This article summarizes the vast number of completed thrombolytic trials that contribute to the proper management of the acute stroke patient. This article will provide clinicians with a pathway for optimal assessment of the stroke patient, as well as a review of past and future thrombolytic trials.
At the end of this activity, the participant should be able to:
• Appropriately manage an acute stroke patient with a clear understanding of indications and contraindications for thrombolytic therapy.
• Perform a rapid evaluation of all acute stroke patients including a neurologic exam, laboratory analysis, an assessment of vital signs, and a brain computed tomography.
• Execute therapeutic decisions for various clinical scenarios with a new appreciation for recent thrombolytic studies and ongoing clinical stroke trials.
Neurologists and psychiatrists
Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide Continuing Medical Education for physicians.
Mount Sinai School of Medicine designates this educational activity for a maximum of 3.0 Category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity. Credits will be calculated by the MSSM OCME and provided for the journal upon completion of agenda.
It is the policy of Mount Sinai School of Medicine to ensure fair balance, independence, objectivity and scientific rigor in all its sponsored activities. All faculty participating in sponsored activities are expected to disclose to the audience any real or apparent discussion of unlabeled or investigational use of any commercial product or device not yet approved in the United States.
This activity has been peer-reviewed and approved by
Eric Hollander, MD, professor of psychiatry, Mount Sinai School of Medicine. Review Date: May 12, 2005.
To Receive Credit for This Activity
Read this article, and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME quiz. To obtain credits, you should score 70% or better. Termination date: July 31, 2007. The estimated time to complete this activity is 3 hours.
CNS Spectr. 2005;10(11):877-882
Dr. Tillisch is assistant clinical professor of medicine in the Division of Digestive Diseases in the Department of Medicine at the Center for Neurovisceral Sciences & Women’s Health at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA). Dr. Mayer is professor of medicine in the Departments of Medicine, Physiology, and Psychiatry and Biobehavioral Sciences at the Center for Neurovisceral Sciences & Women’s Health at the David Geffen School of Medicine at UCLA.
Disclosure: Dr. Tillisch does not have an affiliation or financial interest in any organization that might pose a conflict of interest. Dr. Mayer receives grant support from Eli Lilly and GlaxoSmithKline. Dr. Mayer is the recipient of National Institute of Diabetes and Digestive and Kidney Diseases grants DK64539, AT002681, and DK 48351.
Funding/Support: This article has been supported in part by This article was submitted on June 8, 2005, and accepted on July 22, 2005.
Please direct all correspondence to: Kirsten Tillisch, MD, Center for Neurovisceral Sciences & Women’s Health, GLA-VA MC, Building 115, Room 223, 11301 Wilshire Blvd, Los Angeles, CA 90073; E-mail: firstname.lastname@example.org.
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by chronic abdominal discomfort or pain in the absence of detectable organic disease. IBS is common and is associated with a significant impairment in health-related quality of life. Enhanced perception of visceral stimuli (“visceral hypersensitivity”) appears to be an important pathophysiological mechanism. Early IBS studies using functional brain imaging techniques suggest an alteration in central pain modulation circuits, rather than an increased sensitivity of peripheral visceral pain pathways. The frequent comorbidity with psychiatric disorders suggests the possibility of shared pathophysiological mechanisms and etiologic factors.
