Pathophysiology and Clinical Presentationof Achalasia

RICHARD EARLAM

Achalasia of the oesophagus is a disease which has achieved more importancethan would be expected, considering its extreme rarity. This is due partiallyto the excitement of seeing a large dilated oesophagus on x-ray but mainlybecause it demonstrates what can go wrong with normal physiology. Thehealthy oesophagus consists of a hollow muscular tube closed by a sphincterat each end, and is normally kept completely empty by a primary peristalticwave which sweeps the lumen clear after each swallow. The cricopharyngealsphincter prevents air entering when one breathes and the lower oesophagealsphincter stops the reflux of gastric contents. A secondary peristaltic wavecan occur in response to distension by refluxed gastric contents and this is anadditional mechanism to keep the oesophagus empty. In achalasia there isretention of food and drink in the body of the oesophagus and the normalreflexes for completely clearing the lumen are absent. There are no peristalticwaves in the body of the oesophagus and the lower oesophageal sphincterfails to relax in response to each swallow. These abnormalities are due to theloss of ganglion cells in Auerbach's plexus. The denervated muscle can stillcontract, but it is inefficient and incoordinated.

INCIDENCE

Achalasia affects males and females equally. It occurs in all races and doesnot predominate in white Caucasians alone. The high incidence in SouthAmerica, especially in certain parts of Brazil, is due to Chagas' disease, anendemic disease caused by an infection with Trypanosoma cruzi. Otherwise,throughout the world the incidence of patients diagnosed is approximately1:100000 (Earlam, Ellis and Nobrega, 1969). The majority present betweenthe ages of 35 and 45, having had their symptoms for about five years,although 20 per cent have a one-year history and 20 per cent longer than 10years (Ellis and Olsen, 1969). In about 10 per cent the disease commenced inchildhood. Neonates have been described but so have people in theirseventies. There is no evidence of any outbreaks suggesting an infectiveorigin and there are no definite familial or hereditary influences in the fewlow density epidemiological studies available, although a few siblings have

Clinics in Gastroenterology—\o\. 5. No. 1, January 1976. 73

74 . RICHARD EARLAM

been affected. Man's best friend, the dog, may also suffer from achalasia. Inshort, achalasia is one of the classical diseases of unknown aetiology thatoccurs entirely by chance.

GROSS PATHOLOGY

The typical autopsy appearance of the oesophagus is of a thin-walledelongated bag tapering down to the narrow gastro-oesophageal junction.Retained contents are present instead of the normal emptiness. Althoughsuch specimens predominate in pathology museums they represent theend-stage of the disease when the musculature has given up its struggle toempty the lumen and has atrophied. There is always dilatation but themuscle wall may be normal. In the sphincter region it can even be thickened.The epithelium may be ulcerated and in about one per cent there is asquamous-cell carcinoma. It has been estimated that this rare changerequires at least 20 years of antecedent history (Pierce, MacVaugh andJohnson, 1970). It has been calculated that the chance of a carcinomadeveloping is increased by seven times in achalasia (Joske and Benedict,1959). The carcinoma is always squamous-celled, occurs in the body of theoesophagus, and is diagnosed late because it is asymptomatic or causessymptoms that cannot be differentiated from those in achalasia. It can occureven after a Heller's myotomy (Just-Viera and Haight, 1969). For someunknown reason the association of carcinoma with achalasia is commoner inEurope (up to 20 per cent in one series; Ellis, 1960) than in the United States,where only 0.5 per cent developed carcinoma (Wychulis et al, 1971).

MICROSCOPY

In achalasia there are always changes in the ganglion cells of Auerbach'splexus, situated between the inner circular and outer longitudinal layers ofmuscle (Smith, 1970). These intrinsic neurones may be completely absent(Figure 1) or reduced in number, with actual evidence of their degeneration.Other changes in Auerbach's plexus are infiltration with nonspecific roundcells and fibrosis. The body of the oesophagus is always affected and thisincludes not only the lower smooth muscle part but also the upper one-thirdwhere there is striated muscle, innervated by the vagus. These changes mayalso affect the lower oesophageal sphincter and in rare cases extend on to thestomach. Correlation of the extent and severity of the ganglion cell changeswith the clinical picture is a controversial subject. In general terms round-cell infiltration occurs early, and fibrosis in patients with a long history.Similarly, extension to the sphincter and stomach correlates with the moresevere gross pathological changes.

