Primary esophageal motility disorders are characterized by abnormalities of esophageal peristalsis or contractions that interfere with swallowing and transit of food through the esophagus, producing symptoms of dysphagia and chest pain. The disorder is considered primary (idiopathic) when the cause of the patient’s symptoms and altered motility cannot be attributed to other systemic diseases (e.g., diabetes mellitus, scleroderma, amyloidosis, or neuromuscular disorders that affect striated muscle). The classic presentation is achalasia, a disorder characterized by failure of the lower esophageal sphincter (LES) to relax. There are several nonspecific esophageal motility disorders, including diffuse esophageal spasm (DES), nutcracker esophagus, ineffective esophageal motility (IEM), and other abnormalities of the LES. Whether these represent true disorders, a continuum of disease or merely abnormal motility patterns that are associated with but not the physiologic causes of symptoms remains a controversy (Table 33-1). Lack of a meaningful classification system adds to this confusion. Current systems classify the disorder based on aberrant esophageal motility patterns documented on manometric studies in the context of dysphagia and pain that cannot be explained by other thoracic or cardiac disease. These systems fall short because the cause of most motility abnormalities is unknown. Patients can have abnormal manometric tracings and be perfectly healthy. Conversely, therapies may correct the abnormal tracing, but symptoms do not improve. Strategies for managing esophageal dysmotility disorders include conservative management, treatment with drugs and other agents, and surgery. In the sections that follow we review current knowledge about the pathophysiology of the primary esophageal motility disorders and recent advances in diagnosis and treatment.

Normal Esophagus

The normal human esophagus uses two sphincters to control the passage of food and prevent the reflux of stomach contents: the upper esophageal sphincter (UES) and the LES. The LES is often adversely affected in primary esophageal motility disorders. The normal LES is located in the most distal portion of the esophagus and acts as the barrier between the esophagus and the stomach. It has a resting pressure of 15 to 25 mm Hg, which is usually sufficient to prevent gastroesophageal reflux. The body of the esophagus is composed of layers of motor, mixed, and smooth muscle that contract and relax in a coordinated fashion during peristalsis. A normal swallow begins with the relaxation of the LES and initiation of a peristaltic wave that moves the food bolus through the entire esophagus, terminating at the gastroesophageal junction (GEJ), where the relaxed LES permits the food bolus to progress into the stomach. Immediately after the bolus passes, the sphincter resumes its contracted state, forming a barrier between the highly caustic stomach contents and the esophageal lumen.

Neuronal control of normal peristalsis of the human esophagus involves both central (CNS) and enteric (ENS) components of the nervous system. The proximal esophagus, composed of striated muscle, depends on direct motor neuron sequencing by the CNS. In contrast, the distal esophagus is composed of smooth muscle. Propulsive motility in this region is controlled by a combination of central and myenteric neural circuitry. Peristalsis in the smooth muscle segment of the healthy esophagus can be described as a progressive aboral wave of contraction, preceded by inhibition of distal segments, including the LES. The occurrence, amplitude, and duration of the contraction and the velocity of propagation depend critically on the coordination of excitatory and inhibitory neuronal influences.¹ The excitatory innervation is mediated predominantly by acetylcholine, which acts on the muscarinic receptors, whereas inhibitory innervation involves mostly nitric oxide (NO) synthesis.²

The inhibitory function of NO is ubiquitous in the gastrointestinal tract.³ Its synthesis from l-arginine results from the activation of neuronal nitric oxide synthase (nNOS). NO mediates smooth muscle relaxation via an enzymatic cascade involving activation of soluble guanylate cyclase, production of guanosine 3,5-monophosphate (cGMP), and stimulation of cGMP-dependent protein kinase. Nerves and fibers immunoreactive for nNOS in the esophagus are localized to circular muscle in the distal segment.² The normal peristaltic contraction likely depends on a balance between a cholinergic excitatory tone and an inhibition that is progressively more profound in distal segments.² NO also plays a critical role in relaxation of the LES,⁴ although inhibitory neuropeptides, particularly vasoactive intestinal peptide, also have been implicated in LES relaxation.⁵