Irritable bowel syndrome (IBS) is a common functional gastrointestinal (GI) disorder affecting as much as 15% of the United States population.1 In the absence of generally agreed upon biological markers, IBS is defined by abdominal pain or discomfort associated with alterations in bowel habits, such as constipation, diarrhea, or both.2 Abdominal pain is reported by 30% of IBS patients as their most bothersome symptom,3 and the frequency and severity of abdominal pain is an important determinant of health-related quality of life (HRQoL) impairment4 and healthcare utilization.5 In addition to painful symptoms, many patients complain of non-painful discomfort, such as sensations of abdominal bloating and incomplete evacuation, suggesting that the underlying problem is a visceral hypersensitivity. There are different time courses to certain aspects of IBS symptomatology. Typically, patients experience intermittent, crampy abdominal pain in the lower abdomen preceding bowel movements and relief of symptoms following a bowel movement. Frequently, symptoms of incomplete rectal evacuation persist and patients may only have relief after several bowel movements. In contrast to these intermittent symptoms, a subset of patients during the course of a day develops progressive sensations of fullness and bloating, which is sometimes associated with visible abdominal distension. These symptoms may be absent upon awakening or in the absence of food intake. However, they may increase to their maximum in the evening. Symptoms are typically experienced over the entire abdomen. Some patients report persistent pain. On physical examination, a majority of patients have a tender, palpable sigmoid colon and report excessive discomfort during endoscopic examination (associated with mechanical manipulation) of the sigmoid colon.
This article hypothesizes that several physiological processes may individually, or in combination, contribute to the IBS symptom complex of abdominal pain and discomfort: crampy pain related to high amplitude propagated contractions of a hypersensitive distal colon; more persistent lower abdominal pain related to a sustained tonic contraction of the sigmoid colon; and persistent non-painful discomfort related to gas distension and/or chemical stimulation of a hypersensitive small/large intestine. Specific disorders of GI motility have not been consistently shown in IBS, nor has there been evidence that convincingly links patient symptoms with altered motility. It seems that the development of discomfort or pain may occur as an exaggerated sensory response to normal physiologic activity.
In the absence of detectable organic lesions in the GI tract, which could explain these findings, it has been suggested that symptoms may be related to visceral hypersensitivity to naturally occurring stimuli, such as contractions, distension, and possibly specific contents of the intestinal lumen, including bacterial products, bile salts, and undigested lactose.6
Experimental evidence for visceral hypersensitivity
The hypothesis of enhanced perceptual responses to visceral stimuli (subsequently referred to as “visceral hypersensitivity”) has been investigated intensively using controlled distension of different regions of the human GI tract.7-12 Visceral discomfort thresholds are generally measured in the rectum. They can also be tested in other regions of the colon, small bowel, esophagus, and stomach. This is accomplished by placement of a balloon catheter in the upper or lower GI tract, which is then inflated by an automated distension device called a barostat. Ratings of sensation, discomfort, or pain during the balloon inflations are recorded. Since the original description of visceral hypersensitivity by Ritchie and colleagues,7 numerous studies have confirmed the existence of altered visceral perception in IBS.13,14 As a group, IBS patients show lower rectal and sigmoid colon discomfort thresholds and have greater intensity and unpleasantness ratings during distension than do control subjects.8,9 The differences in perceptual threshold between control subjects and IBS subjects is most pronounced at higher pressures of rectal balloon inflation,15 though most rectal distension studies use inflations only in the range of discomfort and mild pain.
While abnormal basal perceptual thresholds for discomfort are only seen in ~40% to 60% of patients, some degree of altered perception (as evidenced by lower discomfort threshold, aberrant referral area, or reproduction of IBS symptoms by balloon distension) is seen in nearly all patients.9,16 Bouin and colleagues15 found that rectal barostat inflation to 40 mmHg had good sensitivity (95.5%) and specificity (71.8%) to identify IBS patients. This contrasted with other functional disorders, such as functional dyspepsia, functional constipation, or functional abdominal pain, in which rectal discomfort thresholds were not different than those seen in control subjects.
While hypervigilance toward potentially aversive visceral stimuli appears to be present in most IBS patients, alterations in the perception of controlled rectosigmoid distension are most pronounced in female patients with constipation-predominant bowel habit. It is nearly absent in male patients with diarrhea-predominant bowel habit.17,18 Though the concept of enhanced perception of visceral stimuli in IBS is supported by clinical and experimental data, techniques to quantify perceptual abnormalities related to visceral sensations remain suboptimal.