In the past, ganglion cells have been subdivided on the basis of theirmorphological and silver staining appearances into motor, with one largeaxon, and sensory, with multiple dendrites. A recent concept is thatAuerbach's plexus is predominantly motor, whereas Meissner's plexus, theneural plexus situated under the mucosa deep to the muscularis mucosae, ismainly sensory. In the oesophagus, where peristalsis is both fast and motor

PATHOPHYS1OLOGY AND CLINICAL PRESENTATION OF ACHALAS1A 75

activity almost independent of any afferent input, the sensory side andMeissner's plexus are usually absent. Changes in ganglion cells can thereforeonly be found from a muscle and not an epithelial biopsy. This is incontradistinction to Hirschsprung's disease where a mucosal biopsy may beof use clinically because ganglion cells can be shown to be absent inMeissner's plexus.

Figure 1. Auerbach's plexus, between the two muscular layers, contains no ganglion cells.

Muscle changes (Harrison, 1969) are present in the body of the oesophagusand the lower sphincter (Figure 2). By light microscopy this appears as anonspecific sclerosis (Alnor, 1958). With electron-microscopy, changes canbe demonstrated in individual muscle cells and the normal low resistanceconnections between muscle cells, called nexuses, are lost. A nexus is thesmooth muscle equivalent to the intercalated disc that can be seen by lightmicroscopy in cardiac muscle, but it is so small that it can only be seen withan electron-microscope. The significance of these muscular changes is notclear. There is certainly more damage than would be expected from simpledenervation alone.

Apart from the pathology in the ganglion cells, there are also changes in thepreganglionic fibres and their central nuclei (Figure 3). Degeneration ofindividual axones in the trunks of the vagus has been found with light andelectron-microscopy (Cassella et al, 1964). It is known that the vagus ispredominantly an afferent nerve at the level of the diaphragm, but there is noevidence as to whether the degenerating fibres are motor or sensory. Centralchanges in the dorsal motor nucleus of the vagus and in the nucleus ambiguus,

76 RICHARD EARLAM

responsible for the motor innervation of the smooth and striated muscleportions of the oesophagus respectively, are found in the medulla oblongata(Cassella et al, 1964). It must be emphasised that the reduction in neuronesoccurs in two different isolated nuclei situated on either side of the medulla,and the changes in the nerve trunks are in both the right and left vagus. It is

*PW

Figure 2. Light microscopy reveals patchy sclerosis in the smooth muscle.

therefore extremely unlikely that such widespread preganglionic changeswould result from one central lesion.

AETIOLOGY

The motor disturbances in achalasia can be explained by the effect ofdenervation on the smooth muscle of the body of the oesophagus and thelower sphincter, but the cause of the ganglion cell loss is unknown. Most ofthe earlier theories suggested local destruction due to toxins, nerve gases,infections, vitamin deficiencies and local inflammation. Infections areunlikely to affect only one part of the gut and Chagas' disease provides noexception (Earlam, 1972b). In this disease the trypanosome enters theintermuscular lymphatics and either by local effect, inflammation or toxins,destroys the neurones which are also there. The process may take up to 30years. It affects all the gut at the same time, but because of local differencesin function the colon is enlarged about six times more frequently than theoesophagus. Even distension itself was proposed as a way of destroying

PATHOPHYS1OLOGY AND CLINICAL PRESENTATION OF ACHALASIA 77

ganglion cells with sublime disregard of Hirschsprung's disease in which theenlarged portion of the gut contains perfectly normal ganglion cells.However, from the previous section it should be apparent that the ganglioncell changes do not exist in isolation. There are muscular abnormalities aswell as a reduction in the number of ganglion cells in the oesophagus itself

meaulia - cross—section medulia—suoenorasDec: dorsal motor/ nucleusot vagus

-iungs• )

abdomen .

oesoonagus

preganglionic lesions — in specific cans of theoorsai motor nuaeus oi the vaguson Don sides

