

IBS treatment modalities target abdominal pain, bloating, abdominal distention, and altered bowel function—described in the literature as global symptoms. IBS-M patients should direct their treatment to the predominant symptom (constipation or diarrhea). The following sections describe available treatment options. The FIGURE^1,3,4,9,25 shows a treatment workflow based on IBS subtype and symptom severity.

Treatments for all IBS subtypes

Lifestyle modification. Exercise provides overall positive health benefits. With such a variety of exercise forms, however, it is difficult to identify specific exercises that are better for IBS patients.²⁸ A study of 305 IBS patients found that exercise alleviated constipation but not other IBS symptoms, and did not improve quality of life.³ Based on low cost and low risk of adverse effects, exercise should be recommended to all IBS patients.

Dietary restriction therapies have become an area of focus for patients, clinicians, and researchers. Modification of the diet is thought to improve global symptoms and intestinal health through modification of gut microbiota, immune activation, and a decrease in levels of fecal short-chain fatty acids.²⁹

Continue to: The 2 main diets...

The 2 main diets studied for the treatment of IBS are a diet low in fermentable oligo-, di- and monosaccharides and polyols—the so-called low-FODMAP diet (TABLE 3³⁰)—and a gluten-free diet. Evidence behind the benefits of both diets conflicts; trials of the low-FODMAP diet are more favorable.

A small study with 20 patients with IBS-D and IBS-M who followed a low-FODMAP diet found improvement in IBS symptoms and a reduction in serum levels of proinflammatory cytokines, fecal bacteria, and total fecal short-chain fatty acid levels.²⁹ Several meta-analyses have shown improvement in overall IBS symptoms for patients who follow a low-FODMAP diet. Because of the heterogeneity of the studies, however, the quality of the data is low.^31-34

Data supporting the use of a gluten-free diet for IBS patients are insufficient.³¹

The American College of Gastroenterology (ACG) gave a weak recommendation for the low-FODMAP diet and recommended against the gluten-free diet in IBS patients.³ More data are needed regarding the safety profile of using a low-FODMAP diet for an extended period: There is concern about the risk of nutritional deficiencies associated with long-term use of this diet.³

Supplementation with poorly fermentable soluble fiber has been shown to alleviate global IBS symptoms; insoluble fiber does not yield improvement of symptoms. Psyllium fiber is recommended over wheat bran.^3,35

Continue to: Consider a low-FODMAP diet...

Consider a low-FODMAP diet and soluble fiber as initial treatment for all IBS patients.

Modification of intestinal microbiota. Understanding the difference between prebiotics and probiotics is important when considering treatment for IBS. Prebiotics are foods or dietary supplements that generate changes in the composition and activity of intestinal microbiota. Probiotics are live microorganisms that can improve intestinal health.³

A meta-analysis of 729 IBS patients found that prebiotics do not reduce gastrointestinal symptoms or improve the quality of life of IBS patients.³⁶ Evidence supporting the benefit of probiotics is favorable; however, data in these studies have significant heterogeneity. Several meta-analyses studied the benefits of Lactobacillus spp and Bifidobacterium spp in alleviating IBS symptoms. The studies found improvement in abdominal pain, bloating and distention, and flatulence.^3,37-40 Consider recommending probiotics for all IBS patients; for some, however, the high cost of some of these products might be an obstacle.

Consider recommending probiotics for all IBS patients, although high cost might be an obstacle for some.

Researchers are also studying the use of fecal microbiota transplantation (FMT) to treat IBS. Studies have evaluated the delivery of FMT orally (as capsules) and endoscopically. Evidence does not show improvement in global IBS symptoms with FMT. More studies, with larger sample populations, are needed.^41-43

Antispasmodic medications and peppermint oil. Antispasmodic medications have been considered a mainstay therapy for IBS because of their effect on intestinal dysmotility. Hyoscine and dicyclomine are commonly used. Meta-analyses have shown improvement in global symptoms and abdominal pain, but effects were modest.^3,44 Use this class of drugs as first-line treatment for mild IBS symptoms.

Continue to: Peppermint oil has been...

Peppermint oil has been found useful in improving IBS global symptoms and abdominal pain in several studies.^44-46 A common adverse effect of peppermint oil is heartburn, resulting from relaxation of esophageal muscle.³ Peppermint oil can be considered an adjuvant agent in treating IBS.

Antidepressants. Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) have been studied for the treatment of IBS. Meta-analyses show that both are effective in reducing pain and overall IBS symptoms.^1,3,47 The number needed to treat (NNT) for TCAs is 4.5; for SSRIs, 5.⁴⁷ Data do not show that either drug class is superior to the other for IBS. Based on the adverse effect profile, TCAs are more suitable for IBS-D patients; SSRIs are better for IBS-C patients.⁴⁷

New data show that serotonin-­norepinephrine reuptake inhibitors, such as duloxetine and milnacipran, can alleviate IBS symptoms through their pain-modifying properties.⁴⁷

Based on the adverse effect profile and stigma associated with antidepressant medications, patients might be less likely to take them for IBS symptoms than for these drugs’ primary indications. Clinicians should still consider this drug class if other first-line treatments do not provide full resolution of symptoms.

Psychotherapy. Several psychotherapeutic modalities have been evaluated for efficacy in reducing global IBS symptoms. The approaches studied most often were provider-directed cognitive behavioral therapy, relaxation therapy, hypnotherapy, and multicomponent psychological therapy. The NNT for these modalities is 4, but studies had significant heterogeneity.³ Consider referring patients for psychotherapeutic intervention if they have not responded to medical therapy after 12 months.⁴

Continue to Treatment of IBS-C

Treatment of IBS-C

Prosecretory agents. Linaclotide and plecanatide are amino-acid peptides that act as a guanylate cyclase C agonist. Both increase gastrointestinal transit rate by increasing electrolyte and fluid transport into the intestinal lumen. They also decrease the activity of pain-sensing nerves by increasing extracellular cyclic guanosine-3'5'-monophosphate levels.^3,48 In a recent meta-analysis, both treatments produced improvement in global symptoms. However, linaclotide showed superior improvement in abdominal pain and global symptoms compared to other secretory agents.^48,49 Diarrhea was the most common adverse effect of linaclotide and plecanatide, although less so with plecanatide.⁴⁹

Lubiprostone activates the intestinal chloride channel type 2 on the small intestine, leading to an increase in chloride and water efflux into the intestinal lumen, in turn accelerating gastrointestinal transit.³ A meta-analysis with 1468 IBS patients found that lubiprostone improved constipation, stool consistency, abdominal pain, degree of straining, and abdominal bloating.⁵⁰ Diarrhea and nausea are commonly reported adverse effects of lubiprostone.^49,50

Linaclotide, plecanatide, and lubiprostone should be considered first-line therapies for patients with IBS-C. High cost is still a roadblock to the use of these agents.