Lower discomfort thresholds are not strongly correlated with variations in overall IBS symptom severity. The correlations reported tend to be small and may vary depending on the protocol used during rectal stimulation, as well as the criteria used to define severity.19,20 Mertz and colleagues9 reported that rectal discomfort thresholds varied temporally with changes in symptom severity, while a more recent study21 found a gradual normalization of visceral hypersensitivity over the period of 12 months without a change in IBS symptom severity.
In addition to alterations in discomfort threshold, other abnormalities in visceral pain perception have been noted in IBS patients, consistent with alterations in central (spinal and/or supraspinal) pain processing. In response to rectal distension, IBS patients tend to describe larger areas of somatic pain referral, including regions of the right and upper abdomen.9,22 Enlarged and atypical referral areas of naturally occurring and experimentally induced visceral sensations are possible evidence for the presence of central (spinal and/or supraspinal) sensitization.6
It has been hypothesized6 that visceral hypersensitivity in IBS patients may be related to the induction of central (spinal) sensitization by intense repetitive mechanical stimulation, as occurring naturally during high amplitude-propagated contractions or prolonged sigmoid contractions. Consistent with such a hypothesis, Munakata and colleagues23 showed that patients with IBS were more likely to develop rectal hyperalgesia following a series of repetitive noxious sigmoid distensions, regardless of whether they initially had lower than normal rectal discomfort thresholds.23 Some patients had persistent abdominal discomfort outlasting the rectosigmoid distension. A similar phenomenon of alterations in temporal summation of repetitive noxious somatic stimuli has been described in patients with fibromyalgia.24 It is of interest, that in both IBS and fibromyalgia patients, this greater tendency for the development of temporal summation was seen predominantly in female patients.
Recognition of altered pain sensation in IBS patients is important not only in understanding the disorder but also in patient management. Normalization of bowel function alone, with either antidiarrheals or laxatives, is not sufficient to improve a patient’s global symptoms. Pain symptoms must also be addressed, commonly with low-dose tricyclic antidepressants that are believed to decrease visceral hypersensitivity via unclear mechanisms. Providing the patient with an understanding of visceral hypersensitivity in the setting of normal physiologic function may also help resolve the perceived disjunction between their symptom severity and the lack of objective findings on physical examination or diagnostic tests.
Evidence for altered somatic pain perception
Whether IBS patients have generalized abnormalities in generalized pain perception or alterations specific to visceral sensations has been a topic of controversy. Studies25-27 have assessed somatic pain sensitivity using various somatic stimuli (electrical stimulation, heat, cold, pressure) with many showing normal or decreased somatic sensitivity among IBS patients. Other studies have shown somatic hyperalgesia in IBS.28,29 The differences may have to do with the mode of somatic stimulation or the comorbid conditions in the patient populations. The presence of fibromyalgia, a functional pain condition commonly seen in conjunction with IBS, may alter somatic pain sensitivity in IBS patients, leading to somatic pain thresholds lower than those observed in controls. However, this is not seen in patients with IBS alone, who seem to have normal or decreased somatic pain sensitivity.25 Studies of IBS patients often do not indicate if comorbid fibromyalgia has been identified. Careful attention to comorbid conditions and mode of pain stimulation are necessary in designing future studies to determine somatic pain responses in IBS patients.
