Esophageal motility abnormalities in gastroesophageal reflux disease

Esophageal motility abnormalities are among the main factors implicated in the pathogenesis of gastroesophageal reflux disease. The recent introduction in clinical and research practice of novel esophageal testing has markedly improved our understanding of the mechanisms contributing to the development of gastroesophageal reflux disease, allowing a better management of patients with this disorder. In this context, the present article intends to provide an overview of the current literature about esophageal motility dysfunctions in patients with gastroesophageal reflux disease. Esophageal manometry, by recording intraluminal pressure, represents the gold standard to diagnose esophagealmotility abnormalities. In particular, using novel techniques, such as high resolution manometry with or without concurrent intraluminal impedance monitoring, transient lower esophageal sphincter (LES) relaxations, hypotensive LES, ineffective esophageal peristalsis and bolus transit abnormalities have been better defined and strongly implicated in gastroesophageal reflux disease development. Overall, recent findings suggest that esophageal motility abnormalities are increasingly prevalent with increasing severity of reflux disease, from nonerosive reflux disease to erosive reflux disease and Barrett's esophagus. Characterizing esophageal dysmotility among different subgroups of patients with reflux disease may represent a fundamental approach to properly diagnose these patients and, thus, to set up the best therapeutic management. Currently, surgery represents the only reliable way to restore the esophagogastric junction integrity and to reduce transient LES relaxations that are considered to be the predominant mechanism by which gastric contents can enter the esophagus. On that ground, more in depth future studies assessing the pathogenetic role of dysmotility in patients with reflux disease are warranted.     

Gastroesophageal reflux in cirrhotic patients with esophageal varices without endoscopic treatment

BACKGROUND: Portal hypertension in patients with liver cirrhosis causes manifestations such as esophageal varices, ascites and edema. Some studies have been conducted about the role of esophageal varices in the development of esophageal motor disorders and abnormal gastroesophageal reflux in these patients. Ascites could be a factor promoting gastroesophageal reflux and it has been questioned whether reflux would favor the rupture of varices. However there are a few studies using ambulatory esophageal pH recording in the evaluation of these patients. AIMS: Evaluate gastroesophageal reflux by pH recording in cirrhotic patients with esophageal varices and possible predictors. METHODS: Fifty one patients (28 men, 23 women, mean age of 54 years) with liver cirrhosis, diagnosed by clinical, laboratorial, image and histological findings were prospectively evaluated. All patients had esophageal varices confirmed by endoscopy and were submitted to a questionnaire about typical gastroesophageal reflux disease symptoms (heartburn and or acid regurgitation). pH recording was performed with the probe placed 5 cm above the superior lower esophageal sphincter limit, as determined by manometry. Abnormal reflux (% total time with pH < 4 >4.5%) was related to the size of varices, congestive gastropathy, ascites, severity of cirrhosis and typical gastroesophageal reflux disease symptoms. RESULTS: The caliber of the varices was considered to be small in 30 patients (59%), medium in 17 (33%) and large in 4 (8%), 21 (41%) congestive gastropathy. Ascites was observed in 17 (33%), 32 patients (63%) were classified as Child-Pugh A, 17 (33%) Child-Pugh B and 2 (4%) Child-Pugh C. Twenty seven patients (53%) presented with typical gastroesophageal reflux disease symptoms. Abnormal reflux at pH recording was found in 19 patients (37%). One of them presented with erosive esophagitis at endoscopy. There was no relation between ascites, variceal size, congestive gastropathy and Child-Pugh score and abnormal reflux. There was a correlation between typical gastroesophageal reflux disease symptoms and abnormal reflux. CONCLUSION: Abnormal gastroesophageal reflux was found in 37% of the patients with hepatic cirrhosis and esophageal varices. Only typical gastroesophageal reflux disease symptoms predicted these findings.     

The effects of inhaled albuterol and oral theophylline on gastroesophageal reflux in patients with gastroesophageal reflux disease and obstructive lung disease.