Use antispasmodic medications as first-line treatment for mild IBS symptoms.

The US Food and Drug Administration (FDA) approved tenapanor in September 2019; however, the drug is not commercially available in the United States (it is available in Canada). Tenapanor is a sodium–­hydrogen exchanger 3 inhibitor that reduces sodium absorption from the intestine and colon. The drug increases water secretion into the intestinal lumen, thus accelerating gut transit time. It also inhibits active absorption of phosphate in the intestine.

Tenapanor was approved for treating both IBS-C and hyperphosphatemia in patients with chronic kidney disease on dialysis or end-stage renal disease.²⁶ In a recent meta-analysis, the drug showed benefit in alleviating global IBS symptoms, and ranked first in reducing bloating.⁴⁹ It is too soon to know if tenapanor will perform clinically better than other prosecretory agents.

Continue to: Serotonergic agents

Serotonergic agents. Serotonin (5-hydroxytryptamine [5-HT]) modulates gastrointestinal secretions, gut motility, and visceral sensation. Researchers have developed IBS treatments that target receptors involved in these functions.

Tegaserod is a partial, selective 5-HT₄ agonist indicated for the treatment of IBS-C in women. A study with 661 women with IBS-M and IBS-C showed that tegaserod increased the number of bowel movement episodes. Patients also reported higher stool consistency scores and fewer days with straining compared to placebo.²⁷ The medication was removed from the market in 2007 because of its potential for cardiovascular adverse effects³; however, it was reintroduced in 2019 for women < 65 years of age with IBS-C. Consider prescribing tegaserod if other treatment options fail to alleviate symptoms.

Treatment of IBS-D

Antibiotics. The nonabsorbable antibiotic rifaximin is approved by the FDA for IBS-D at a dosage of 550 mg tid for 2 weeks.¹ Several studies show improvement in IBS global symptoms with the recommended treatment course^51-53; benefit persisted for the 10-week follow-up study period.¹ A meta-analysis found that the NNT for rifaximin is 8-11.⁵⁴ Preliminary data indicate that the rates of Clostridioides difficile infection and microbial resistance among rifaximin users are low.³ Consider using rifaximin as a first-line treatment option for patients with IBS-D. Retreatment might be necessary because the drug’s effect gradually disappears.⁹

Antidiarrheals. Eluxadoline is a µ-opioid and κ-opioid receptor agonist and δ-opioid receptor antagonist with effects on the intestinal nervous system.³ Several meta-analyses demonstrated that eluxadoline improves abdominal pain scores and daily stool consistency in IBS-D patients.^53,54 Eluxadoline should be considered early in the management of IBS-D patients. The most common adverse effect is constipation.

The FDA issued a safety warning in 2017 regarding an increased risk of pancreatitis in patients taking eluxadoline who do not have a gallbladder. In addition, eluxadoline should be avoided in patients with a history of sphincter of Oddi dysfunction, alcohol abuse, or severe liver problems.^3,54

Continue to: The high cost of...

The high cost of eluxadoline can be a significant barrier to use.

Serotonergic agents. Alosetron is a selective 5-HT₃ antagonist developed to treat IBS-D.³ In a meta-analysis comprising 9844 patients, alosetron showed superior abdominal pain scores and improved stool consistency compared to ramosetron, rifaximin, and eluxadoline.⁵³ In 2001, the FDA withdrew alosetron, due to severe constipation and a risk of ischemic colitis; however, the medication has become commercially available again through a risk evaluation and mitigation strategy (REMS) program for women who have disabling IBS-D symptoms.^3,54 Because of this special circumstance, alosetron is not considered first-line therapy for IBS-D.

Linaclotide, plecanatide, and lubiprostone should be considered firstline therapies for IBS-C.

Ondansetron has also been used to treat IBS-D. In a meta-analysis with 294 patients, ondansetron showed improvement in stool consistency.⁵⁵ Ondansetron does not improve abdominal pain.⁴ It can be used in patients who have mild-to-moderate symptoms.⁹ Ondansetron is not FDA approved for the treatment of IBS-D.

Bile-acid sequestrants. Traditionally, bile-acid sequestrants have been used to treat bile-acid diarrhea. A meta-analysis of 6 studies of 908 patients with IBS-D found that 28.1% were affected by bile-acid malabsorption. Two small studies that evaluated the benefits of colesevelam for IBS-D found significant improvement in stool consistency.⁵⁴ Another study, which evaluated the benefits of cholestyramine, found improvement in stool consistency, but findings were not significant.⁵⁴ Many patients taking a bile-acid sequestrant stop taking the medication because of considerable adverse effects (constipation, nausea, bloating, flatulence, and abdominal pain).⁵⁴ For that reason, this class of medication is not recommended as first-line treatment for IBS-D and is not FDA approved for IBS-D.

A role for complementaryand integrative medicine?

Recently, complementary and integrative modalities for treating IBS have sparked the interest of researchers.

Continue to: Acupuncture

Acupuncture. In a meta-analysis with 3440 patients, acupuncture was more effective than Western medicine in alleviating IBS symptoms for as long as 3 months. The authors concluded that acupuncture could be used in combination with other therapies to reduce the severity of IBS symptoms.⁵⁶

Concomitant acupuncture and Chinese herbal medicine. In a systematic review and meta-analysis comprising 21 randomized controlled trials, researchers reported that acupuncture combined with Chinese herbal medicine improved IBS symptoms, compared to what was noted in matched controls who were treated with Western medicine or with Western medicine combined with Chinese herbal medicine. The authors were cautious about the results of the meta-analysis, however, because the studies examined were small and of low quality, and presented a high risk of bias.⁵⁷

Agents not to be used routinely for IBS

Loperamide. This peripheral µ-opioid receptor agonist controls diarrhea. However, recent studies showed no significant benefit to loperamide over placebo in IBS-M and IBS-D. In 2018, the FDA issued a safety alert regarding an elevated risk of serious cardiac adverse effects in patients taking loperamide. The ACG recommends against using loperamide to treat IBS symptoms.^3,54

Polyethylene glycol. An osmotic laxative that is not absorbed in the intestinal lumen, polyethylene glycol is highly efficacious for alleviating constipation, but it does not reduce pain or other IBS symptoms. For that reason, the ACG recommends against its use.³

CORRESPONDENCE
Jose M. Villalon-Gomez, MD, MPH, Emory Healthcare Family Medicine, 4500 North Shallowford Road, Dunwoody, GA 30338; [email protected]

Irritable bowel syndrome (IBS) continues to pose a diagnostic and therapeutic challenge to clinicians and patients—a challenge that arises from the varying manifestations of the condition, its complex pathophysiology, lack of effective treatment, and psychological consequences for patients. In this article, I explore new findings related to the pathophysiology, diagnosis, and management of IBS subtypes.

