Esophageal and Gastric Motility Disorders Motility disorders of the esophagus: I. Upper esophageal sphincter and hypopharynx: (oropharyngeal dysphagia) food bolus cannot be propelled from pharynx and hypopharynx, through UES and into body of esophagus Æ can result in tracheobronchial aspiration or nasopharyngeal regurgitation. • Differs from globus sensation where bolus is transferred into the esophagus and sensation improves after swallow. Globus can occur with GERD and some distal motor d/o (i.e achalasia), most is idiopathic. a. Cricopharyngeal dysfunction: i. Characterizes by obstructive symptoms in the region of the UES, can be associated with Zenker’s diverticulum. ii. Barium esophagogram: shows prominent indentation of cricopharyngeus muscle with barium passing muscle slowly and muscle relaxing poorly during swallow. Ballooning of pharynx and aspiration can be present – termed spasm of cricopharyngeus and cricopharyngeal achalasia (Figure) iii. If radiographic study is abnormal, EGD should be done to r/o proximal esophageal neoplasm which can produce similar clinical and radiographic features. iv. High‐resolution manometry can detect elevated trans‐sphincteric gradient across UES. v. Tx –Bougienage short lasting. Often with cricopharyngeal myotomy b/c no medications available – increased amount of fibrous tissue found in sections of muscle. b. Neurologic disorders i. Strokes: oropharyngeal dysphagia is abrupt, occurs 1/3 of all CVAs, results from damage to the swallowing center or motor nuclei controlling striated muscles of hypopharynx and upper esophageal region. ii. Parkinson’s disease: untreated pt has stasis in the hypopharynx and associated failure of UES opening due to imbalance of dopaminergic and cholinergic ganglia in the brainstem – improves with tx of PD iii. Other: 1. Multiple sclerosis: UES dysfunction observed, plaquelike lesions in brainstem by MRI. 2. Other diseases involving brainstem can result in proximal esophageal dysfunction including ALS (denervation of skeletal muscles), Huntington’s, brainstem tumors, poliomyelitis (dysphagia occurs decades after initial disease), cervical spinal cord injury (1/3 pts affected). 3. Cranial nerve injury and their branches can results in poor UES opening and oropharyngeal dysphagia – occurs with malignancy, accidental injury during neck surgery, generalized or focal cranial neuropathies (diphtheria, DM, tetanus) c. Myopathic disorders i. Inflammatory myopathies: dermatomyositis and polymyosiitis affecting striated muscle of the esophagus 1. Dysphagia occurs in 10‐15% pt with these myopathies 2. Radiographically – poor contraction of pharyngeal constrictors, pooling and retention of barium in valleculae, and nasal regurgitation of bolus 3. Manometry – decreased contraction in the pharynx with reduction in UES resting tone, low amplitude contraction waves in proximal esophageal body. 4. Tx – steroids can improve the function in some patients. 5. Inclusion body myositis: adult onset d/o skeletal muscle – chronic, painless, usually resistant to immunosuppressive therapy; decreased pharyngeal peristalsis – cricopharyngeal myotomy may be required. ii. Muscular dystrophies: 1. Myotonia dystrophica: familial dz characterized by myotonia, myopathic facies, muscle wasting with swan neck, frontal baldness, testicular atrophy and cataracts; decrease contraction pressures in pharynx and upper esophagus and decrease resting pressures UES. 2. Oculopharyngeal dystrophy: occurs late in life, presents with ptosis and dysphagia. iii. Myasthenia Gravis: successive pharyngo‐esophageal transfer worsens with repeated swallows or as meal progresses with improvement after resting. iv. Other diseases affecting striated musculature: hyperthyroidism/ hypothyroidism; Stiff‐man syndrome‐ diffuse striated muscle disease due to uninhibited muscle stimulation – can occur as paraneoplastic process associated with anti‐Ri antibodies. d. Treatment of UES and hypopharynx dysfunction i. Compensatory strategies: 1. Adjustment of head and body and alterations of food consistency, volume and delivery rate. Avoid medications that cause decrease salivation. ii. Indirect therapy: improve neuromuscular controls necessary for swallowing w/o actually producing