Patients with gastroesophageal reflux disease may have pulmonary symptoms due to repeated aspiration of gastric contents or reflex bronchospasm during a reflux event. Oral bronchodilators are known to worsen gastroesophageal reflux and may lead to vicious cycle when gastroesophageal reflux causes bronchospasm. The effect of inhaled bronchodilators on gastroesophageal reflux is unknown. We compared the severity of gastroesophageal reflux in patients with documented gastroesophageal reflux disease and obstructive lung disease while they were taking inhaled albuterol or oral theophylline. Nine patients with gastroesophageal reflux disease had 24-hour esophageal pH studies on two separate days approximately 1 week apart. On one study day, the patients received 0.5 mg of albuterol in 2.5 mL of normal saline vias hand-held nebulizer, four times a day. On the other day, the patients received sustained-release theophylline, 200 mg twice a day, or in a dosage taken previously to achieve a serum theophylline level of 55 to 110 mumol/L. The patients had 40% reduction in the total time the pH was less than 4.0 with albuterol than with theophylline (9.7% vs 16.1%). Seven patients had less gastroesophageal reflux while taking albuterol, and two patients had essentially no change. Patients with gastroesophageal reflux disease, who require bronchodilator therapy for obstructive lung disease, have less reflux with inhaled albuterol.     

Effect of hyoscine N-butylbromide on gastroesophageal reflux in normal subjects and patients with gastroesophageal reflux disease

OBJECTIVES: Recent studies have shown that atropine reduces gastroesophageal reflux in normal subjects and patients with gastroesophageal reflux. The aim of the study has been to assess the effects of an atropine derivative, hyoscine N-butylbromide in normal subjects and patients with gastroesophageal reflux disease by recording esophageal and gastric pH-metry for a 24-h period. METHODS: Ten normal subjects and 10 patients with gastroesophageal reflux disease were evaluated. PH-metry was performed using two glass pH flexible probes with distal incorporated electrodes. The two catheters were introduced nasally under fluoroscopy. One probe was positioned in the gastric body; the other was placed 5 cm above the lower esophageal sphincter which had been evaluated manometrically before the study. Recording lasted without interruption for 48 h. Patients and normal subjects were assigned to receive hyoscine N-butylbromide (10 mg p.o. t.i.d.) for 24 h followed by a placebo for another 24 h or vice versa in a random manner. The pH was analyzed for a total number of acid refluxes and percentage of the period with pH <4 in the esophagus and the mean gastric pH in 24 h, before and after treatment with hyoscine N-butylbromide. RESULTS: The number of reflux episodes was significantly greater with hyoscine N-butylbromide in comparison with a placebo in patients with gastroesophageal reflux disease and normal subjects (p < 0.02). The percentage of time with pH <4, was also significantly greater in patients with gastroesophageal reflux disease and in controls (p < 0.05). The mean 24-h gastric pH after hyoscine N-butylbromide was not different from placebo in gastroesophageal reflux disease and controls. CONCLUSIONS: Hyoscine N-butylbromide, an anticholinergic agent, increases the total number of esophageal acid refluxes in patients with gastroesophageal reflux disease and in controls, therefore it is not recommended in the treatment of gastroesophageal reflux disease.     

Mechanisms of reflux perception in gastroesophageal reflux disease: a review

Patients with reflux symptoms often do not have excessive esophageal acid exposure, and patients with severe gastroesophageal reflux often do not have reflux symptoms. Understanding why different types of reflux induce symptoms in different patients is vital for addressing therapeutic gaps in the treatment of gastroesophageal reflux disease (GERD). Here we review studies providing insight into how gastroesophageal reflux is perceived, with a focus on comparing reflux characteristics and esophageal sensitivity among subgroups of patients with GERD. The available studies indicate that patients with nonerosive reflux disease have fewer acid reflux episodes and thus less esophageal acid exposure than patients with reflux esophagitis but perceive less intense stimuli because of greater esophageal sensitivity. Reflux characteristics other than acidity, such as the presence of bile, pepsin, liquid, or gas in reflux, and the proximal extent or volume of reflux, may also contribute to symptom perception. Factors contributing to greater esophageal sensitivity may include impaired mucosal barrier function, peripherally mediated esophageal sensitivity (enhanced esophageal receptor signaling), and centrally mediated esophageal sensitivity (physiological stressors, sensitization of spinal sensory neurons). Further insight into mechanisms of reflux perception may require a shift toward studies aimed at understanding predisposing cellular, molecular, and genetic factors.     