Start with the Rome IV classification of IBS

The Rome Foundation published its latest IBS classification and diagnostic criteria (known as Rome IV) in 2016.¹ IBS is defined as abdominal pain that (1) has recurred, on average, ≥ 1 time per week during the past 3 months and (2) is associated with ≥ 2 of these criteria¹:

• related to defecation
• associated with a change in stool frequency
• associated with a change in the appearance of stool.

Onset of symptoms should be present for 6 months before a diagnosis of IBS is made.¹

IBS subtypes—constipation-predominant (IBS-C), diarrhea-predominant (IBS-D), mixed (IBS-M), and unclassified (IBS-U) (TABLE 1)¹—are based on the frequency of specific stool forms, as described and illustrated in the Bristol Stool Scale (www.webmd.com/digestive-disorders/poop-chart-bristol-stool-scale).²

A widespread, costly, potentially debilitating disorder

IBS affects 10% to 12% of adults worldwide. The condition is more common among women and people younger than 50 years.^1,3 Women with IBS tend to have more constipation ­symptoms (IBS-C); men with IBS, more diarrhea symptoms (IBS-D).⁴

The financial burden of IBS on the health care system and patients is significant. In a 2013 appraisal of 35 studies, the authors note that estimates of the direct cost of IBS care in the United States vary considerably—from $1562 to $7547 for a patient annually.⁵

A recent study found that almost 25% of IBS patients report absenteeism from work due to IBS symptoms.⁶ A Danish study that followed 7278 patients for 5 years found that IBS patients utilized more health care, sick days, and disability pension benefits than non-IBS patients, and had increased utilization of medical resources because of psychiatric conditions.⁷

Continue to: IBS patients also have comorbidities

IBS patients also have comorbidities:

• More than 20% of IBS patients have functional dyspepsia, gastroesophageal reflux disease, incontinence, or pelvic floor dyssynergia.⁴
• The frequency of fibromyalgia syndrome in IBS patients is reported to be 20% to 65%.⁸
• 14% of IBS patients meet criteria for chronic fatigue syndrome.⁸
• Interstitial cystitis and dyspareunia are common among IBS patients.⁹

Pathophysiology is complex

Models describing the pathophysiology of IBS have evolved through the years. Recent models describe it as a combination of altered gastrointestinal motility, visceral hyperalgesia, increased intestinal permeability, immune activation, altered intestinal microbiota, and dysfunction in the brain–gut axis. Certain environmental and psychological variables (eg, previous gastroenteritis, food intolerance, chronic stress, diverticulitis, and surgery) increase the risk of IBS.^1,10,11

In the past several years, considerable attention has been paid to the roles played by the immune system, brain–gut axis function, and intestinal microbiota in IBS manifestations. Research focus in these areas might assist in the development of specific treatment modalities targeting IBS subtypes.

Immune system. A recent meta-­analysis of the records of 706 IBS patients found an increased number of mast cells and CD3 T cells in biopsy specimens from the rectosigmoid and descending colon of IBS patients.¹² Another study found a significant increase in mast cells in the ileum of IBS patients¹³; this increase is evident not only on intestinal biopsy but also at the serologic level. IBS-D patients have a higher plasma interleukin (IL)-6 level than the general population.¹⁴ Another meta-analysis found an imbalance in the serum level of tumor necrosis factor-α and IL-10 in IBS patients.¹⁵

Brain–gut axis. A 2016 meta-analysis showed that patients with anxiety and depression have a 2-fold increased risk of IBS.¹⁶ A more recent study, using data from the National Health Insurance Research Database that included 22,356 patients with IBS, found a 3.6-fold increased risk of psychiatric disorders in IBS.¹⁷ These findings reflect the complex interaction between the brain and the intestinal tract in IBS.

Continue to: Intestinal microbiota

Intestinal microbiota. Research evaluating the role of altered intestinal microbiota in IBS has yielded mixed results. A meta-­analysis of 777 IBS patients showed an increase in Firmicutes spp, a decrease in Bacteroidetes spp, and an increase in the ratio of Firmicutes spp to Bacteroidetes spp in subjects’ fecal specimens.¹⁸ Another study, of 1340 patients, found no difference in Bacteroides spp and Enterococcus spp between healthy controls and IBS patients, but did find (1) lower fecal counts of Lactobacillus spp and Bifidobacterium spp and (2) higher fecal counts of Escherichia coli and Enterobacter spp in IBS patients.¹⁹

Postinfectious IBS. The Rome Foundation introduced the diagnosis of postinfectious IBS (PI-IBS) in 2019. PI-IBS develops in 10% of patients who have had infectious enteritis. Female gender, younger age, psychological distress during or before the enteritis episode, and severity of the acute episode are risk factors for this IBS variant.²⁰ A study of 21,421 enteritis patients found that 42% with protozoal or parasitic infection and 14% with bacterial infection developed IBS.

To identify possible "red flags" or other disorders, take a history that includes the course of symptoms, triggers, and alleviating factors.

Patients with nonviral enteritis often have a more severe course of enteritis, typically requiring antibiotics. It is believed that the resulting irregularities in the intestinal microbiota make these patients more likely to develop PI-IBS.²¹ PI-IBS patients are likely to improve or fully recover over time. Symptoms of PI-IBS are managed in a manner similar to how non-PI-IBS patients are managed.²⁰

Challenges in making the IBS diagnosis

Historically, the diagnosis of IBS has been made clinically after excluding red flags (ie, signs or symptoms that might reflect other underlying medical problems) in the clinical presentation. For this reason, obtain a thorough clinical history that includes the course of symptoms, triggers, and alleviating factors. Any of the following are considered red flags^1,22,23:

• age > 50 years at onset of symptoms
• new-onset constipation in the elderly
• rectal bleeding
• unexplained weight loss or anemia
• family history of organic gastrointestinal disease
• palpable abdominal or rectal mass
• nocturnal symptoms.

