Tegaserod for the treatment of irritable bowel syndrome and chronic constipation.

BACKGROUND: IBS is a complex disorder that encompasses a wide profile of symptoms. The symptoms of chronic constipation frequently resemble those of constipation-predominant IBS. Current drug treatments for irritable bowel syndrome (IBS) are of limited value. Many target specific symptoms only. Tegaserod, a 5HT(4) partial agonist, represents a novel mechanism of action in the treatment of IBS and chronic constipation. OBJECTIVES: The objective of this review was to evaluate the efficacy and tolerability of tegaserod for the treatment of IBS and chronic constipation in adults and adolescents aged 12 years and above. SEARCH STRATEGY: MEDLINE 1966-December 2006 and EMBASE 1980 to December 2006 were searched. The text and key words used included "tegaserod", "HTF 919", "irritable bowel", "constipation" and "colonic diseases, functional". The Cochrane Central Register of Controlled Trials, and the Inflammatory Bowel Disease Review Group Specialized Trials Register were also searched. Searches stopped on 15th December 2006. Relevant articles were retrieved, and their reference lists were also reviewed. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing tegaserod with placebo, no treatment or any other intervention (pharmacological or non-pharmacological) in subjects aged 12 years and above with a diagnosis of IBS or chronic constipation, focusing on clinical endpoints were considered for review. DATA COLLECTION AND ANALYSIS: Study inclusion and exclusion, data extraction and quality assessment was undertaken by two authors independently. Meta-analysis was performed where study populations, designs, outcomes, and statistical reporting allowed combination of data in a valid way, using the summary statistics relative risk for dichotomous data and weighted mean difference for continuous data, both with 95% CI. Thirteen short-term placebo-controlled studies fulfilled the inclusion criteria. These were predominantly conducted in women. Ten studies evaluated the efficacy of tegaserod on global gastrointestinal (GI) symptoms in patients with constipation-predominant IBS (C-IBS). One small study evaluated safety in patients with diarrhoea-predominant IBS. Two studies evaluated the effectiveness of tegaserod for the treatment of chronic constipation. MAIN RESULTS: In patients with C-IBS, the relative risk (RR) of being a responder in terms of global relief of GI symptoms during the last 4 weeks of treatment was significantly higher with both tegaserod 12 mg and 4 mg doses compared with placebo. Although the pooled results indicate statistically significant benefit with tegaserod, the a priori minimal clinically important differences set in two of three studies were not reached. The responder rate for this endpoint was also higher when considered for the first 4 weeks of treatment (tegaserod 12 mg only). Tegaserod did not significantly improve the patients' individual symptoms of abdominal pain and discomfort although bowel habit showed a statistically significant improvement with tegaserod 4 mg and there was a non-significant trend in this outcome in favour of tegaserod 12 mg. In patients with chronic constipation, the RR of being a responder in terms of complete spontaneous bowel movements per week with tegaserod 12 mg was 1.54 (95% CI 1.35 to 1.75), WMD for this endpoint compared with placebo 0.6 (95% CI 0.42 to 0.78). Differences between tegaserod and placebo in increases in frequency of bowel movements were small (less than one per week). The proportion of patients with either diagnosis who experienced diarrhea was significantly higher in the tegaserod 12 mg group compared with placebo (RR 2.80, 95% CI 2.13 to 3.68), with a number needed to harm (NNH) of 20. Effects of tegaserod on GI symptoms such as bloating, stool consistency, and straining were not consistent across the studies. AUTHORS' CONCLUSIONS: Tegaserod appears to improve the overall symptomatology of IBS, and the frequency of bowel movements in those with chronic constipation. The clinical importance of these modest improvements is not clear. There are currently few data on its effect on quality of life. In addition, more information is needed about its efficacy in men. It would also be of interest to know whether treatment with tegaserod leads either directly, or indirectly, to changes in visceral sensitivity or psychopathology, which are also considered important in the pathophysiology of these conditions.

Unique aspects of central nervous system immunology.