Reflux cough

Cough can be an extraesophageal manifestation of gastroesophageal reflux disease. This article summarizes recent progress in our understanding of the pathophysiology, diagnosis, and treatment of the reflux cough syndrome. Recent studies have provided further evidence for a role of weakly acidic gastroesophageal reflux in inducing cough. It has also been established that although reflux may induce cough, cough may also trigger reflux in some patients, and distinguishing between the two requires objective detection of cough burst (ie, by esophageal manometry). Treatment of the reflux cough syndrome is an issue of ongoing controversy and further studies.     

A gastroenterologists view of chest pain

Esophageal disorders are common, but have been underemphasized as causes of chest pain in patients with “chest pain and normal coronary arteries,” as well as in patients with documented coronary disease. Reasons include failure to pursue evaluation once cardiac sources have been excluded; the atypical nature, location and/or radiation of pain in many patients, leading one away from proper consideration of the esophagus as a pain source; performing tests (upper GI series, fiberoptic endoscopy, oral cholecystography) that have low sensitivity for the detection of the diseases most likely to be the cause of chest pain (gastroesophageal reflux disease, the primary esophageal motility disorders). Esophageal motility testing, esophageal acid perfusion, acid reflux testing and the use of pharmacologic agents to induce chest pain and dysmotility are of greater value. In general, these tests can be performed in less than two hours. In some instances, prolonged recording of distal esophageal pH and/or motility may help identify gastroesophageal reflux or a painful primary esophageal motility disorder as the cause of chest pain. Treatment of gastroesophageal reflux disease is effective in most patients. One must be especially aggressive in the treatment of reflux in patients with coexistent coronary disease. The aim of treatment should be to eliminate pain episodes, since in these patients, pain emanating from an acid-sensitive esophagus may be confused with angina or, in some instances, actually induce myocardial ischemia. While therapy in the painful primary esophageal motility disorders is less effective than for reflux disease, several newer treatments show promise.     

Felodipine does not increase the reflux episodes in patients with gastroesophageal reflux disease

BACKGROUND/AIMS: Calcium channel blocking agents have been reported to increase the risk of gastroesophageal reflux. However, whether felodipine, a newer calcium channel blocker, increases reflux episodes and decreases esophageal acid clearance in patients with gastroesophageal reflux disease has never been studied. Therefore, the aim of this study was to evaluate whether felodipine increases the incidence of gastroesophageal reflux in patients with gastroesophageal reflux disorder. METHODOLOGY: Nine patients with gastroesophageal reflux disease, 6 men and 3 women, with a mean age of 62.6 +/- 14.4 years (range: 37-80 years) were studied. They received ambulatory esophageal pH monitoring for 45.7-48 hours (mean: 47.1 +/- 0.8 hours). Various pH parameters were evaluated during a similar interval of monitoring time before and after receiving 5 mg of felodipine. RESULTS: No significant difference was noted in any pH parameter by the Wilcoxon signed Ranks test, including reflux episodes (P = 0.552), reflux episodes longer than 5 min (P = 0.683), esophageal acid clearance (P = 0.663) and fraction time of pH < 4 (P = 0.752) before and after the use of felodipine. CONCLUSIONS: Felodipine does not increase reflux episodes or impair esophageal acid clearance in patients with gastroesophageal reflux disease.     

Distinct phenotypic presentations of gastroesophageal reflux disease: a new view of the natural history

For decades the natural history of gastroesophageal reflux disease (GERD) has been approached as spectrum-continuum, emphasizing the potential progress over time of patients along the spectrum. This commonly adopted conceptual framework had a profound impact on the field, affecting our research priorities and current management of GERD patients. A recent new conceptual framework has been proposed, suggesting that in response to factors that promote gastroesophageal reflux, patients may develop 3 distinct phenotypic presentations: non-erosive reflux disease; erosive esophagitis, and Barrett's esophagus. Most studies thus far, albeit unsatisfactory in their design, have demonstrated a very limited movement in between the 3 phenotypic presentations of GERD, further suggesting that those once determined remain true to form. The new conceptual framework emphasizes the importance of understanding symptom generation in GERD and the need to focus on the etiology and management of each phenotypic presentation of GERD. Additionally, it supports the usage of on-demand or intermittent antireflux treatment in clinical practice and provides better understanding of one of the most important clinical dilemmas - proton pump inhibitor failure.     