New studies demonstrate that several inflammatory markers can help exclude inflammatory bowel disease from the differential diagnosis in patients in whom IBS is suspected and being investigated.²⁴ In 2019, the American Gastroenterological Association published a clinical practice guideline updating the laboratory evaluation of functional diarrhea and IBS-D in adults,²⁵ and made several recommendations:

• Obtain the level of fecal calprotectin (normal level, ≤ 50 mcg/g) or fecal lactoferrin (≤ 4.0-7.25 mcg/g); if these tests are not available or results are not accessible, the C-reactive protein level is a reasonable option.
• Do not routinely use the erythrocyte sedimentation rate or C-reactive protein level to screen for inflammatory bowel disease.
• Test for Giardia lamblia with an antigen or polymerase chain reaction test.
• Do not test for ova and parasites (other than Giardia) in patients who do not have a history of travel or who have not emigrated from a high-risk area recently.
• Obtain testing for celiac disease with immunoglobulin A (IgA) tissue transglutaminase and with a second test, of immunoglobulin G (IgG) tissue transglutaminase and IgG or IgA deaminated gliadin peptides, to detect celiac disease in IgA-deficient patients.
• Order testing for bile-acid diarrhea with selenium homotaurocholic acid nuclear medicine scanning (if available in your region; the test is available in Europe); measurement of bile acid from a 48-hour stool collection; or an assay of fibroblast growth factor 19, which measures defective feedback of bile-acid synthesis. If these tests are unavailable, consider an empiric trial of a bile-acid binder.
• Do not use available serologic IBS testing.

Continue to: Continue to obtain a...

Continue to obtain a complete blood count for the evaluation of anemia. Endoscopic procedures are indicated in patients with a red flag.¹

Treat based on subtype

The first step in the treatment of all IBS patients (TABLE 2^{1,3,4,9,26,27}) is for you to develop a strong relationship with the patient: You must acknowledge the disease and empower the patient to manage their symptoms. A strong physician–patient relationship leads to more effective outcomes.⁴

Low cost and low risk of adverse effects makes exercise worth recommending to all IBS patients.

IBS treatment modalities target abdominal pain, bloating, abdominal distention, and altered bowel function—described in the literature as global symptoms. IBS-M patients should direct their treatment to the predominant symptom (constipation or diarrhea). The following sections describe available treatment options. The FIGURE^1,3,4,9,25 shows a treatment workflow based on IBS subtype and symptom severity.

Treatments for all IBS subtypes

Lifestyle modification. Exercise provides overall positive health benefits. With such a variety of exercise forms, however, it is difficult to identify specific exercises that are better for IBS patients.²⁸ A study of 305 IBS patients found that exercise alleviated constipation but not other IBS symptoms, and did not improve quality of life.³ Based on low cost and low risk of adverse effects, exercise should be recommended to all IBS patients.

Dietary restriction therapies have become an area of focus for patients, clinicians, and researchers. Modification of the diet is thought to improve global symptoms and intestinal health through modification of gut microbiota, immune activation, and a decrease in levels of fecal short-chain fatty acids.²⁹

Continue to: The 2 main diets...

The 2 main diets studied for the treatment of IBS are a diet low in fermentable oligo-, di- and monosaccharides and polyols—the so-called low-FODMAP diet (TABLE 3³⁰)—and a gluten-free diet. Evidence behind the benefits of both diets conflicts; trials of the low-FODMAP diet are more favorable.

A small study with 20 patients with IBS-D and IBS-M who followed a low-FODMAP diet found improvement in IBS symptoms and a reduction in serum levels of proinflammatory cytokines, fecal bacteria, and total fecal short-chain fatty acid levels.²⁹ Several meta-analyses have shown improvement in overall IBS symptoms for patients who follow a low-FODMAP diet. Because of the heterogeneity of the studies, however, the quality of the data is low.^31-34

Data supporting the use of a gluten-free diet for IBS patients are insufficient.³¹

The American College of Gastroenterology (ACG) gave a weak recommendation for the low-FODMAP diet and recommended against the gluten-free diet in IBS patients.³ More data are needed regarding the safety profile of using a low-FODMAP diet for an extended period: There is concern about the risk of nutritional deficiencies associated with long-term use of this diet.³

Supplementation with poorly fermentable soluble fiber has been shown to alleviate global IBS symptoms; insoluble fiber does not yield improvement of symptoms. Psyllium fiber is recommended over wheat bran.^3,35

Continue to: Consider a low-FODMAP diet...

Consider a low-FODMAP diet and soluble fiber as initial treatment for all IBS patients.

Modification of intestinal microbiota. Understanding the difference between prebiotics and probiotics is important when considering treatment for IBS. Prebiotics are foods or dietary supplements that generate changes in the composition and activity of intestinal microbiota. Probiotics are live microorganisms that can improve intestinal health.³

A meta-analysis of 729 IBS patients found that prebiotics do not reduce gastrointestinal symptoms or improve the quality of life of IBS patients.³⁶ Evidence supporting the benefit of probiotics is favorable; however, data in these studies have significant heterogeneity. Several meta-analyses studied the benefits of Lactobacillus spp and Bifidobacterium spp in alleviating IBS symptoms. The studies found improvement in abdominal pain, bloating and distention, and flatulence.^3,37-40 Consider recommending probiotics for all IBS patients; for some, however, the high cost of some of these products might be an obstacle.

Consider recommending probiotics for all IBS patients, although high cost might be an obstacle for some.

Researchers are also studying the use of fecal microbiota transplantation (FMT) to treat IBS. Studies have evaluated the delivery of FMT orally (as capsules) and endoscopically. Evidence does not show improvement in global IBS symptoms with FMT. More studies, with larger sample populations, are needed.^41-43

Antispasmodic medications and peppermint oil. Antispasmodic medications have been considered a mainstay therapy for IBS because of their effect on intestinal dysmotility. Hyoscine and dicyclomine are commonly used. Meta-analyses have shown improvement in global symptoms and abdominal pain, but effects were modest.^3,44 Use this class of drugs as first-line treatment for mild IBS symptoms.

Continue to: Peppermint oil has been...

Peppermint oil has been found useful in improving IBS global symptoms and abdominal pain in several studies.^44-46 A common adverse effect of peppermint oil is heartburn, resulting from relaxation of esophageal muscle.³ Peppermint oil can be considered an adjuvant agent in treating IBS.

Antidepressants. Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) have been studied for the treatment of IBS. Meta-analyses show that both are effective in reducing pain and overall IBS symptoms.^1,3,47 The number needed to treat (NNT) for TCAs is 4.5; for SSRIs, 5.⁴⁷ Data do not show that either drug class is superior to the other for IBS. Based on the adverse effect profile, TCAs are more suitable for IBS-D patients; SSRIs are better for IBS-C patients.⁴⁷

New data show that serotonin-­norepinephrine reuptake inhibitors, such as duloxetine and milnacipran, can alleviate IBS symptoms through their pain-modifying properties.⁴⁷

Based on the adverse effect profile and stigma associated with antidepressant medications, patients might be less likely to take them for IBS symptoms than for these drugs’ primary indications. Clinicians should still consider this drug class if other first-line treatments do not provide full resolution of symptoms.

