Primary Motility  Disorders of the  Esophagus
 The Esophageal
 Esophagogastric  Junction

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Volume: Primary Motility Disorders of the Esophagus
Chapter: Achalasia of the S.E.S. Oropharyngeal dysphagia

Is the mitochondrial origin of oropharyngeal dysphagia proven ?

K. Geboes J. Mebis (Leuven)


In humans the pharyngeal muscles (predominantly the three constrictors) join the tubular esophagus at the level of the cricopharyngeus, which, aided by the inferior constrictor, forms the upper esophageal sphincter. The esophageal tunica muscularis itself is composed of striated and smooth muscle fibers. The striated muscle fibers form the major portion of the uppermost esophagus. Two major, histochemically distinct, populations of striated muscle fibers can be distinguished : slow-twitch or type I fibers and, fast-twitch or type II fibers. In the human esophagus, they occur in a proportion of two to one, with similar distribution close to the pharynx and more distally[l, 2]. The average skeletal muscle has about twice as many type II fibers (60-65 %) as type I fibers (35-40 %) [3] (figure 1).

The terms « cricopharyngeal achalasia » and « achalasia of the upper esophageal sphincter» are often used for the description of deglutative disorders of the pharyngoesophageal junction. In fact the terms were firstly introduced by radiologists for a condition characterized by a persistent impression at the pharyngoesophageal junction of the posterior wall [4, 5]. Confusion exists however whether this lesion is due to achalasia (failure to relax); spasm (excessive contraction) or other defects. « Cricopharyngeal or oropharyngeal dysphagia » are therefore more


Figure 1. Diagram showing the relative proportion of different striated muscle fiber types.

preferable names. They refer mainly to symptoms that occur when the oropharyngeal or cricopharyngeal component of swallowing are disrupted by either a mechanical or a functional abnormality.

Functional abnormalities can be disorders such as a) the cricopharyngeus which fails to relax fully ; b) the relaxation phase which is out of phase with the pharyngeal contraction; or c) the contraction phase which is premature. The causes of oropharyngeal dysphagia are numerous (table 1). Many of these causes are quite rare and frequently the exact cause is not determined.


Studies of the pathology of the various conditions causing oropharyngeal dysphagia are scanty at least with regard to the local tissue changes. There are a few reports of intrinsic cricopharyngeal disease described as hypertrophic cricopharyngeal stenosis in which the cricopharyngeus was thickened and firm, apparently as the result of interstitial fibrosis and degenerative changes of the striated muscle cells [6]. These cases are probable end stage cases. In a more recent study seven patients who had dominant cricopharyngeal dysphagia associated with gastroesophageal reflux, were evaluated. Ultrastructural studies of cricopharyngeal muscle biopsy specimens obtained during myotomy showed numerous aberrant mitochondria, increased glycogen, and especially numerous nemaline rods [7].

Mitochondrial abnormalities have also been described in patients having oculopharyngeal muscular distrophy. This is a rare but well documented syndrome characterized by progressive palpebral ptosis and dysphagia. In most cases a clear autosomal dominant transmission pattern can be found but recessive cases as well

Table 1. Etiologic factors in cricopharyngeal dysphagia


Central nervous system disease.

Cerebrovascular accident ; bulbar polio ; cerebral palsy ; multiple sclerosis ; amyotrophic lateral sclerosis ; brain stem tumor...


Peripheral nerve disease.

Lead poisoning ; infections (diphtheria ; botulism ; tetanus)...


Muscular disease.

Oculopharyngeal myopathy ; myotonic muscular dystrophy...

Inflammatory muscular disease ; metabolic myopathy.

Progressive systemic sclerosis.


Local problems.

Neoplasia, inflammation, malformations, trauma.



Table 2. Oculopharyngeal muscular dystrophy

Synonyms and variants

- Oculopharyngeal myopathy

Ocular myopathy

- Progressive external ophtalmoplegia

- Oculocranioskeletal neuromuscular disease

- Descending ocular myopathy

Oculocraniosomatic disease

- Oculopharyngodistal myopathy

- Kearns-Shy syndrome

Ophtalmoplegia plus

as sporadic cases have also been reported. The impairment of the extraocular muscles may be associated with disturbance of several other voluntary muscles. Hence several synonyms (or variants) of this disorder can be found in the literature (table 2).

Pathologically the disease is characterized by a multifocal muscle fiber atrophy especially of type II fibers [8, 9]. Transmission electron microscopy confirms the myopathic changes seen with the light microscope and reveals mitochondrial abnormalities such as the presence of bizarrelly structured giant mitochondria, with scarcely evident cristae, and abundant electron dense matrix.

Paracrystalline inclusions with variable structure are frequently described [9]. The major abnormalities occur in clusters in many muscle cells. Considerable deposits of glycogen granules and lipid bodies can be seen, associated with the mitochondrial abnormalities. Occasionally, abnormal metallic mitochondrial inclusions have even been observed [8] as well as subsarcolemmal « fingerprint» inclusions [10]. The multifocal fiber lesions and the ultrastructural lesions point towards a primary muscular involvement.