Evidence From Functional Brain Imaging Studies
Suggestive evidence for an alteration in central pain modulation mechanisms comes from functional brain imaging studies. In an activation study using 15O positron emission tomography (PET),30 IBS patients have shown increased activation of the dorsal subdivision and decreased activation of ventral subdivisions of the anterior cingulate cortex (ACC) in response to a visceral stimulus.Alterations in the relative activity of these two subdivisions of ACC have also been reported in other research data.31,32 While the dorsal ACC components are associated with cognitive and attentional aspects of stimulus response,33 the ventral components are closely linked to affective aspects and autonomic responses. Dorsal and ventral subregions of ACC have also been implicated in different aspects of the autonomic response to various stimuli.34 They also may play a role in providing differential input to subcortical endogenous pain inhibitory circuits33 and to subcortical pain facilitatory circuits.35 The relative balance between these simultaneously activated pain modulation systems determines the overall modulation of perception.36 The finding of greater dorsal ACC activation by a visceral stimulus in IBS is consistent with an earlier functional magnetic resonance imaging study37 and with the concept of greater attentional attribution to a visceral stimulus in IBS. On the other hand, the decreased activation of ventral ACC and medial prefrontal cortical regions (involved in executive function such as behavior modulation) in IBS is suggestive of possible deficiencies in the activation of endogenous pain inhibition systems. The combination of these mechanisms could play an important role in the enhanced perception of aversive visceral stimuli.
Consistent with this view is a recent PET study by Chang and colleagues38 comparing perceptual and brain responses to a visceral and a somatic aversive stimulus between patients with IBS with and without comorbid fibromyalgia. While patients with IBS alone showed enhanced dorsal ACC responses to a visceral (but not somatic) stimulus, those with associated fibromyalgia showed greater ACC responses to the somatic stimulus.
Several reported brain imaging studies comparing healthy control subjects and IBS failed to demonstrate group differences in insular cortical activation by aversive visceral stimuli. Since the insular cortex functions as an interoceptive cortex and its activation is directly related to the perceived intensity of a stimulus, this lack of enhanced insula activation in IBS suggests that the brain apparently does not receive enhanced visceral afferent input from the colon, but rather amplifies the peripheral signal.
Comorbidity of Psychiatric Disorders with Abdominal Pain and Irritable Bowel Syndrome
The concept of an altered cognitive-emotional modulation of visceral afferent stimuli explaining the clinical presentation of chronic abdominal pain and discomfort is supported by clinical observation and by a growing number of recent experimental studies. These studies39-42 have demonstrated that the perception of pain, including visceral pain, is modulated by psychological state, attention, or distraction. For example, when exposed to a psychological stressor, IBS patients tend to show a greater increase in the subjective ratings of rectosigmoid distension compared with healthy controls.40 Healthy volunteers also have a greater sensitivity to experimentally induced visceral stimuli during a condition of increased mental attention to abdominal sensations.42
It is traditionally assumed that the frequent association of psychiatric symptoms and functional GI disorders in referral clinics reflects a selection bias, with patients that suffer from IBS and depression being more likely to consult a physician than those without psychiatric comorbidity.43 However, large population-based surveys44,45 have demonstrated that symptoms of abdominal pain and discomfort are also more common in unselected individuals with altered affect and mood. While these surveys did not use specific symptom criteria to determine the prevalence of IBS and other functional GI disorders, the findings suggest a possible pathophysiological relationship between affective and mood disorders and symptoms of abdominal pain and discomfort.
Emerging pathophysiological model of altered pain perception in Irritable bowel syndrome
A growing body of literature supports the concept of an enhanced stress-responsiveness playing a role in the development of IBS symptoms in a subset of patients. An individual’s response to stress is generated by a central network comprised of integrative brain structures, referred to as the “emotional motor system” (EMS).46,47 The main output systems of the EMS are the autonomic nervous system, the hypothalamic-pituitary-adrenal (HPA) axis, endogenous pain modulatory systems, and ascending dopoaminergic pathways (Figure).