Psychotherapy. Several psychotherapeutic modalities have been evaluated for efficacy in reducing global IBS symptoms. The approaches studied most often were provider-directed cognitive behavioral therapy, relaxation therapy, hypnotherapy, and multicomponent psychological therapy. The NNT for these modalities is 4, but studies had significant heterogeneity.³ Consider referring patients for psychotherapeutic intervention if they have not responded to medical therapy after 12 months.⁴

Continue to Treatment of IBS-C

Treatment of IBS-C

Prosecretory agents. Linaclotide and plecanatide are amino-acid peptides that act as a guanylate cyclase C agonist. Both increase gastrointestinal transit rate by increasing electrolyte and fluid transport into the intestinal lumen. They also decrease the activity of pain-sensing nerves by increasing extracellular cyclic guanosine-3'5'-monophosphate levels.^3,48 In a recent meta-analysis, both treatments produced improvement in global symptoms. However, linaclotide showed superior improvement in abdominal pain and global symptoms compared to other secretory agents.^48,49 Diarrhea was the most common adverse effect of linaclotide and plecanatide, although less so with plecanatide.⁴⁹

Lubiprostone activates the intestinal chloride channel type 2 on the small intestine, leading to an increase in chloride and water efflux into the intestinal lumen, in turn accelerating gastrointestinal transit.³ A meta-analysis with 1468 IBS patients found that lubiprostone improved constipation, stool consistency, abdominal pain, degree of straining, and abdominal bloating.⁵⁰ Diarrhea and nausea are commonly reported adverse effects of lubiprostone.^49,50

Linaclotide, plecanatide, and lubiprostone should be considered first-line therapies for patients with IBS-C. High cost is still a roadblock to the use of these agents.

Use antispasmodic medications as first-line treatment for mild IBS symptoms.

The US Food and Drug Administration (FDA) approved tenapanor in September 2019; however, the drug is not commercially available in the United States (it is available in Canada). Tenapanor is a sodium–­hydrogen exchanger 3 inhibitor that reduces sodium absorption from the intestine and colon. The drug increases water secretion into the intestinal lumen, thus accelerating gut transit time. It also inhibits active absorption of phosphate in the intestine.

Tenapanor was approved for treating both IBS-C and hyperphosphatemia in patients with chronic kidney disease on dialysis or end-stage renal disease.²⁶ In a recent meta-analysis, the drug showed benefit in alleviating global IBS symptoms, and ranked first in reducing bloating.⁴⁹ It is too soon to know if tenapanor will perform clinically better than other prosecretory agents.

Continue to: Serotonergic agents

Serotonergic agents. Serotonin (5-hydroxytryptamine [5-HT]) modulates gastrointestinal secretions, gut motility, and visceral sensation. Researchers have developed IBS treatments that target receptors involved in these functions.

Tegaserod is a partial, selective 5-HT₄ agonist indicated for the treatment of IBS-C in women. A study with 661 women with IBS-M and IBS-C showed that tegaserod increased the number of bowel movement episodes. Patients also reported higher stool consistency scores and fewer days with straining compared to placebo.²⁷ The medication was removed from the market in 2007 because of its potential for cardiovascular adverse effects³; however, it was reintroduced in 2019 for women < 65 years of age with IBS-C. Consider prescribing tegaserod if other treatment options fail to alleviate symptoms.

Treatment of IBS-D

Antibiotics. The nonabsorbable antibiotic rifaximin is approved by the FDA for IBS-D at a dosage of 550 mg tid for 2 weeks.¹ Several studies show improvement in IBS global symptoms with the recommended treatment course^51-53; benefit persisted for the 10-week follow-up study period.¹ A meta-analysis found that the NNT for rifaximin is 8-11.⁵⁴ Preliminary data indicate that the rates of Clostridioides difficile infection and microbial resistance among rifaximin users are low.³ Consider using rifaximin as a first-line treatment option for patients with IBS-D. Retreatment might be necessary because the drug’s effect gradually disappears.⁹

Antidiarrheals. Eluxadoline is a µ-opioid and κ-opioid receptor agonist and δ-opioid receptor antagonist with effects on the intestinal nervous system.³ Several meta-analyses demonstrated that eluxadoline improves abdominal pain scores and daily stool consistency in IBS-D patients.^53,54 Eluxadoline should be considered early in the management of IBS-D patients. The most common adverse effect is constipation.

The FDA issued a safety warning in 2017 regarding an increased risk of pancreatitis in patients taking eluxadoline who do not have a gallbladder. In addition, eluxadoline should be avoided in patients with a history of sphincter of Oddi dysfunction, alcohol abuse, or severe liver problems.^3,54

Continue to: The high cost of...

The high cost of eluxadoline can be a significant barrier to use.

Serotonergic agents. Alosetron is a selective 5-HT₃ antagonist developed to treat IBS-D.³ In a meta-analysis comprising 9844 patients, alosetron showed superior abdominal pain scores and improved stool consistency compared to ramosetron, rifaximin, and eluxadoline.⁵³ In 2001, the FDA withdrew alosetron, due to severe constipation and a risk of ischemic colitis; however, the medication has become commercially available again through a risk evaluation and mitigation strategy (REMS) program for women who have disabling IBS-D symptoms.^3,54 Because of this special circumstance, alosetron is not considered first-line therapy for IBS-D.

Linaclotide, plecanatide, and lubiprostone should be considered firstline therapies for IBS-C.

Ondansetron has also been used to treat IBS-D. In a meta-analysis with 294 patients, ondansetron showed improvement in stool consistency.⁵⁵ Ondansetron does not improve abdominal pain.⁴ It can be used in patients who have mild-to-moderate symptoms.⁹ Ondansetron is not FDA approved for the treatment of IBS-D.

Bile-acid sequestrants. Traditionally, bile-acid sequestrants have been used to treat bile-acid diarrhea. A meta-analysis of 6 studies of 908 patients with IBS-D found that 28.1% were affected by bile-acid malabsorption. Two small studies that evaluated the benefits of colesevelam for IBS-D found significant improvement in stool consistency.⁵⁴ Another study, which evaluated the benefits of cholestyramine, found improvement in stool consistency, but findings were not significant.⁵⁴ Many patients taking a bile-acid sequestrant stop taking the medication because of considerable adverse effects (constipation, nausea, bloating, flatulence, and abdominal pain).⁵⁴ For that reason, this class of medication is not recommended as first-line treatment for IBS-D and is not FDA approved for IBS-D.

A role for complementaryand integrative medicine?

Recently, complementary and integrative modalities for treating IBS have sparked the interest of researchers.