Gastroesophageal reflux disease and Helicobacter pylori infection

The prevalence of Helicobacter pylori infection has been decreasing while the prevalence of gastroesophageal reflux disease and esophageal adenocarcinoma has been increasing in developed countries since the 1930s. This has raised concerns that H. pylori infection may protect against esophageal disease and that the disappearance of H. pylori from the population might lead to a further increase in gastroesophageal reflux disease. Some studies have suggested that eradication of H. pylori in patients with duodenal ulcer disease results in an increase in the incidence of erosive esophagitis, whereas other studies have shown no such increase. Studies on gastric acid secretion have demonstrated that proton pump inhibitors are more effective in controlling gastric pH in individuals who are infected with H. pylori. Studies on the impact of therapy in patients with erosive esophagitis have been conflicting. This article reviews each of the issues in the debate separately and concludes that there is little evidence to suggest a major effect of H. pylori eradication on the outcome of gastroesophageal reflux disease.     

How reflux causes symptoms: Reflux perception in gastroesophageal reflux disease

In gastroesophageal reflux disease (GERD) symptoms arise due to reflux of gastric content into the oesophagus. However, the relation between magnitude and onset of reflux and symptom generation in GERD patients is far from simple; gastroesophageal reflux occurs several times a day in everyone and the majority of reflux episodes remains asymptomatic. This review aims to address the question how reflux causes symptoms, focussing on factors leading to enhanced reflux perception. We will highlight esophageal sensitivity variance between subtypes of GERD, which is influenced by peripheral sensitization of primary afferents, central sensitization of spinal dorsal horn neurons, impaired mucosal barrier function and genetic factors. We will also discuss the contribution of specific refluxate characteristics to reflux perception, including acidity, and the role of bile, pepsin and gas and proximal extent. Further understanding of reflux perception might improve GERD treatment, especially in current partial responders to therapy.     

What is nonacid reflux disease?

Proton pump inhibitors (PPIs) are the gold standard treatment for gastroesophageal reflux disease. In clinical practice, failure of PPIs occurs frequently, and may affect up to 30% of patients in a typical gastroenterology practice. Multichannel impedance monitoring combined with pH monitoring helps to detect nonacid reflux, and if symptoms correlate with these nonacid reflux episodes, nonacid reflux disease can be diagnosed. In contrast to PPIs, reflux inhibitors target transient lower esophageal sphincter relaxations, which are involved in the pathophysiology of reflux disease and may be the appropriate future treatment for nonacid reflux disease. The present article discusses the current understanding of nonacid reflux disease, its diagnosis and treatment.     

Endoscopic therapy of gastroesophageal reflux disease: outcomes of the randomized-controlled trials done to date

Endoscopic therapies to treat gastroesophageal reflux disease have been developed as another option for patients with reflux symptoms who do not want to continue medications indefinitely or are unwilling to undergo surgical intervention. The endoscopic treatments can be divided into those that pleat or plicate the upper stomach, deliver thermal energy into the lower esophageal sphincter, or inject or implant biopolymers into the gastroesophageal junction. Although capable to improve reflux symptoms for the majority of treated patients for a short while, durability has been variable among the various treatments, and there have been safety issues with some of the therapies. Although symptom improvement has been universally shown in short-term follow-up, there has been variable outcome for reduced need of antisecretory medications and pH studies show normalization of the distal esophageal acid exposure for only the minority of treated patients. Patients with significant reflux esophagitis or Barrett esophagus are not typically candidates for this antireflux intervention. Except for the NDO Plicator, in sham-controlled studies, there have been no significant differences between treated and sham-treated individuals for ability to discontinue medications or normalize pH. One issue in interpreting the results of these preliminary studies is the influence of the learning curve of a new technology. Another is that the devices and techniques have not been optimized. Currently, only the Davol/Bard EndoCinch and the NDO Plicator are available for commercial use. There are several newer devices under study or in development, and further testing and experience will demonstrate their capabilities in the treatment of gastroesophageal reflux disease.     