In this review the authors discuss three immunologically unique aspects of the central nervous system (CNS). The first relates to whether the CNS is really an immunologically privileged site. Although still somewhat controversial, the answer to that question is that the CNS is, to a large extent, an immunologically privileged site. The second unique aspect of the CNS is the origin and significance of the microglial cell. Some microglial cells seem to originate from the systemic circulation, whereas other microglial cells seem to have a primary CNS origin. The function of the microglial cell is that of a macrophage. In addition it may play an important role in the immune response of the CNS. Present evidence suggests that the microglial cell can be classified as a lymphoreticular cell and as such is the only member of this cell type present in the CNS under normal circumstances. The final unique aspect of the central nervous system is the cerebrospinal fluid (CSF). Under normal circumstances this fluid is essentially acellular, and the only immunoglobulins present are those that are passively derived by diffusion from the systemic circulation. However, in pathological situations (i.e., demyelinating diseases, infections, and possibly even tumors) a local immune response occurs within the CNS and can result in the production of immunoglobulins. At present the detection of such local immune responses in CSF is predominately of diagnostic value only. However, these local CNS immune responses almost certainly play an important role in the pathogenesis of the diseases in which they occur.

Comparison of the infratentorial and transtentorial approaches to the pineal region.

During the past 10 years, two different operative approaches to the pineal region have been recommended by different authors. Numerous reports have appeared in the literature, indicating the safe use of one or the other of these two techniques for the excision of masses in the pineal region. This paper reports experience with both techniques in the treatment of 15 patients with mass lesions in this area. Four patients underwent a supracerebellar infratentorial approach and 11 patients underwent an occipital transtentorial approach to the pineal region. These two approaches are compared in terms of anatomical exposure, technical difficulties, and real or potential complications. The authors prefer the occipital transtentorial approach in dealing with lesions in the pineal region.

Enhancement of experimental cerebral edema after decompressive craniectomy: implications for the management of severe head injuries.

Decompressive craniectomy has been advocated as a treatment for the cerebral edema associated with massive head injury. Although craniectomy has been successful in lowering intracranial pressure after head injury, a comparison of computerized tomographic scans of comparable patients with traumatic brain edema treated by medical means or decompressive craniectomy showed that bony decompression resulted in apparent exacerbation of edema. To investigate the possibility of enhancement of brain edema by craniectomy, we produced standardized cold lesions in the brains of 10 dogs. Five animals served as controls. In the other 5 animals we performed large decompressive craniectomies after lesioning. Physiological parameters were comparable in both groups. The dogs were killed 8 hours after lesioning. After fixation, their brains were cut into 1-mm-thick slices. We used an image analysis facility built around a PDP 11/105 computer to measure the volume of edema as outlined by Evans blue staining. The mean volume of the brain edema in the control animals was 0.27 +/- 0.19 ml. Mean edema volume was over 7 times greater in craniectomized animals (1.96 +/- 1.89 ml). This difference is statistically significant (p less than 0.05). The driving force for the formation of edema fluid is the difference between intravascular and interstitial presssure. Decompression of the brain by bone removal probably results in a reduction of interstitial fluid pressure and edema enhancement. The clinical literature contains no evidence that craniectomy decreases the morbidity or mortality of human head injury. In view of our experimental findings, this is not surprising. Indeed, pathological evidence indicates that severe edema (such as that accentuated by craniectomy) may produce permanent changes in the neuropil.

Visual evoked potentials: a noninvasive technique to monitor patients with shunted hydrocephalus.

Visual evoked potentials (VEPs) to repetitive flash stimuli were abnormal in 10 patients with documented hydrocephalus. Abnormalities included latency delays, fatigability, and asymmetries. Both latency and wave form disturbances improved in the postshunt period. Clinical progression of the hydrocephalus occurred in several patients, and this correlated well with worsening of the VEPs. We suggest that this noninvasive technique may be valuable in following patients with cerebrospinal fluid shunts, patients with presumed "arrested" hydrocephalus, and patients who are being weaned from their shunts.

Microsurgical evaluation of the pterional approach to aneurysms of the distal basilar circulation.