Continue to: Acupuncture

Acupuncture. In a meta-analysis with 3440 patients, acupuncture was more effective than Western medicine in alleviating IBS symptoms for as long as 3 months. The authors concluded that acupuncture could be used in combination with other therapies to reduce the severity of IBS symptoms.⁵⁶

Concomitant acupuncture and Chinese herbal medicine. In a systematic review and meta-analysis comprising 21 randomized controlled trials, researchers reported that acupuncture combined with Chinese herbal medicine improved IBS symptoms, compared to what was noted in matched controls who were treated with Western medicine or with Western medicine combined with Chinese herbal medicine. The authors were cautious about the results of the meta-analysis, however, because the studies examined were small and of low quality, and presented a high risk of bias.⁵⁷

Agents not to be used routinely for IBS

Loperamide. This peripheral µ-opioid receptor agonist controls diarrhea. However, recent studies showed no significant benefit to loperamide over placebo in IBS-M and IBS-D. In 2018, the FDA issued a safety alert regarding an elevated risk of serious cardiac adverse effects in patients taking loperamide. The ACG recommends against using loperamide to treat IBS symptoms.^3,54

Polyethylene glycol. An osmotic laxative that is not absorbed in the intestinal lumen, polyethylene glycol is highly efficacious for alleviating constipation, but it does not reduce pain or other IBS symptoms. For that reason, the ACG recommends against its use.³

CORRESPONDENCE
Jose M. Villalon-Gomez, MD, MPH, Emory Healthcare Family Medicine, 4500 North Shallowford Road, Dunwoody, GA 30338; [email protected]

THE CASE

A 55-year-old woman presented to the emergency department (ED) with a bifrontal headache that she’d had for one day. She also had blurred vision and was vomiting shortly before coming to the hospital. The patient had no history of hypertension, migraine headaches, seizure disorder, autoimmune disorders, or cerebrovascular disease.

Her vital signs, including a blood pressure of 114/63 mm Hg, were normal, but a physical examination revealed subjective vision loss. She was only able to see objects moving on a horizontal plane. Her finger-to-nose exam, pupillary reflexes, and extra-ocular movements were normal, but peripheral vision was limited on her left side. No other neurologic deficits were noted.

The patient was admitted to the hospital and most of her laboratory work-up was normal, including a basic metabolic panel, complete blood count, coagulation studies, brain natriuretic peptide test, and cardiac enzymes. Her white blood cell count was 19,700/mcL, but no source of infection was found. A computed tomography (CT) scan of her head without contrast showed low-density, patchy areas in the subcortical regions of the parietal and occipital lobes bilaterally (FIGURE 1, arrows), with relative sparing of the cortex.

THE DIAGNOSIS

Based on our patient’s presentation and radiologic findings, we made a diagnosis of posterior reversible encephalopathy syndrome (PRES). However, because we could not rule out an ischemic cerebrovascular event at the time of presentation, we started the patient on aspirin and clopidogrel 75 mg to prevent possible future ischemic events. The next day, we ordered magnetic resonance imaging (MRI) of the head and neck, which documented the edema and confirmed the diagnosis of PRES (FIGURE 2).

DISCUSSION

PRES is a neurotoxic state associated with a unique pattern of brain vasogenic edema seen on CT or MRI. The edema is often widespread but is predominantly found in the parietal and occipital regions.¹ PRES is seen in patients with a variety of conditions, including hypertension and bone marrow or organ transplantation, as well as in those receiving immunosuppressive or cytotoxic medications.¹ Patients with PRES typically present with headaches and seizures.² Visual abnormalities (most commonly cortical blindness), occur in 15% to 20% of patients with PRES.^2-4

Hinchey et al³ first described reversible posterior leukoencephalopathy syndrome (which later became known as PRES) in 1996. Most of the 15 patients included in this original report had a history of hypertension or immunosuppression. These cases were associated with cerebral edema in portions of the posterior cerebral white matter. It is thought that hypertension alters the blood-brain barrier and causes the acute changes that occur in PRES.³

Besides hypertension and immunosuppression, the risk factors most commonly associated with PRES include preeclampsia/eclampsia; sepsis, particularly due to grampositive organisms; Wegener’s granulomatosis, scleroderma, and polyarteritis nodosa; cancer chemotherapy; bone marrow or stem cell transplantation; and renal disease.^1,4-6

Although a clear cause of PRES has not yet been established, researchers have proposed 2 theories. The first postulates that a sudden increase in systemic blood pressure causes vasoconstriction, which leads to ischemia and edema.^1-4,7,8 However, several studies have also described cases of PRES in patients with mild elevations in blood pressure,^1,5-7 and mild edema has been observed even in normotensive patients^1,5 (as was the case with our patient).

The second theory links PRES to the loss of brain autoregulation, a function that maintains steady blood flow when blood pressure fluctuates.⁶ A loss of this regulatory mechanism causes endothelial dysfunction, capillary leakage, and disruption in the blood-brain barrier.^1,2,4,6-8 These changes then lead to cerebral vasodilatation and edema.² Immunotherapy has also been associated with increased endothelial dysfunction.²

The evidence on the link between the severity of PRES and clinical outcomes is conflicting.

One study that followed 113 PRES patients over 6 years did not find an association between the severity of clinical presentation and the extent of vasogenic edema found on imaging studies.⁵ Of these 113 patients, 69 had PRES primarily due to hypertension, and 21 were receiving cytotoxic medications.⁵ In contrast, a larger retrospective study that followed patients with PRES for 12 years found that severe cases, which included patients with severe cerebral edema and altered mental status, had poor outcomes.⁴ Small studies have reported that 14% of patients with PRES develop cerebral hemorrhage.⁸

When to suspect this condition. PRES should be part of the differential diagnosis for any patient who presents with headache and vision loss. It is important to distinguish PRES from an acute cerebrovascular accident (CVA) because the 2 conditions are managed differently.² In addition, PRES lesions can be misdiagnosed as tumors, especially in a patient with a history of malignant disease in whom the condition appears after chemotherapy.⁹

Treatment targets the underlying causes

Treatment options for PRES are limited. Hypertension in a patient with PRES requires prompt intervention to avoid progression of the disease.² The use of intravenous (IV) calcium-channel blockers or IV beta-blockers for these patients is common.^2,8

Patients with seizures should be treated with anticonvulsant medication, but longterm antiepileptic treatment usually is not required.² Patients who take immunosuppressant or cytotoxic drugs should stop them indefinitely upon presenting with PRES.²

PRES lesions can be misdiagnosed as tumors—especially in patients with a history of malignant disease who have undergone chemotherapy.

For a pregnant woman with preeclampsia/eclampsia, delivery of the placenta, which is considered to be the cause of PRES in these cases, is curative.¹ However, women can develop PRES several weeks after delivery.¹

In most cases, the symptoms associated with PRES will resolve once treatment is initiated, and neurologic recovery can be expected within 2 weeks.²

Our patient regained her sight the following morning and was discharged home 2 days after admission. Her blood pressure remained normal. She returned to the hospital unresponsive the day after she had been discharged. Family members stated that she had taken 15 packets of an aspirin/caffeine combination to control a new headache.