Yet these ultrastructural findings even though supporting the mitochondrial origin of the disease give no real help to the nosographic problem, since abnormal mitochondria are found in several other types of myopathies such as dermatomyositis and even in metabolic disorders such as hypothyroidism[10, 9] (table 3).

Table 3. Ultrastructurally abnormal mitochondria in striated muscle fibers


The group of ocular myopathies


Other myopathies

- progressive limb-girdle myopathy

- distal myopathy

- facioscapulohumeral myopathy

congenital myopathies

- sudanophil myopathies


Other conditions

chronic polymyositis

- hypothyroidism


- Eaton-Lambert syndrome

Charcot-Marie disease

- cases of mental retardation

Furthermore, myopathic changes have been described secondary to denervation[ll].

Myopathic alterations have also been described in conditions such as myotonic muscular dystrophy and Zenker's diverticulum. Myotonic muscular dystrophy is characterized by necrosis of the esophageal striated muscle with variability in fiber size, and internalized nuclei.

In Zenker's diverticulum [12, 13], variability in fiber size is equally noted together with necrosis and the presence of ragged red fibers and of nemaline rods. In addition there is a shift from type II to type I fibers. The latter means a (relative) increase of slow twitch fibers. The morphological changes found in Zenker's diverticulum correlate well with changes of contractility properties as assessed on isolated fresh biopsy specimens of the cricopharyngeus, showing a less absolute force and a slower contraction in patients with Zenker's diverticulum.


Cricopharyngeal achalasia or rather dysphagia is a symptom that occurs when oropharyngeal swallowing is disturbed either by mechanical or motor abnormalities. The latter may be due to central or peripheral nervous disease or to muscular disease. Some myopathies are certainly associated with mitochondrial abnormalities. Whether those are the primary lesion in all or some of these myopathies remains to be proven.

The mitochondrial abnormalities will however probably lead to uncoupling of oxidative phosphorylation and other cellular metabolic disturbances. Or if they are not responsible for these disturbances, the mitochondrial appearance is at least the expression of such disturbances. The myopathies probably result in a shift from type II to type I fibers in the Cricopharyngeal and esophageal striated muscle. The further increase of these type I fibers must result in contractility alterations because of the nature of these fibers (sustained slow but less forceful contraction).


1. Whitmore 1. (1982) Esophageal striated muscle arrangement and histochemical fibre types in guinea pig, marmoset, macaque and man. J Anat 134: 685-695.

2. Geboes K, Mebis J, Desmet V (1988) The esophagus: Normal ultrastructure and pathological patterns. In Ultrastructure of the Digestive Tract. Motta PM, Fujita H. Eds: Martinus Nijhoff Publishers, Boston, Dordrecht, Lancaster, p. 17-34.

3. Heffner RR (1989) Muscle biopsy in neuromuscular disorders. In : Diagnostic Surgical Pathology. Sternberg SS Ed., Raven Press, New York, 119-139.

4. Asherson N (1950) Achalasia of the cricopharyngeal sphincter. J Laryngol 64 : 747-758.

5. Seaman WB (1969) Functional disorders of the pharyngo-esophageal junction. Radiol Clin. North Am 7: 113-119.

6. Benedict EB, Sweet RH (1955) Dysphagia due to hypertrophy of the cricopharyngeal muscle. N Engl J Med 253: 1161-1162.

7. Hanna W, Henderson RD (1980) Nemaline rods in cricopharyngeal dysphagia. Am J Clin Pathol 74: 86-191.

8. Pratt MF, Meyers PK (1986) Oculopharyngeal muscular dystrophy : recent ultrastructural evidence for mitochondrial abnormalities. Laryngoscope 96 : 368-373.

9. Palmucci L, Bertolotto A, Caviochioli D, Monga G, Schiffer D (1978) Sporadic Oculopharyngeal myopathy with abnormal mitochondria. Acta Neurol Belg 78 : 373-382.

10. Julien J, Vital Cl, Vallat JM, Vallat M, Le Blanc M (1974) Oculopharyngeal muscular dystrophy. A case with abnormal mitochondria and « Fingerprint» inclusions. J Neurol Sci 21 : 165-169.

11. Schneck L, Adachi M, Briet P, Wolintz A, Volk BW (1973) Ophthalmoplegia plus with morphological and chemical studies of cerebellar and muscle tissue. J Neurol Sci 19: 37-44.

12. Lerut T, Guelinckx P, Dom R, Geboes K, Gruwez J (1988) Does the M. cricopharyngeus play a role in the genesis of Zenker's diverticulum ? Enzyme histochemical and contractility properties. In: Diseases of the Esophagus. Siewert JR, Holscher AH Eds, Springer Verlag, New York, Heidelberg, Berlin, 1018-1023.

13. Cook IJ, Blumbergs P, Cash K, Graham S, Jamieson GG, Hains JD, Shearman DJ (1989) Zenker's diverticulum : evidence for a restrictive cricopharyngeal myopathy. Gastroenterology 96: A98.

Publication date: May 1991 OESO©2015