The microsurgical correlates the pterional approach to the distal basilar circulation were evaluated in 20 cases of posterior circulation aneurysms, 50 human cadaver dissections, and a variety of other intracranial surgical lesions. The pterional approach permitted successful clipping of the aneurysm in 13 of 15 basilar bifurcation aneurysms, 1 of 2 basilar-posterior cerebral aneurysms, and 2 of 3 basilar-superior cerebellar aneurysms. In each of the failed attempts via the pterional approach, the subtemporal route ultimately resulted in proper clip application. The interposition of the posterior clinoid process was the impediment to successful clipping in three of the four cases that could not be managed via the pterional approach. All 3 of these patients had a basilar bifurcation that was below the level of the posterior clinoid on angiography, whereas none of the remaining 17 aneurysm patients demonstrated a low-lying bifurcation. Posterior displacement of the basilar artery away from the posterior clinoid exceeded 1 cm in only 13% of our cases and was not an impediment to successful clipping of the aneurysm via the pterional route. We conclude that, when the anatomical situation is appropriate, the pterional approach offers the advantages of less brain retraction and better visualization of the parent arteries and important perforating branches when compared to the subtemporal approach.

Serial computerized tomographic scanning and the prognosis of severe head injury.

Serial (two or three) computerized tomographic (CT) scans were performed on a series of 58 patients with severe head injury. The protocol called for scans to be done upon admission and on Days 3 and 7 after injury. New lesions (i.e., lesions not visualized on the initial CT scans but appearing on subsequent scans) were a frequent finding, occurring in over half of all patients. For the purposes of this study a new lesion was classified as edema involving two or more lobes, extra-axial hematoma, parenchymal hemorrhage, or infarction. Significant correlation was found between good outcome and the absence of new lesions and between bad outcome and the development of new lesions (p less than 0.001). Several patients did well in spite of the development of new lesions, but these patients were unique in that most had small, unilateral parenchymal hematomas located at or near the frontal or temporal poles. In most cases, patients who did poorly in spite of not developing new lesions had severe injuried visualized on their initial scans (massive intracerebral hematoma, hemorrhage of the corpus callosum) or succumbed to medical complications. The pertinent literature is reviewed, and other CT findings associated with a poor prognosis are noted. The authors suggest that serial CT scanning may be used to make prognostic assessments in severely head-injured patients and may be of value in increasing the confidence in and accuracy of assessments made on clinical grounds alone. (Neurosurgery, 5: 566--569, 1979).

Significance of the so-called absorptive reserve in communicating hydrocephalus: a preliminary report.

Twelve patients with communicating hydrocephalus were studied with a servocontrolled lumbar infusion technique to measure net cerebrospinal fluid (CSF) absorptive capacity and resting pressure. Each patient showed a significant absorptive reserve; the rate of CSF absorption exceeded the rate of formation over a physiological range of pressure. The size of the ventricles did not correlate with either the absorptive capacity or the resting pressure parameter, or both. The data suggest that communicating hydrocephalus does not reflect a simple imbalance between the rates of CSF formation and absorption. Other factors must be of etiological importance and are considered in the discussion.

Cerebrospinal fluid dynamics in patients with pseudotumor cerebri.

CSF dynamics were determined as a function of intracranial pressure in patients with pseudotumor cerebri. Servocontrolled variable rate lumbar infusions were used to determine net CSF-absorptive capacities and resting pressures in 10 patients; serial studies were done in 5 of the patients. Nearly all of the patients had abnormally low CSF-absorptive capacities. On the other hand, marked elevations in resting pressure were not a constant feature of the disease. Concurrent changes in the cerebrovascular bed could introduce errors into this manometric determination of CSF dynamics; the significance of this potential artifact is examined. The results of this study suggest that the CSF compartment may be of etiological importance in the pathophysiology of pseudotumor cerebri.

Servo-controlled lumbar infusions: a clinical tool for the determination of CSF dynamics as a function of pressure.

The variable rate lumbar subarachnoid infusion technique allows rapid quantitative study of the cerebrospinal fluid (CSF) compartment. Numerous pressure plateaus are studied in a brief time period with a servo-controlled system. The test determines the difference between rates of CSF absorption and formation as a function of pressure. On-line computer data analysis increases experimental efficiency to guarantee statistical significance. Animal and patient data are presented in the report.