Her blood pressure was elevated at 159/79 mm Hg. A CT of the brain showed a hemorrhagic stroke within the left occipital lobe and posterior parietal lobe with a midline shift of 8 mm. We don’t know if the aspirin use contributed to the hemorrhagic event or if it was a sequela of PRES.

The patient died 4 days later.

THE TAKEAWAY

PRES is a neurotoxic condition that causes headache, seizures, and vision loss. Most patients will present with elevated blood pressure and imaging studies will reveal a specific pattern of vasogenic edema that is predominately found in the parietal and occipital regions.

Treating the hypertension may result in a more favorable recovery. Normotensive patients are harder to treat because there is no specific therapy for PRES. Follow-up imaging may help to assess the resolution of the syndrome.

THE CASE

A 55-year-old woman presented to the emergency department (ED) with a bifrontal headache that she’d had for one day. She also had blurred vision and was vomiting shortly before coming to the hospital. The patient had no history of hypertension, migraine headaches, seizure disorder, autoimmune disorders, or cerebrovascular disease.

Her vital signs, including a blood pressure of 114/63 mm Hg, were normal, but a physical examination revealed subjective vision loss. She was only able to see objects moving on a horizontal plane. Her finger-to-nose exam, pupillary reflexes, and extra-ocular movements were normal, but peripheral vision was limited on her left side. No other neurologic deficits were noted.

The patient was admitted to the hospital and most of her laboratory work-up was normal, including a basic metabolic panel, complete blood count, coagulation studies, brain natriuretic peptide test, and cardiac enzymes. Her white blood cell count was 19,700/mcL, but no source of infection was found. A computed tomography (CT) scan of her head without contrast showed low-density, patchy areas in the subcortical regions of the parietal and occipital lobes bilaterally (FIGURE 1, arrows), with relative sparing of the cortex.

THE DIAGNOSIS

Based on our patient’s presentation and radiologic findings, we made a diagnosis of posterior reversible encephalopathy syndrome (PRES). However, because we could not rule out an ischemic cerebrovascular event at the time of presentation, we started the patient on aspirin and clopidogrel 75 mg to prevent possible future ischemic events. The next day, we ordered magnetic resonance imaging (MRI) of the head and neck, which documented the edema and confirmed the diagnosis of PRES (FIGURE 2).

DISCUSSION

PRES is a neurotoxic state associated with a unique pattern of brain vasogenic edema seen on CT or MRI. The edema is often widespread but is predominantly found in the parietal and occipital regions.¹ PRES is seen in patients with a variety of conditions, including hypertension and bone marrow or organ transplantation, as well as in those receiving immunosuppressive or cytotoxic medications.¹ Patients with PRES typically present with headaches and seizures.² Visual abnormalities (most commonly cortical blindness), occur in 15% to 20% of patients with PRES.^2-4

Hinchey et al³ first described reversible posterior leukoencephalopathy syndrome (which later became known as PRES) in 1996. Most of the 15 patients included in this original report had a history of hypertension or immunosuppression. These cases were associated with cerebral edema in portions of the posterior cerebral white matter. It is thought that hypertension alters the blood-brain barrier and causes the acute changes that occur in PRES.³

Besides hypertension and immunosuppression, the risk factors most commonly associated with PRES include preeclampsia/eclampsia; sepsis, particularly due to grampositive organisms; Wegener’s granulomatosis, scleroderma, and polyarteritis nodosa; cancer chemotherapy; bone marrow or stem cell transplantation; and renal disease.^1,4-6

Although a clear cause of PRES has not yet been established, researchers have proposed 2 theories. The first postulates that a sudden increase in systemic blood pressure causes vasoconstriction, which leads to ischemia and edema.^1-4,7,8 However, several studies have also described cases of PRES in patients with mild elevations in blood pressure,^1,5-7 and mild edema has been observed even in normotensive patients^1,5 (as was the case with our patient).

The second theory links PRES to the loss of brain autoregulation, a function that maintains steady blood flow when blood pressure fluctuates.⁶ A loss of this regulatory mechanism causes endothelial dysfunction, capillary leakage, and disruption in the blood-brain barrier.^1,2,4,6-8 These changes then lead to cerebral vasodilatation and edema.² Immunotherapy has also been associated with increased endothelial dysfunction.²

The evidence on the link between the severity of PRES and clinical outcomes is conflicting.

One study that followed 113 PRES patients over 6 years did not find an association between the severity of clinical presentation and the extent of vasogenic edema found on imaging studies.⁵ Of these 113 patients, 69 had PRES primarily due to hypertension, and 21 were receiving cytotoxic medications.⁵ In contrast, a larger retrospective study that followed patients with PRES for 12 years found that severe cases, which included patients with severe cerebral edema and altered mental status, had poor outcomes.⁴ Small studies have reported that 14% of patients with PRES develop cerebral hemorrhage.⁸

When to suspect this condition. PRES should be part of the differential diagnosis for any patient who presents with headache and vision loss. It is important to distinguish PRES from an acute cerebrovascular accident (CVA) because the 2 conditions are managed differently.² In addition, PRES lesions can be misdiagnosed as tumors, especially in a patient with a history of malignant disease in whom the condition appears after chemotherapy.⁹

Treatment targets the underlying causes

Treatment options for PRES are limited. Hypertension in a patient with PRES requires prompt intervention to avoid progression of the disease.² The use of intravenous (IV) calcium-channel blockers or IV beta-blockers for these patients is common.^2,8

Patients with seizures should be treated with anticonvulsant medication, but longterm antiepileptic treatment usually is not required.² Patients who take immunosuppressant or cytotoxic drugs should stop them indefinitely upon presenting with PRES.²

PRES lesions can be misdiagnosed as tumors—especially in patients with a history of malignant disease who have undergone chemotherapy.

For a pregnant woman with preeclampsia/eclampsia, delivery of the placenta, which is considered to be the cause of PRES in these cases, is curative.¹ However, women can develop PRES several weeks after delivery.¹

In most cases, the symptoms associated with PRES will resolve once treatment is initiated, and neurologic recovery can be expected within 2 weeks.²

Our patient regained her sight the following morning and was discharged home 2 days after admission. Her blood pressure remained normal. She returned to the hospital unresponsive the day after she had been discharged. Family members stated that she had taken 15 packets of an aspirin/caffeine combination to control a new headache.

Her blood pressure was elevated at 159/79 mm Hg. A CT of the brain showed a hemorrhagic stroke within the left occipital lobe and posterior parietal lobe with a midline shift of 8 mm. We don’t know if the aspirin use contributed to the hemorrhagic event or if it was a sequela of PRES.

The patient died 4 days later.