It has been proposed that nutcracker esophagus, DES, and achalasia may represent a continuum of disease resulting from a progressive neuropathy primarily involving inhibitory innervation in the distal esophagus and LES.⁶ The nature of the pathology underlying the loss of inhibitory innervation is not clear, although an autoimmune interpretation is supported by the finding that sera obtained from a subset of achalasia patients bind to myenteric neuronal elements, including apparently nNOS-containing neurons.⁷ This model offers an appealingly cogent interpretation of these esophageal disorders. At early stages, such a pathologic process would be expected to alter the balance in favor of excitation, leading to the high amplitude but still peristaltic contractions characteristic of nutcracker esophagus. Further compromise of inhibitory influence would lead to loss of coordinated propagation, as observed in diffuse spasm, and finally, aperistalsis, loss of LES relaxation, and the sequelae of obstruction that is characteristic of achalasia (Fig. 33-1).

This interpretation is supported by case reports of apparent clinical transition from nutcracker esophagus to diffuse spasm^8,9 and from diffuse spasm to achalasia.^6,10 It is also in agreement with a variety of clinical and pathologic experimental evidence. In patients with diffuse spasm, achalasia, or intermediate disease, the degree of swallow-induced receptive inhibition measured manometrically correlates inversely with peristaltic velocity.¹¹ IV glyceryl trinitrate, an NO donor, produces dose-dependent increases in latency and propagation velocity, decreases the duration of swallow-induced contractions, and alleviates the symptoms in patients with DES.¹² In achalasia patients, distal relaxation in response to esophageal distention is impaired, but proximal contractile responses are preserved.¹³ In vitro circular smooth muscle strips from the LES of normal control individuals exhibit spontaneous tone and relaxation during electrical field stimulation, whereas similar strips from patients with achalasia exhibit a contraction mediated by muscarinic receptors.¹⁴

Histologic quantitation of NADPH-diaphorase–positive (nNOS containing) neurons in LES and gastric fundus muscles of achalasia patients indicates a significant reduction of such neurons relative to cancer control individuals.¹⁵ Similarly, immunohistochemical staining demonstrates an absence of nNOS in the LES of achalasia patients.¹⁶ Normal esophageal smooth muscle is innervated by fibers immunoreactive for vasoactive intestinal peptide and neuropeptide Y, whereas few such fibers are evident in smooth muscles obtained from patients with achalasia.¹⁷

Knowledge of this pathophysiology has suggested several strategies for medical treatment. Sildenafil blocks enzymatic degradation of cGMP and thus enhances relaxation of smooth muscle. In normal volunteers, sildenafil reduces contraction amplitude in the esophageal body and LES tone, and this drug shows apparent benefit for a subset of patients with nutcracker esophagus.¹⁸ Botulinum toxin acts by inhibiting autonomic acetylcholine release and has been shown to be an effective treatment for achalasia by reducing LES pressure.¹⁹ Though less effective, it provides a less risky alternative to more invasive treatments such as dilation or myotomy.

Etiology

The term achalasia originates from Greek, meaning “does not relax.” The etiology of achalasia is unknown. It is a rather uncommon disorder with an annual incidence of 1 per 100,000.²⁰ In achalasia, the LES remains in its tonically contracted state after a swallow and fails to completely relax. This may be associated with the loss of peristalsis in the body of the esophagus, predominantly in the smooth muscle segment, or lower two-thirds of the esophagus. The loss of inhibitory neuronal drive is believed to be the cause of these effects.