— in the nucleus ambiguuson both sides of the meaulia

— in both trunks of thevagus

Ganglion cell Damage — loss always in the oody ofthe oesopnagus. extendingfrequently into the gasvo-oesopnageai sphincter andrarely to tne stomach

Musce Damage — non-specific necrosechanges, ana electronmicroscope evidence ofaosent nexuses in bothlayers

- dilatation of the oesophaguswith thin musoe layers

— occasional thickening ofgastro - oesophageaisphincter

outer longitudinalaver of muscle

Auerbach sinner circular

layer of muscle

Figure 3. A summary of all the pathological changes in achalasia including those in the brainstem, vagus nerves, ganglion cells and muscle.

and then a whole series of preganglionic changes, so the disease should beanalysed in the same fashion as any neurological disorder. Viewed neuro-logically there are two explanations; either (1) the peripheral ganglion cellsare primarily affected and the preganglionic neurones disappear secondarilydue to retrograde degeneration, or (2) the central changes are primary andthe peripheral loss of ganglion cells occurs secondarily because of tran-

78 RICHARD EARLAM

synaptic degeneration. Transynaptic degeneration does not usually occur.Viewed teleologically, this means that when preganglionic fibres are des-troyed, the intrinsic neurones are quite happy to go on functioning regardlessof the loss of central control. This is shown very easily by a simpleexperiment. Vagotomy is never followed by loss of ganglion cells. On theother hand, retrograde degeneration, which would occur if Auerbach'splexus were primarily destroyed, has been demonstrated experimentally andcould account for the widespread central lesions found in achalasia. Althoughthe central changes in achalasia have only recently been demonstrated, thishas in effect served to emphasise that the primary changes must be in thewall of the oesophagus itself and not in the brain. Confirmation that theprimary pathology must be in the oesophageal wall also comes from Chagas'disease, since central lesions in the dorsal motor nuclei of the vagus havebeen demonstrated as a secondary effect subsequent to the trypanosomaldestruction of ganglion cells (Lopes, Tafuri and Chapadeiro, 1969).

One possible method of destroying the intrinsic nerve cells is by ischaemia(Cannon and Burket, 1913). The principle is based on the fact that of thefour basic tissues — epithelium, muscle, connective tissue and nerve — thelatter is the most sensitive to anoxia and is also the only one unable toregenerate. It follows that an infarct, producing temporary ischaemia forfour hours is enough to kill neurones and could cause the primary ganglioncell loss and the muscle changes, leaving other tissues to regenerate. Theauthor has suggested that this could have occurred in utero due to an excessof the normal rotation of the gut while there is still a large umbilical hernia(Earlam, 1972a). The evidence is all circumstantial; there is no definite prooffor this hypothesis although it fits most of the facts. The destruction ofganglion cells in achalasia still remains one of nature's most perfect crimes,completely unsolved.

MANOMETRY

Oesophageal pressure studies have revolutionized our knowledge of achalasia.Although the majority of patients are diagnosed by radiology, doubtfulpatients ideally should have the benefit of manometry so that an accuratediagnosis can be made. On swallowing there is normally a peristaltic wavewhich passes from top to bottom of the oesophagus sweeping it clear. Inachalasia simultaneous waves are recorded (Figure 4a) and if any oneperistaltic wave is found the diagnosis must be rejected. The lumen isdilated and contains swallowed fluid and food. Consequently, the intra-oesophageal pressure in achalasia is raised, usually above atmospheric.Intraluminal pressures recorded after swallowing may be:1. Simultaneous with maximum pressures up to 80 cm H2O (Figure 10).2. Multiple repetitive, gradually fading after three or four contractions

(Figure 4b).3. Feeble simultaneous contractions less than 20 cm H2O.4. No response at all.

It must be remembered that the oesophagus is always dilated and therecording units are measuring pressures in one common cavity. A rise in

88 RICHARD EARLAM

ACKNOWLEDGEMENTS

Figures 2 to 10 are taken from Clinical Tests of OesophagealFunction, Earlam, R. J. (1976) andappear with kind permission of the publishers, Crosby, Lockwood, Staples (London).

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