The responsiveness of the EMS and its various output pathways is under partial genetic control, and is modulated by pre-48 and postnatal49 aversive events and by certain types of pathological stress.50 In humans, early (pre- and postnatal) life adverse experiences are known to lead to long-lasting stress hyper-responsiveness, presumably in part due to permanent, stress-induced corticotropin-releasing factor (CRF) hypersecretion51 resulting in a wide range of health impairments in adult life.52 Long-term consequences of early aversive events also include an increased vulnerability for stress-sensitive disorders, such as IBS and posttraumatic stress disorder.53
In addition to findings in humans regarding changes in endogenous pain modulation systems and stress hyper-responsiveness are recent corroborative results from animal models. In rodents, maternal separation is a well-characterized model of early-life stress. Daily separation from the dam for 180 minutes gives rise to a phenotype in the offspring characterized by a long-lasting elevation of HPA axis reactivity to stress.54 Neurochemical changes in the brain include increased release of CRF in response to stress, altered expression of glucocorticoid receptors, and changes in the norepinephrine and g-aminobuytric acid systems.55,56 Adverse early-life experiences also affect the function of the GI tract in adult rats. A mild stressor has been demonstrated to increase ion secretion and permeability to antigens in the colonic mucosa in maternally separated rats.57 Coutinho and colleagues58 have recently reported that maternal separation predisposes adult Long Evans rats to develop visceral hypersensitivity (“stress-induced visceral hyperalgesia”) in response to a psychological stressor. This finding was associated with a compromised activation of stress-induced cutaneous analgesia. Based on experiments with naloxone, an opioid antagonist, a compromised endogenous opioidergic pain inhibitory system was suggested as one possible underlying mechanism of alterations in both visceral and somatic nociceptive responses.
These preclinical data are consistent with the interpretation that early-life stress in genetically predisposed individuals can lead to a permanently enhanced stress responsiveness, which in turn may result in alterations in stress-induced pain modulation systems. This model not only explains the well-documented stress sensitivity of IBS symptoms14 but could also be the basis for the frequent comorbidity between psychiatric disorders and functional GI disorders. Research to provide experimental validation for this model in humans is necessary and is the focus of ongoing research.
Abdominal pain or discomfort is a salient feature of IBS and considerable evidence supports the presence of altered central pain modulation and autonomic nervous system mechanisms in the pathophysiology of the disorder. IBS patients tend to have a lower tolerance to visceral distension, a marker of visceral hypersensitivity which may play a role in the prominence of pain in the IBS symptom complex. As in other disorders, pain symptoms appear to be exacerbated by psychological stressors, a potential explanation for symptom flares often noted by patients under stress. Early-life stressors also appear to be important in the development of IBS, though whether this results from an alteration in central pain processing, HPA axis modulation or from psychological vulnerability is not clear. While the factors that lead to the development of Pin symptoms in IBS remain incompletely understood, the syndrome is likely a multi-factorial process influenced by genetics, perinatal events, life stressors, comorbid illness, and possibly inflammatory events. The frequent comorbidity of IBS with psychiatric disorders, such as anxiety, depression, and somatization, and other chronic pain disorders, such as fibromyalgia and interstitial cystitis, points toward the possibility of shared underlying pathophysiologic mechanisms.
1. Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology. 2002;123:2108-2131.
2. Drossman DA, Corazziari E, Talley NJ, Thompson WG, Whitehead WE, eds. ROME II. The Functional Gastrointestinal Disorders. Diagnosis, Pathophysiology and Treatment: A Multinational Consensus. 2nd ed. McLean, VA: Degnon Associates; 2000.
3. Lembo T, Naliboff B, Munakata J, et al. Symptoms and visceral perception in patients with pain-predominant irritable bowel syndrome. Am J Gastroenterol. 1999;94:1320-1326.
4. Spiegel BM, Gralnek IM, Bolus R, et al. Clinical determinants of health-related quality of life in patients with irritable bowel syndrome. Arch Intern Med. 2004;164:1773-1780.
5. Sandler RS, Drossman DA, Nathan HP, McKee DC. Symptom complaints and health care seeking behavior in subjects with bowel dysfunction. Gastroenterology.1984;87:314-318.
6. Mayer EA, Gebhart GF. Basic and clinical aspects of visceral hyperalgesia. Gastroenterology. 1994;107:271-293.
7. Ritchie J. Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome. Gut. 1973;14:125-132.
8. Whitehead WE, Holtkotter B, Enck P, et al. Tolerance for rectosigmoid distention in irritable bowel syndrome. Gastroenterology. 1990;98(5 pt 1):1187-1192.