a swallow ‐ exercise programs for tongue coordination and chewing iii. Direct therapies: changes swallow physiology – medical tx of primary disease, maxillofacial prosthesis, cricopharyngeal myotomy, botox injection of UES, endoscopic myotomy and dragged balloon dilation up to 20mm in diameter. II. Esophageal body a. Achalasia: Greek term meaning “failure to relax” i. Incidence ‐ 0.5‐1/100,000; M=F, onset usually 30‐50s, <5% pts have symptoms b/f adolescence. ii. Feature of poorly relaxing LES causing functional obstruction of the esophagus. iii. Cause: unknown. Hypothesis of viral cause (no viral particles or genomic produces are found), genetic (association w/ HLA‐DQw1), autoimmune (Autoantibodies to myenteric neurons found in ~1/2 pts with achalasia). iv. Pathophysiology: results from degeneration of neurons in the esophageal wall. 1. Histologic exam shows decreased numbers of neurons (ganglion cells) in the myenteric plexuses. Remaining ganglion cells often surrounded by lymphocytes, and some eosinophils. 2. Inflammatory degeneration directed towards nitric‐oxide producing, inhibitory neurons that controls relaxation of smooth muscle; cholinergic neurons that contributes to LES smooth muscle contraction is relatively spared. 3. EM of esophageal vagal branches shows degeneration of myelin sheaths and damage of axonal membranes Æ vagal changes can affect inhibitory stimulation to sphincter. 4. In some pts, fragmentation and dissolution of nuclear material is found in ganglion cells of dorsal motor nucleus of the vagus in the brainstem. 5. Also may have subtle defect in reflex relaxation of UES. In response to esophageal distention that occurs when gas from stomach enters, normal pts have UES relaxation to allow belching versus achalasic pts having paradoxical increase in UES pressure w/o belch. Precise neural pathway of this reflex is unclear. v. Symptoms: durations of symptoms for several years at presentation, s/s dysphagia to solids (2/3 pts at onset) and liquids (40% at onset), weight lost (usually in the range of 5‐10kg but can be more), retrosternal chest pain (precipitated by eating, dissociated from dysphagia so that treatment improving dysphagia have little effect on chest pain), 60‐90% with regurgitation, heartburn. Use of postural changes (lifting neck or throwing shoulder back) to help with symptoms by increasing intraesophageal pressure. Achalasia also associated with adrenal glucocorticoid deficiency. vi. Diagnosis: 1. Barium swallow with fluoroscopy: screening test, barium retention with air fluid level in esophagus, bird’s beak (contrast pooling in dilated esophagus in tapered point at tight, nonrelaxing esophagus). (figure) 2. Endoscopy: to r/o other disease mimicking achalasia (pseudoachalasia – malignancies at GEJx) and evaluate esophageal mucosa prior to therapy. a. Findings of dilated esophagus and atony of esophageal body, and puckered, closed LES does not open during procedure (but unlike obstruction due to cancer or fibrotic strictures, contracted LES can be traverse with gentle pressure). b. Sometimes can see inflammation and ulceration 2/2 retained food or pills, or candida infection 2/2 esophageal stasis. 3. Manometry: important to do when radiographs are normal or inconclusive. Aperistalsis in the smooth muscle portion ‐ distal esophagus, elevated resting LES pressure (>45mmHg) in 55‐90% untreated patients, incomplete sphincter relaxation after a swallow. (figure) 4. High‐resolution manometry: can further subtype the disease a. Type I achalasia: swallow results in no significant change in esophageal pressurization b. Type II achalasia: swallow results in moderate, simultaneous pressurization that spans the entire length of the esophagus. c. Type III achalasia: swallow results in abnormal, lumen‐ obliterating contractions (spasms). d. Type II has best responses to all types of achalasia treatment (Botox, pneumatic dilation, pneumatic dilation, surgical myotomy), type III has worse response. vii. Treatment: 1. Pharmacotherapy: SL Isordil 5‐10mg qac, calcium channel blockers (placebo controlled trials have not shown consistent clinical benefits) 2. Botulinum Toxin injection: 80U injected circumferentially at level of LES with response in 60‐75% pts but sxs reappear w/in a year in majority of pts. Suited for pts with benefits from short term effects or not tolerate more aggressive tx. 3. Dilation: pneumatic or balloon dilators. a. Short term f/u: prospective study – 54 consecutive pts treated with PD f/u every 2 years for 10 years – clinical remission after single dilatation in only 59% pt after 1st yr, 26% after 5 years1. Repeat dilation increased longer remission – 89% for first year after 3 dilations. b. 2 main predictors of outcome following PD – post dilation LES pressure (to <10mmHg increases remission) and age (<40y/o predicts poor response). 