Clinical Spectrum

The disease affects men and women equally. The diagnosis is usually made between the ages of 25 and 60 years, with peak diagnosis at ages 30 to 40 years. The disease can present in children (see Chapter 51) as well as in patients over the age of 65 years. The hallmark features at presentation include dysphagia for liquids and solids. Patients typically have had symptoms for at least 2 to 3 years preceding the diagnosis. Dysphagia for solids occurs in about 90% of patients, and dysphagia for liquids occurs in approximately 85%. Other common features include difficulty belching, regurgitation (often undigested food is noted on one’s pillow on awakening from a recumbent position), chest pain, heartburn, and weight loss (average 5–10 kg). These symptoms occur either singly or in various combinations in approximately 50% of patients.²¹ Patients very often have a sensation of retrosternal fullness radiating to the throat that is relieved by vomiting before bedtime. There may be chest pain, especially in younger patients, but attempts to differentiate these symptoms by manometric characteristics have not been forthcoming.²² Heartburn is usually associated with decreased LES pressures and resultant reflux. In patients with achalasia, heartburn may occur due to inflammatory changes in the esophageal mucosa secondary to candidiasis or irritation from pills, various ingested foods, and exposure to lactate from the bacterial formation of carbohydrates. Additional symptoms reported by patients include hiccups, possibly secondary to obstruction of the distal esophagus, and a globus sensation from esophageal distention caused by retained food. Children with achalasia may present with deficient tear production or alacrima and adrenal glucocorticoid deficiency (Allgrove syndrome). In one published report from the adult literature, 4 of 20 patients (20%) with achalasia had alacrima.

In addition to clinical symptoms, patients with achalasia carry a significant risk of developing squamous cell carcinoma of the esophagus. In a Scandinavian study, the calculated risk of developing esophageal cancer over several years was 16 times higher in achalasia patients compared to controls. In one study of over 200 patients in the United States, a similar risk was noted. Despite these findings, the cost-effectiveness of routine endoscopic screening for cancer among achalasia patients has not been established.

Diagnosis

The diagnosis of achalasia is based initially on clinical symptoms and confirmed by radiographic, endoscopic, and manometric evaluation and criteria. Many patients are treated initially for gastroesophageal reflux disease or misdiagnosed as a result of the very often slow progression of clinical symptoms. In one study, the average duration of symptoms before diagnosis was 4 to 5 years.²² Therefore, patients occasionally don’t get diagnosed until later stages of the disease. In these cases, signs of achalasia can sometimes even be seen on plain chest films that demonstrate a widened mediastinum secondary to a dilated esophagus. In addition, a gastric air bubble is often absent because of incomplete relaxation of the LES.

Barium swallow is the initial radiographic examination of choice for patients with suspected achalasia. The classic finding is a dilated esophagus with a beak-like narrowing at the GEJ. This finding is over 90% accurate for the diagnosis of achalasia²³ (Fig. 33-2). The beak-like narrowing is caused by the persistent contraction of the LES, which fails to relax completely, thus decreasing the passage of contrast through the area. With primary achalasia, the narrowing at the GEJ is symmetric. One must suspect a secondary cause of achalasia (e.g., invasion of the GEJ by a tumor) if the narrowing is asymmetric. On fluoroscopy, loss of peristalsis can be noted in the smooth muscle, or lower two-thirds, segment of the esophagus. Occasionally, high-amplitude nonperistaltic contractions termed vigorous achalasia are noted.

Esophageal manometry performed with nonperfused catheter systems can confirm the initial presumptive diagnosis of achalasia made from clinical symptoms and radiographic findings.²⁴ The classic features of achalasia on conventional esophageal manometry include: (1) aperistalsis in the smooth muscle segment of the esophagus, usually accompanied by low-amplitude contractions secondary to a dilated esophagus, (2) elevation of the LES resting pressure, and (3) incomplete relaxation of the sphincter after a wet swallow (Fig. 33-3). Often, the esophageal body resting pressure may be higher than the gastric pressure, as the elevated LES pressure prevents the intraluminal pressure from relaxing to the gastric baseline. Achalasia is classified as vigorous when the amplitude of the simultaneous contractions in the esophageal body is greater than the lower limit of normal (>30 mm Hg). The vigorous form may represent an earlier presentation of achalasia when some of the intramural ganglion cells are still present, and some prior studies suggested that the response to therapy may be better in this subgroup.²⁵