Risk of intracranial aneurysm surgery in the good grade patient: early versus late operation.

To evaluate the risk of definitive intracranial microsurgical aneurysm obliteration as a function of the timing of the operative intervention, we retrospectively reviewed 106 consecutive patients in good clinical condition who underwent such surgery. The patients who were operated upon within the first 8 days of their most recent subarachnoid hemorrhage formed the "early" group; the patients operated upon between the 9th and 31st day were considered to have undergone "late" surgery. On the basis of their clinical outcome the patients were allocated to one of four outcome categories ("good," "fair," "death") both at the time of their hospital discharge and at their most recent clinical re-evaluation, a minimum of 6 months after discharge from the hospital. There was no significant difference in the operative mortality in each group (early surgery, 5%; late surgery, 4%); additionally, no significant difference was noted in the incidence of either intraoperative complications or postoperative morbidity. A suggestive but statistically insignificant increase in the incidence of postoperative cerebral ischemic events was seen in the "early" surgery group (8% vs. 4% for the "late" surgery group). The potential significance of these findings for the timing of intracranial aneurysm surgery is discussed.

Physiological features of the pressure-volume function of brain elasticity in man.

The intracranial pressure-volume relationship of brain elasticity was examined in 20 patients with suspected disorders of the cerebrospinal fluid (CSF) system. Elasticity measurements were made as the patients were studied with a servo-controlled lumbar infusion technique to measure CSF absorptive capacity. The data were evaluated to determine the relationship between intracranial pressure (ICP) and volume, and between ICP variability and the level of ICP. The results confirm the exponential nature of the pressure-volume elasticity function in patients who are not critically ill. Eight of the 20 patients were shown to have normal CSF absorptive capacities, and there was no difference between their elasticity measurements and those of patients with absorptive defects. In addition, ICP variability was shown to be linearly related to the actual level of ICP. The physiological features of the pressure-volume elasticity function are reviewed. Based on these considerations, the clinical value and significance of elasticity measurements is questioned.

Servo-controlled lumbar infusions in children. A quantitative approach to the problem of arrested hydrocephalus.

Servo-controlled variable-rate lumbar infusions were performed in 11 children with presumed cerebrospinal fluid (CSF) absorptive defects. The CSF dynamics were determined as a function of intracranial pressure in terms of CSF absorptive capacity and resting pressure. These physiological measurements showed poor correlation with traditional clinical signs. On the basis of the CSF measurements there were four children with arrested hydrocephalus, one with compensated hydrocephalus, three with active hydrocephalus, and three with brain atrophy. Retrospective management decisions based on the clinical presentations, physical findings, and traditional diagnostic tests disagreed with management as indicated by the CSF measurements in eight of 11 cases. It is suggested that this technique may be a useful diagnostic tool for difficult clinical problems.

Surgical management of unruptured asymptomatic aneurysms.

The natural history of unruptured asymptomatic aneurysms in nuclear. Because of this uncertainty regarding risk of ultimate enlargement and/or hemorrhage, and in view of the significant mortality and morbidity traditionally involved in aneurysm surgery, clinicans have varied in their advocacy of surgical management of such lesions. Forty-nine consecutive patients harboring 52 such aneurysms were treated surgically over a 57-month period. There were no surgical deaths and morbidity was within acceptable limits. Patient population characteristic and surgical technique are discussed.

Malignant pineal region tumors. A clinico-pathological study.