1 Eckardt et al. Predictors of outcome in patients with achalasia treated by pneumatic dilatation. Gastroenterology 1992; 103: 1732. 4. Esophagomyotomy: Modified Heller procedure‐divide circular muscle fibers down to level of mucosa extending <1cm into stomach and several cm above LES Æ 80‐90% efficacy with GER being most sig complications. viii. Complications: esophagitis, aspiration, higher prevalence of esophageal carcinoma (squamous cell type) with mean interval b/t diagnosis to carcinoma 15‐20years. No surveillance recommendations currently although can consider EGD for pts with achalasia more than 15‐20years. ix. Secondary or pseudoachalasia 1. Chagas disease: infection with Trypanosoma cruzi Æ loss of intramural ganglion cells Æaperistalsis and incomplete LES relaxation. 2. Malignancy: can cause pseudoachalasia by invading esophageal neural plexuses directly or via release of humoral factors that disrupt esophageal function as part of paraneoplastic syndrome. 3. Other: amyloidosis, sarcoidosis, neurofibromatosis, EoGastroenteritis, MEN 2B. b. Spastic disorders – spectrum of nonachalasic disorders with hypermotility features. i. Clinical features: mean age 40y/o, F>M¸chest pain 80‐90% often more severe than pain 2/2 CAD lasting minutes‐hours and swallowing not impaired during episode; dysphagia 30‐60% but neither progressive nor severe enough to cause weight lost like in achalasia, heartburn and regurgitation. ii. Diffuse esophageal spasm 1. Diagnosis is suggested when 20% or more simultaneous contractions were found during standardized motility testing. The smooth muscle is primarily involved. 2. Radiographically: indentations produced by dysfunctional circular muscle contractions – “corkscrew esophagus” or “rosary bead esophagus.” (figure) Most often, it can be normal. 3. Pathophysiology: unclear but small study with 5 patients suggest malfunction in endogenous nitric oxide synthesis and/or degradation2. iii. Hypercontracting esophagus 2 Konturek et al. Diffuse esophageal spasm: A malfunction that involves nitric oxide? Scand J Gastroenterology 1995;20:1041. 1. Nutcracker esophagus: term used to describe manometric finding of high amplitude peristaltic contractions in the distal 10cm of esophagus. Identified by finding of average distal esophageal peristaltic pressure >220mmg after 10 or more 5ml liquid swallows during manometric testing. 2. Many pts with nutcracker esophagus also have hypertensive or poorly relaxing LES. 3. High‐frequency intraluminal u/s shows asynchronous contractions of the circular and longitudinal muscles layers that was reversible with atropine Æ suggests that nutcracker esophagus has component of hypercholinergic state. 4. Controversy regarding relationship of this finding to symptoms – it is a purely manometric finding that does not describe a disease or disorder. However, it remains to be one of the most common manometric finding in pts with unexplained chest pain (~12 of pts). iv. Hypertensive LES 1. Defined as resting, midrespiratory pressure >45mmHg sometimes with incomplete relaxation. v. Treatment: consider r/o cardiac dz, GERD 1. Predominantly pain: short and long acting nitrite, calcium channel blockers (randomized, double blind x‐over study with found diltiazem 60‐90mg qid sig relieved chest pain compared to placebo in 22pts with nutcracker esophagus).3 2. Antidepressants: trazodone 100‐150mg/qday4 and imipramine(50mg/qday)5 resulted in global improvement and reduced distress from esophageal sxs in pts with nonspecific spastic d/o. TCAs and SSRIs. 