9. Mertz H, Naliboff B, Munakata J, Niazi N, Mayer EA. Altered rectal perception is a biological marker of patients with irritable bowel syndrome. Gastroenterology. 1995;109:40-52.
10. Lembo T, Munakata J, Mertz H, et al. Evidence for the hypersensitivity of lumbar splanchnic afferents in irritable bowel syndrome. Gastroenterology. 1994;107:1686-1696.
11. Bradette M, Pare P, Douville P, Morin A. Visceral perception in health and functional dyspepsia. Crossover study of gastric distension with placebo and domperidone. Dig Dis Sci. 1991;36:52-58.
12. Trimble KC, Farouk R, Pryde A, Douglas S, Heading RC. Heightened visceral sensation in functional gastrointestinal disease is not site-specific. Evidence for a generalized disorder of gut sensitivity. Dig Dis Sci. 1995;40:1607-1613.
13. Naliboff B, Mayer EA. Sensational developments in the irritable bowel. Gut. 1996;39:770-771.
14. Whitehead WE, Palsson OS. Is rectal pain sensitivity a biological marker for irritable bowel syndrome: psychological influences on pain perception. Gastroenterology. 1998;115:1263-1271.
15. Bouin M, Plourde V, Boivin M, et al. Rectal distension testing in patients with irritable bowel syndrome: Sensitivity, specificity, and predictive values of pain sensory thresholds. Gastroenterology. 2002;122:1771-1777.
16. Mertz H. Review article: visceral hypersensitivity. Aliment Pharmacol Ther. 2003;17:623-633.
17. Schmulson M, Lee OY, Chang L, Naliboff B, Munakata J, Mayer EA. Differences in viscerosensory processing between IBS patients with constipation and diarrhea. Am J Gastroenterol. 1998;93:1699.
18. Chang L, Naliboff BD, Schmulson M, Lee OY, Olivas TI, Mayer EA. The role of gender and bowel habit predominance on visceral perception in IBS. Gastroenterology. 2001;120:A755.
19. Whitehead WE, Diamant N, Meyer K, et al. Pain thresholds measured by the barostat predict the severity of clinical pain in patients with irritable bowel syndrome. Gastroenterology. 1998;114:859.
20. Tillisch K, Naliboff BD, Bolus R, Olivas TI, Mayer EA, Chang L. Rectosigmoid sensory measures distinguish IBS patients from controls and correlate with self ratings of GI symptom severity. Gastroenterology. 2003;124:A252.
21. Naliboff BD, Berman S, Chang L, et al. Gender related differences in central responses to rectal and sigmoid distension in irritable bowel syndrome. Gastroenterology. 2002;122:A310.
22. Swarbrick ET, Hegarty JE, Bat L, Williams CB, Dawson AM. Site of pain from the irritable bowel. Lancet. 1980;ii:443-446.
23. Munakata J, Naliboff B, Harraf F, et al. Repetitive sigmoid stimulation induces rectal hyperalgesia in patients with irritable bowel syndrome. Gastroenterology. 1997;112:55-63.
24. Staud R, Vierck CJ, Cannon RL, Mauderli AP, Price DD. Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain. 2001;91:165-175.
25. Chang L, Mayer EA, Johnson T, FitzGerald L, Naliboff B. Differences in somatic perception in female patients with irritable bowel syndrome with and without fibromyalgia. Pain. 2000;84:297-307.
26. Prior A, Colgan SM, Whorwell PJ. Changes in rectal sensitivity after hypnotherapy in patients with irritable bowel syndrome. Gut. 1990;31:896-898.
27. Accarino AM, Azpiroz F, Malagelada JR. Selective dysfunction of mechanosensitive intestinal afferents in irritable bowel syndrome. Gastroenterology. 1995;108:636-643.