Eight patients with primary malignant pineal tumors have been seen at this institution over the past 6 years; six of them underwent definitive surgical exploration. Complete gross microsurgical excision of well encapsulated tumors was possible in four of these patients. In two cases of pineal germinomas, a biopsy and a subtotal resection were carried out because of the known radiosensitivity of this tumor. These six surgical patients all received postoperative craniospinal radiation and continue to do well up to 6 years postoperatively. Two nonoperative patients were initially treated at other institutions by ventriculoperitoneal shunt and radiation and were the only ones to develop metastatic disease. One patient had metastasis of her pineoblastoma to her unirradiated spinal canal and the other patient had metastasis of his germinoma to the peritoneum. The former patient was quadriplegic on admission, although her pineal tumor was no longer visible on computerized tomography (CT), and she died of pneumonia. The latter patient's tumor secreted the beta chain of human chorionic gonadotropin (HCG). This patient's massive metastatic tumor burden completely regressed as determined by body CT scan and HCG levels after four courses of chemotherapy with bleomycin, vinblastine, and cis-platinum. In 20 patients with lesions of the pineal region, craniotomy was associated with only one death (a patient with metastatic adenocarcinoma). Thus, microsurgery for pineal tumors provides either a reasonably safe potential for complete tumor extirpation and possible cure, or a tissue diagnosis which is necessary for appropriate therapeutic planning for radiotherapy and/or chemotherapy. The traditional therapeutic approach of empiric radiotherapy without a tissue diagnosis for pineal lesions may no longer be warranted.

Halo immobilization of cervical spine fractures. Indications and results.

Thirty-three patients with a spectrum of cervical spine fractures or subluxations were treated with immobilization by a halo apparatus. All spines were assumed to be unstable because of the nature of the fracture or because of a subluxation noted on spine films. Treatment consisted of immobilization and fracture reduction followed by application of a halo plaster cast or molded halo plastic vest. Patient acceptance was high. Complications were few and minor. No patient experienced neurological deterioration during treatment. Reduction was well maintained during an average halo immobilization period of over 3 months. Use of the halo resulted in healing of bone and ligament and restoration of stability in 85% of the patients. Halo immobilization was efficacious in the treatment of odontoid and hangman's fractures as well as complex fractures involving multiple areas of a single vertebra. It was also used successfully as an adjunct to posterior cervical fusion. Although several patients with subluxations or angulation without bone injury were treated successfully, two of the four therapy failures occurred in this group of patients, and the halo must be used with caution in this clinical setting. Contraindications to the use of the halo include complete cervical spinal cord injury with anesthetic skin, tomographic and/or myelographic evidence of disc or bone within the spinal canal, and unsatisfactorily reduced subluxations. The halo has provided more effective and reliable immobilization than other orthoses. It is an acceptable alternative to cervical fusion for the achievement of stability in a wide variety of cervical spine fractures and dislocations avoiding both the short-term and perhaps long-term complications of spinal fusion.

Brain elasticity changes with ventriculomegaly.

The pressure-volume relationship of brain elasticity was determined in 32 patients during servo-controlled variable-rate lumbar infusions to measure net cerebrospinal fluid (CSF) absorptive capacity. Several indices were used to estimate ventricular size from computerized tomography scans. The results show a linear relationship between ventricular size and the elasticity slope which relates the natural logarithm of pressure to volume. It follows that a hydrocephalic patient should show a greater intracranial pulse amplitude at a given pressure than does a patient with normal-sized ventricles. Although these elasticity changes may simply be the result of the ventriculomegaly, it seems possible that the pressure-volume elasticity relationship may be of etiological importance in disorders of the CSF system.

Dexamethasone and severe head injury. A prospective double-blind study.

A prospective double-blind study of the effects of dexamethasone administration on the outcome of patients with severe head injuries was performed. Patients were stratified for severity of neurological injury and were treated with placebo, low-dose dexamethasone (16 mg/day), or high-dose dexamethasone (96 mg/day) for a period of 6 days. Outcome was evaluated at 6 months following injury. Of the 76 patients available for analysis, a good outcome was achieved in 37% of placebo-treated patients, 44% of low-dose-treated patients, and 29% of high-dose-treated patients. These differences are not statistically significant. Similarly dexamethasone administration had no statistically significant effect on intracranial pressure patterns or serial neurological examinations during hospitalization. Gastrointestinal bleeding occurred in only one patient. Good outcome was associated with age under 10 years, lighter depth of coma on admission, and the preservation of brain-stem reflexes upon admission. A recalculation of data in previous clinical series purporting to show an improvement in outcome as a result of corticosteroid therapy shows no significant difference in outcome when steroid- and placebo-treated patients are compared. In our series, 90% of all deaths were caused by recurrent intracranial hematomas, medical complications, or diffuse brain injuries with parenchymal hemorrhage and tissue disruption -- causes of death which cannot be affected by corticosteroid therapy. The study suggests that dexamethasone in either high or low dosages has no significant effect on morbidity and mortality following severe head injury.