3. Botox: non‐randomized, uncontrolled trial of 29 symptomatic pt diagnosed with spastic esophageal motility d/o (DES, hypertensive LES, or nutcracker esophagus) treated with 100units of Botox injected at Z‐ line (5 circumferential injections of 20units/ml)Æ 70% pts had at least 3 Cattau et al. Diltiazem therapy for symptoms associated with nutcracker esophagus. Am J Gastroenterology 1991; 330:1411. Clouse et al. Low dose trazodone for symptomatic patients with esophageal contraction abnormalities: A double‐blind, placebo controlled trial Gastroenterology 1987; 92: 1027. 5 Cannon et al. Imipramine in patients with chest pain despite normal coronary angiograms. NEJM 1994; 330: 1411. 4 50% reduction in chest pain, 48% had complete relief of pain lasting ~7months on average6. 4. Peppermint oil (smooth muscle relaxant): case series of 8 pts shows improved manometric abnormalities in pts with DES – 2 pt with improvement in chest pain. 5. Sildenafil (50mg qday prn) – associated symptomatic relief in 11 pts with nutcracker esophagus or DES7. c. Systemic disorders affecting esophageal motility ‐ Hypomotility i. Progressive Systemic Sclerosis (figure) 1. ~74% of pts with typical skin sxs have e/o esophageal involvement at autopsy. Muscle atrophy and fibrosis affecting smooth muscle Æ failure of muscle contraction in distal esophagus and incompetency of LES (causing GERD) 2. Treatment is directed toward GERD and its complication since cannot reverse the esophageal motor abnormalities. Motility disorders of the stomach: I. Postsurgical syndromes: a. Truncal vagotomy: receptive relaxation is impaired. i. Early phase of liquid emptying is accelerated Æ rapid emptying of hyperosmolar solutions into proximal small intestine (dumping syndrome). ii. Impaired motor responses to feeding Æ postvagotomy diarrhea b. Gastrectomy: i. Antral resection Æ stomach incontinent to solids Æ accelerated emptying. “Dumping syndrome” in ~50% Billroth I or II gastrectomy. Early DS occur w/in 10‐20 minutes – includes weakness, nausea, urgency, bororygmi, diarrhea, diaphoresis versus late DS 90‐120 minutes post meal includes hypoglycemia. c. Roux‐en‐Y stasis syndrome: Roux syndrome – severe postprandial abdominal pain, bloating 2/2 motility d/o of the roux limb. Transection of jejunum separates limb from 6 Miller et al. Treatment of chest pain in patients with noncardiac, nonreflux, nonachalasia spastic esophageal motor disorders using botulinum toxin injection into the gastroesophageal junction. Am J. Gastroenterology 2002; 97:1640. 7 Eherer et al. Effect of sildenafil on esophageal motor function in healthy subjects and patients with esophageal motor disorders. Gut 2002; 50: 758. small intestinal pacemaker (in duodenum) Æ ectopic pacemakers in limb cause retrograde contractions in proximal portion. d. Pancreatectomy: postoperative gastric stasis. II. Diabetic gastroparesis: defined as delayed gastric emptying a. Unknown prevalence. Estimated 20‐40% pts with DM (esp. DM1) develops gastroparesis. The association b/t delayed gastric emptying and DM not straightforward because delayed gastric emptying is present in 25‐40% of pts with functional dyspepsia. b. Pathophysiology: i. DG results from impaired neural control of gastric function. Animal models and human pts have abnormal myenteric neurotransmission, impaired inhibitory nitric oxide‐containing nerves, damage of pacemaker interstitial cells of Cajal, and smooth muscle dysfunction. ii. Blood sugar effects: in controls and pts with DM, marked acute hyperglycemia relaxes proximal stomach, suppresses the frequency, propagation and contraction amplitude of antral pressure waves and stimulates phasic pyloric pressure waves Æ retard gastric emptying8. Hypoglycemia leads to accelerated gastric emptying9. c. Diagnosis: combination of compatible symptoms (early satiety, n/v, bloating, postprandial abdominal fullness/bloating), absence of structural obstructing lesion by EGD or barium radiography, delayed gastric emptying (noninvasive measures of liquid and solid gastric emptying by stable isotope breath tests, u/s, MRI or scintigraphy. “gold standard” is scintigraphy ‐ scans after ingestion of test meal containing radionuclide 99m technetium immediately, at 2 and then 4 hours later. III. Other causes: a. Idiopathic gastroparesis: exclusively in young women with intractable symptoms of postprandial fullness, nausea, and bloating and have delayed gastric emptying on formal testing. No histologic confirmation of diffuse motor disorder. Some pt may require supplemental nutrition, gastrostomy, and jejunostomy b. Malignancy‐associated gastroparesis: direct tumor infiltration of celiac plexus or vagus nerve, paraneoplastic 8 Barnett et al. Serum glucose concentration as a modulator of inerdigestive gastric motility. Gastroenterology 1988; 94:739. 