Endoscopic grading of gastroesophageal flap valve and atrophic gastritis is helpful to predict gastroesophageal reflux

Background and Aim: The endoscopic grading of the gastroesophageal flap valve (GEFV) has been suggested to be a good predictor of reflux status. Atrophic gastritis is inversely associated with reflux esophagitis. The aim of the present study was to investigate the association between GEFV, atrophic gastritis and gastroesophageal reflux. Methods: A total of 608 patients (252 men and 356 women; mean age 51.1 years) who underwent endoscopy, esophageal manometry and ambulatory 24‐h pH monitoring were included. GEFV was graded I through IV using Hill's classification: the GEFV was largely classified into two groups: the normal GEFV group (grades I and II) and the abnormal GEFV group (grades III and IV). Atrophic gastritis was classified into two groups by endoscopic atrophic border: closed‐type (C‐type) and open‐type (O‐type). Findings of endoscopy, esophageal manometry and ambulatory pH monitoring were compared among the groups. Results: The incidence of reflux esophagitis and gastroesophageal reflux disease was associated with an abnormal GEFV grade and was inversely associated with open‐type atrophic gastritis. The patients with a coexisting abnormal GEFV and closed‐type atrophic gastritis showed a significantly higher incidence of reflux esophagitis and gastroesophageal reflux disease than the patients with a coexisting normal GEFV and open‐type atrophic gastritis (OR, 20.6 [95% CI, 6.2–68.4], 11.4 [95% CI, 6.3–20.7], respectively). Conclusions: Endoscopic grading of GEFV and atrophic gastritis is simple and provides useful information on the status of gastroesophageal reflux.     

减重手术术后胃食管反流病的研究进展

减重手术做为目前治疗肥胖症有效术式,其安全和持久性得到了广泛的认可。其中腹腔镜袖状胃切除术(LSG)由于操作简单、不改变胃肠道结构、具有安全性高且疗效明显的优点,近年来做为主要的减重术式得到迅速普及应用。但肥胖症患者在行LSG术后,胃食管反流病发病率、疾病的转归、术中是否加做抗反流手术目前尚无统一意见。     

莫沙必利治疗胃食管反流病的随机、双盲、安慰剂交叉对照研究

目前对促胃肠动力药莫沙必利改善中国汉族胃食管反流病（GERD）患者胃食管反流症状和食管运动障碍的作用尚缺乏系统观察。目的：观察莫沙必利对中国汉族人群中GERD患者的治疗作用。方法：采用随机、双盲、安慰剂交叉对照研究设计，选取有典型胃食管反流症状的GERD患者23例行胃食管反流症状评估、食管测压以及24h食管DH和胆红素联合监测，对比研究莫沙必利和安慰剂各1周交叉治疗对胃食管反流症状的改善情况，以及对食管运动功能和胃食管反流事件的影响。结果：与安慰剂治疗相比，莫沙必利治疗可降低胃食管反流总症状积分，加快食管体部蠕动波传导速度，增加湿咽成功率，减少食管下端pH〈4总反流次数和长时间（≥5min）反流次数，降低pH〈4总时间百分比和DeMeester计分，降低食管下端胆汁反流总时间百分比，差异均有统计学意义（P〈0．05）。结论：莫沙必利治疗1周可有效改善本组中国汉族GERD患者的胃食管反流症状，部分改善食管运动障碍以及酸反流和胆汁反流．是治疗GERD安全、有效的药物。     

Precise role of acid in non-erosive reflux disease

The fundamental abnormality in gastroesophageal reflux disease is exposure of the esophageal epithelium to acidic gastric contents, resulting in histopathologic injury and/or symptoms. With increasing understanding of gastroesophageal reflux disease, non-erosive reflux disease (NERD) is found to account for >50% of cases involving gastroesophageal reflux. There is a good correlation between esophageal acid exposure (EAE) and endoscopic changes. Duration of EAE correlates with severity of erosive esophagitis (EE), and the number of prolonged acid reflux episodes and esophageal exposure to acid and pepsin is increased in more severe reflux. However, there is no convincing evidence to support a significant difference in the acid secretory capacity between patients with NERD or EE. Although acid reflux gives rise to similar symptoms in both NERD and EE patients, the underlying mechanism of acid injury may be different. Dilated intercellular spaces may be responsible for the enhanced perception of proximal acid reflux and dilated intercellular spaces are a feature of NERD patients, irrespective of EAE, and can be considered an objective, structural marker of reflux symptoms. Three different mechanisms have been proposed to explain the occurrence of heartburn in endoscopy-negative patients: esophageal visceral hypersensitivity, sustained esophageal contractions, and abnormal tissue resistance. Impaired esophageal mucosal resistance or increased sensitivity, even to small amounts of acid reflux, plays a key role in the pathophysiology of NERD. Moreover, hyperalgesia may be a predominant mechanism in eliciting symptoms in NERD patients. Increasingly seen are patients with a poor response to acid suppression treatment. Moreover, even double proton pump inhibitor dosing does not completely inhibit gastric acid secretion and relieve all symptoms. Thus, current definitions of acid reflux require review to increase the sensitivity to determine the frequency and implication of short periods of acidity in the esophagus. Analysis such as analysis of the area under the H(+) activity time curve is one alternative approach for evaluating acid secretion. The precise role of acid in NERD needs further clarification.     