Tegaserod for the treatment of irritable bowel syndrome.

BACKGROUND: IBS is a complex disorder that encompasses a wide profile of symptoms. Current drug treatments for irritable bowel syndrome (IBS) are of limited value. Many target specific symptoms only. Tegaserod, a 5HT(4) partial agonist, represents a novel mechanism of action in the treatment of IBS. OBJECTIVES: The objective of this review was to evaluate the efficacy and tolerability of tegaserod for the treatment of IBS in adults and adolescents aged 12 years and above. SEARCH STRATEGY: MEDLINE 1966-November 2002 and EMBASE 1980-November 2002 were searched. The text and key words used included "tegaserod", "HTF 919", "irritable bowel", and "colonic diseases, functional". The Cochrane Central Register of Controlled Trials, the Inflammatory Bowel Disease Review Group Specialized Trials Register, and Science Citation Index were also searched. Proceedings from the British Society of Gastroenterology Annual Meeting, and Digestive Disease Week (1998-2002) were hand searched. The manufacturer of tegaserod was contacted. Relevant articles were retrieved, and their reference lists were also reviewed. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing tegaserod with placebo, no treatment or any other intervention (pharmacological or non-pharmacological) in subjects aged 12 years and above with a diagnosis of IBS, focusing on clinical endpoints were considered for review. DATA COLLECTION AND ANALYSIS: Study inclusion and exclusion, data extraction and quality assessment was undertaken by two reviewers independently. Meta-analysis was performed where study populations, designs, outcomes, and statistical reporting allowed combination of data in a valid way, using the summary statistic relative risk with 95% CI. Eight short-term placebo-controlled studies fulfilled our inclusion criteria. These were predominantly conducted in women. Seven studies evaluated the efficacy of tegaserod on global gastrointestinal (GI) symptoms in patients with constipation-predominant IBS (C-IBS). One small study evaluated safety in patients with diarrhoea-predominant IBS. MAIN RESULTS: The relative risk (RR) of being a responder in terms of global relief of GI symptoms was significantly higher with tegaserod 12 mg (RR 1.19, 95% CI 1.09, 1.29) and tegaserod 4 mg (RR 1.15, 95% CI 1.02, 1.31) compared with placebo, with a number needed to treat (NNT) of 14 and 20 respectively. When all tegaserod doses were combined and compared with placebo (n=4040), the RR of being a responder was 1.17 (95% CI 1.08, 1.27), with a NNT of 17. Although the pooled results indicate statistically significant benefit with tegaserod, the a priori minimal clinically important differences set in two of the four pooled studies were not reached. Tegaserod did not significantly improve the patients' individual symptoms of abdominal pain and discomfort although bowel habit showed a statistically significant improvement with tegaserod 4 mg and there was a non-significant trend in favour of tegaserod 12 mg. When GI symptoms were assessed separately, those indicative of GI motility such as number of bowel movements and days without bowel movements were generally improved with tegaserod although the proportion of patients experiencing diarrhoea was significantly higher in the tegaserod 12 mg group compared with placebo (RR 2.75, 95% CI 1.90, 3.97), with a number needed to harm (NNH) of 20. Effects of tegaserod on GI symptoms such as bloating, stool consistency, and straining were not consistent across the studies. REVIEWER'S CONCLUSIONS: Tegaserod appears to improve the overall symptomatology of IBS but there are currently few data on its effect on quality of life. In addition, more information is needed about its efficacy in men. It would also be of interest to know whether treatment with tegaserod leads either directly, or indirectly, to changes in visceral sensitivity or psychopathology, which are also considered important in the pathophysiology of this condition.

Peripheral nerve injury from implantation of chronic stimulating electrodes for pain control.

Complications of implantable stimulating electrodes for pain control are becoming recognized. We present two cases of peripheral nerve injury related to placement of peripheral nerve stimulating electrodes and discuss the relevant literature.