9 Russo et al. Insulin‐induced hypoglycemia accelerates gastric emptying of solids and liquids in long‐standing type 1 diabetes. J Clin Endocrinol Metabolism 2005; 90:4489. i. Paraneoplastic gastrointestinal dysmotility: most associated with small cell lung cancer (rarely breast, ovarian, pancreatic, carcinoid, retroperitoneal sarcoma, Hodgkin lymphoma and cholangioCA). Pt often have antineuronal nuclear (ANNA‐1, anti‐Hu) antibodies that is thought to be directed to epitope shared b/t neuronal elements of enteric nervous system and underlying malignancy10. c. Functional dyspepsia: proposed pathophysiology includes impaired fundic relaxation Æ premature diversion of ingested meal to hypersensitive antrum Æ distention precipitates symptoms. d. Gastric ulcer disease: associated with impaired antropyloric motor function (unclear if this is primary process of 2/2 to ulcer process) e. Motor dysfunction related to viral illness: viral infection associated with development of sxs of gastric motor dysfunction. Pts with functional dyspepsia and delayed gastric emptying with h/o viral prodrome has great prognosis. 1 study of 7 pts show that most cases resolved spontaneously w/in 4weeks to 12 months11. IV. Treatment: a. Dietary modifications: i. Fat delays emptying and nondigestible fiber is poorly emptied b/c requires effective antral motility Æ recommend low‐fat diet without nondigestible fiber, frequent, small meals. b. Dopamine antagonists: i. Metaclopramide – both central and peripheral effects, antiemetic and some prokinetic activity. 25% of pts with side effects most sig are extrapyramidal reactions and tardive dyskinesia. ii. Domperidone (DA2 peripheral dopamine antagonist) does not cross blood‐brain barrier – available only in Europe, Canada, and South America. iii. Both meds may elevated serum prolactin Æ gynecomastia and galactorrhea. iv. These are effective in foregut and have efficacy in gastroparesis, GERD and dyspepsia. Both also have central antiemetics effect. c. Substituted benzamides 10 Lennon et al. Enteric neuronal autoantibodies in pseudoobstruction with small‐cell lung carcinoma. Naftali et al. Post‐infectious gastroparesis: clinical and electerogastrographic aspects. J. Gastroenterol Hepatol 2007; 22: 1423. 11 i. Cisapride: assists acetylcholine release from myenteric neurons thru a 5‐HT4 receptor medicated effect. Pulled from market for concerns of QT interval prolongation and cardiac arrhythmias. ii. Tegaserod: accelerates intestinal transit, reduce esophageal acid exposure, and promote gastric accommodation. d. Macrolides: i. Erythromycin: motilin agonist. Most useful in acute gastroparesis – IV 3mg/kg q8h to “kick start” stomach Æ induces high amplitude gastric propulsive contractions that dumps solids out of stomach, and inhibits accommodation response of proximal stomach after food ingestion. Can continue with po 250mg tid x 5‐7days after IV use. Efficacy with long term oral administration is unclear. ii. Side effects: GI toxicity, ototoxicity, peudomembranous colitis, risk of sudden death due to long QT syndrome. e. Non‐pharmacologic options i. Botox: pilot studies suggest injection into pyloric muscle is effective short term for symptomatic relief of gastroparesis by accelerating gastric emptying and suppressing isolated pyloric pressure waves. 1. Randomized controlled x‐over trial 23 pts – with idiopathic gastroparesis showed no significant benefit of Botox over saline placebo in improving symptoms or rate of gastric emptying12. ii. Gastric stimulation: precise mode of action unclear. 12 Arts et al. Clinical trial: a randomaize‐controlled crossover study of intrapyloric injection of botulinum toxin in gastroparesis. Aliment Pharmacol Therapy 2007; 26: 1251.