Gastroesophageal reflux disease: new concepts in pathophysiology

The explanation as to why gastroesophageal reflux disease develops remains unanswered. We have learned much about the regulation of LES pressure, the single most important factor in the development of reflux disease. Our understanding of factors involved in the clearance of refluxed contents has also increased. The presence of reflux in the postprandial period and with belching suggests that it is serving a physiologic function. This may be a response to increases in gastric volume or pressure accompanying these situations. The question that has not been satisfactorily answered is what factor is responsible for the progression of a physiologic phenomenon to a pathologic condition. The answer to this question lies in the development of more physiologic techniques for monitoring LES pressure changes and a better understanding of the neural and hormonal pathways that regulate lower esophageal sphincter tone.     

The association between gastroesophageal reflux disease and obesity

Nearly all epidemiologic studies have found an association between increasing body mass index (BMI) and symptoms of gastroesophageal reflux disease (GERD). Changes in gastroesophageal anatomy and physiology caused by obesity may explain the association. These include an increased prevalence of esophageal motor disorders, diminished lower esophageal sphincter (LES) pressure, the development of a hiatal hernia, and increased intragastric pressure. Central adiposity may be the most important risk for the development of reflux and related complications such as Barrett's esophagus and esophageal adenocarcinoma. Weight loss, through caloric restriction and behavioral modification, has been studied infrequently as a means of improving reflux. Bariatric surgery and its effects on a number of obesity-related disorders have been studied more extensively. Roux-en-Y gastric bypass (RYGB) has been consistently associated with improvement in the symptoms and findings of GERD. The mechanism of action through which this surgery is successful at improving GERD may be independent of weight loss and needs further examination. Current evidence suggests that laparoscopic adjusted gastric banding should be avoided in these patients as the impact on gastroesophageal reflux disease appears unfavorable.     

Prevalence and demographic determinants of gastroesophageal reflux disease (GERD) in the Turkish general population: A population-based cross-sectional study

Background/aims: We aimed to establish the prevalence and demographic determinants of gastroesophageal reflux disease in the Turkish general population using the Turkish version of the gastroesophageal reflux disease questionnaire. Material and Methods: A total of 8143 volunteers (mean age: 38.5 (13.3) years; 52.3% males) were included in this cross-sectional questionnaire study conducted via face-to-face administration of the questionnaire forms including items on sociodemographic features, past history of gastric disorders, gastroesophageal reflux disease, the influence of reflux symptoms on patients' lives, physician visits, diagnostic tests, and reflux medications. Results: A past history of gastric symptoms was reported in half of the population. More female participants (p<0.001) had a past history of gastric symptoms that yielded a previous diagnosis of gastroesophageal reflux disease in 19.1% of the population. The likelihood of gastroesophageal reflux disease was low in the majority (75.3%) of the subjects evaluated. Gastroesophageal reflux disease with an inconveniencing or disrupting impact on the patient's life was present in 17.9% and 6.8% of the population. Total gastroesophageal reflux disease-questionnaire scores and reflux prevalence were higher in older age groups (p<0.001). Females were more likely to have gastroesophageal reflux disease prevalence based on reflux symptoms. The impact of gastroesophageal reflux disease on sleep and psychological/emotional well-being was more pronounced in older and female patients, whereas the impact on eating/drinking behaviors and physical-social activities was more marked among females independent of their age (p<0.001). Reflux prevalence was higher in subjects from East Anatolia, Central Anatolia, Mediterranean, and Black Sea regions of Turkey (p<0.001 for each). Conclusions: Prevalence and demographic determinants of gastroesophageal reflux disease are compatible with the profile of the disease in the other Western populations, with a predilection for females and older individuals.