THE TAKEAWAY

PRES is a neurotoxic condition that causes headache, seizures, and vision loss. Most patients will present with elevated blood pressure and imaging studies will reveal a specific pattern of vasogenic edema that is predominately found in the parietal and occipital regions.

Treating the hypertension may result in a more favorable recovery. Normotensive patients are harder to treat because there is no specific therapy for PRES. Follow-up imaging may help to assess the resolution of the syndrome.

THE CASE

A 55-year-old woman presented to the emergency department (ED) with a bifrontal headache that she’d had for one day. She also had blurred vision and was vomiting shortly before coming to the hospital. The patient had no history of hypertension, migraine headaches, seizure disorder, autoimmune disorders, or cerebrovascular disease.

Her vital signs, including a blood pressure of 114/63 mm Hg, were normal, but a physical examination revealed subjective vision loss. She was only able to see objects moving on a horizontal plane. Her finger-to-nose exam, pupillary reflexes, and extra-ocular movements were normal, but peripheral vision was limited on her left side. No other neurologic deficits were noted.

The patient was admitted to the hospital and most of her laboratory work-up was normal, including a basic metabolic panel, complete blood count, coagulation studies, brain natriuretic peptide test, and cardiac enzymes. Her white blood cell count was 19,700/mcL, but no source of infection was found. A computed tomography (CT) scan of her head without contrast showed low-density, patchy areas in the subcortical regions of the parietal and occipital lobes bilaterally (FIGURE 1, arrows), with relative sparing of the cortex.

THE DIAGNOSIS

Based on our patient’s presentation and radiologic findings, we made a diagnosis of posterior reversible encephalopathy syndrome (PRES). However, because we could not rule out an ischemic cerebrovascular event at the time of presentation, we started the patient on aspirin and clopidogrel 75 mg to prevent possible future ischemic events. The next day, we ordered magnetic resonance imaging (MRI) of the head and neck, which documented the edema and confirmed the diagnosis of PRES (FIGURE 2).

DISCUSSION

PRES is a neurotoxic state associated with a unique pattern of brain vasogenic edema seen on CT or MRI. The edema is often widespread but is predominantly found in the parietal and occipital regions.¹ PRES is seen in patients with a variety of conditions, including hypertension and bone marrow or organ transplantation, as well as in those receiving immunosuppressive or cytotoxic medications.¹ Patients with PRES typically present with headaches and seizures.² Visual abnormalities (most commonly cortical blindness), occur in 15% to 20% of patients with PRES.^2-4

Hinchey et al³ first described reversible posterior leukoencephalopathy syndrome (which later became known as PRES) in 1996. Most of the 15 patients included in this original report had a history of hypertension or immunosuppression. These cases were associated with cerebral edema in portions of the posterior cerebral white matter. It is thought that hypertension alters the blood-brain barrier and causes the acute changes that occur in PRES.³

Besides hypertension and immunosuppression, the risk factors most commonly associated with PRES include preeclampsia/eclampsia; sepsis, particularly due to grampositive organisms; Wegener’s granulomatosis, scleroderma, and polyarteritis nodosa; cancer chemotherapy; bone marrow or stem cell transplantation; and renal disease.^1,4-6

Although a clear cause of PRES has not yet been established, researchers have proposed 2 theories. The first postulates that a sudden increase in systemic blood pressure causes vasoconstriction, which leads to ischemia and edema.^1-4,7,8 However, several studies have also described cases of PRES in patients with mild elevations in blood pressure,^1,5-7 and mild edema has been observed even in normotensive patients^1,5 (as was the case with our patient).

The second theory links PRES to the loss of brain autoregulation, a function that maintains steady blood flow when blood pressure fluctuates.⁶ A loss of this regulatory mechanism causes endothelial dysfunction, capillary leakage, and disruption in the blood-brain barrier.^1,2,4,6-8 These changes then lead to cerebral vasodilatation and edema.² Immunotherapy has also been associated with increased endothelial dysfunction.²

The evidence on the link between the severity of PRES and clinical outcomes is conflicting.

One study that followed 113 PRES patients over 6 years did not find an association between the severity of clinical presentation and the extent of vasogenic edema found on imaging studies.⁵ Of these 113 patients, 69 had PRES primarily due to hypertension, and 21 were receiving cytotoxic medications.⁵ In contrast, a larger retrospective study that followed patients with PRES for 12 years found that severe cases, which included patients with severe cerebral edema and altered mental status, had poor outcomes.⁴ Small studies have reported that 14% of patients with PRES develop cerebral hemorrhage.⁸

When to suspect this condition. PRES should be part of the differential diagnosis for any patient who presents with headache and vision loss. It is important to distinguish PRES from an acute cerebrovascular accident (CVA) because the 2 conditions are managed differently.² In addition, PRES lesions can be misdiagnosed as tumors, especially in a patient with a history of malignant disease in whom the condition appears after chemotherapy.⁹

Treatment targets the underlying causes

Treatment options for PRES are limited. Hypertension in a patient with PRES requires prompt intervention to avoid progression of the disease.² The use of intravenous (IV) calcium-channel blockers or IV beta-blockers for these patients is common.^2,8

Patients with seizures should be treated with anticonvulsant medication, but longterm antiepileptic treatment usually is not required.² Patients who take immunosuppressant or cytotoxic drugs should stop them indefinitely upon presenting with PRES.²

PRES lesions can be misdiagnosed as tumors—especially in patients with a history of malignant disease who have undergone chemotherapy.

For a pregnant woman with preeclampsia/eclampsia, delivery of the placenta, which is considered to be the cause of PRES in these cases, is curative.¹ However, women can develop PRES several weeks after delivery.¹

In most cases, the symptoms associated with PRES will resolve once treatment is initiated, and neurologic recovery can be expected within 2 weeks.²

Our patient regained her sight the following morning and was discharged home 2 days after admission. Her blood pressure remained normal. She returned to the hospital unresponsive the day after she had been discharged. Family members stated that she had taken 15 packets of an aspirin/caffeine combination to control a new headache.

Her blood pressure was elevated at 159/79 mm Hg. A CT of the brain showed a hemorrhagic stroke within the left occipital lobe and posterior parietal lobe with a midline shift of 8 mm. We don’t know if the aspirin use contributed to the hemorrhagic event or if it was a sequela of PRES.

The patient died 4 days later.

THE TAKEAWAY

PRES is a neurotoxic condition that causes headache, seizures, and vision loss. Most patients will present with elevated blood pressure and imaging studies will reveal a specific pattern of vasogenic edema that is predominately found in the parietal and occipital regions.

Treating the hypertension may result in a more favorable recovery. Normotensive patients are harder to treat because there is no specific therapy for PRES. Follow-up imaging may help to assess the resolution of the syndrome.