Documenta Ophthalmologica 46,2: 391-401, 1979

OCULOPHARYNGEAL DYSTROPHY

DIAGNOSTIC PROBLEMS AND POSSIBILITIES.

L.A.K. BASTIAENSEN, B.P.M. SCHULTE (Tilburg)

Abbrevations: c.p.e.o. = chronic progressive external ophthalmoplegia oc.ph.d. = oculopharyngeal dystrophy

Oculopharyngeal dystrophy is a form of chronic progressive external

ophthalmoplegia (c.p.e.o.) which differs from the other forms in its very

distinctive course and characteristics (Table 1). The disease is considered to be entirely myogenic.

The condition is known as a disease of old age, characterized by ptosis and

dysphagia. This combination has an autosomal dominant hereditary pattern.

It was first described in French-Canadian families (Taylor 1915, Barbeau

1966, 1969) in whom a very constant picture was observed with nearly

100% penetrance and pronounced expressivity of the hereditary anomaly.

In the classical, 'French-Canadian' form the other external ocular and

skeletal muscles are almost or entirely unaffected; dysphonia is the only

further anomaly which is sometimes described. This form of the condition is called palpebro-pharyngeal dystrophy. It has also been described in other

than French Canadians (Dotsenko 1964, Lewis 1966, 1969, Millefiorini & Filippini 1967, Graf 1971, Crone 1973, Fournier et al. 1974, Fernandez-Martin et al. 1975).

The disease usually runs a benign course but a few fatal cases, as the result of severe malnutri t ion or aspiration pneumonia, have been described (Taylor

1915, Myrianthopoulus & Brown 1954, Roberts & Bamforth 1968, Weitzner 1969, Fournier et al. 1974).

Other forms of the condition have also been described with more extensive

muscular involvement: the other ocular muscles, cranial muscles and skeletal

Table 1. Classification of Chronic Progressive External Ophthalmoplegia (c.p.e.o.)

1. Ocular myopathy only (Von Graefe's disease) 2. Descending ocular myopathy (with cranial and further skeletal muscle

involvement) 3. Oculopharyngeal dystrophy 4. Ophthalmoplegia-plus (with retinal pigmentary anomalies, disorders of cardiac

conduction system and/or nervous system) 5. C.p.e.o. in heredo-ataxias

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muscles. The disease has a descending course and the proximal muscles are

more affected than the distal ones, 'oculopharyngeal skeletal myopa thy '

(Noyes 1930, Victor et al. 1962, Weinstein 1964, Felden & Miklos 1968, Aarli 1969, Manigand et al. 1969, Alberca et al. 1971, Julien et al. 1974,

Lessell 1975, Campanella et al. 1975). If the distal muscles of the extremities are more affected than the

proximal ones the condit ion is called oculopharyngeal distal myopathy

(Arnould et al. 1969, Satoyoshi & Kinoshita 1977). Cardiomyopathy has also been described in combination with oc.ph.d. (Petit 1971, Finkel et al.

1972, Goto et al. 1977), and occasionally endocrine disorders (Lundberg

1962) or retinal pigmentary anomalies (Alberca et al. 1971 ). In addit ion to these forms showing variations in the extent of muscular

involvement, forms exist with atypical age of onset and possibly also with a

different hereditary pattern (Table 2). A few cases of oc.ph.d, with dominant heredity have been described in

which the condit ion developed early in life (20 - 40 years) (Thiel 1954,

Roberts & Bamforth 1968, Champion 1971). Early cases may also occur in families with oc.ph.d, of late onset (Murphy & Drachman 1968, Fernandez-Martin et al. 1975).

The diagnosis of oculopharyngeal dyst rophy in a sporadic case is open to doubt , especially when the age of onset is early. It is more likely to be a form of descending ocular myopa thy or ophthalmoplegia-plus, in which case mitochondrial anomalies in a biopsy specimen of muscle are obligatory. Sporadic cases occurring later in life have a clinical picture and course which is in agreement with the diagnosis of oculopharyngeal dyst rophy (Teasdall

et al. 1964, Ellis et al. 1966, Levy & Scaff 1974).

A completely different hereditary pattern makes the diagnosis of oculopharyngeal dys t rophy very doubtful , as in the autosomal recessive

cases described by Matsunaga et al. (1972) and Fried et al. (1975).

Knowledge of the different forms in which oculopharyngeal dyst rophy may occur is desirable in connection with the differential diagnosis. This

Table 2. Forms of Oeulopharyngeal Dystrophy

A. Forms according to extent of muscular involvement 1. Palpebropharyngeal dystrophy. Classical 'French-Canadian' form with dominant

heredity, ptosis and dysphagia in later life. 2. 'Oculopharyngeal skeletal myopathy'. As 1 but extending to external ocular

muscles and (proximal) skeletal muscles 3. 'Oculopharyngeal distal myopathy'. As 2 but the distal muscles of the extremities

are most affected, sometimes cardiomyopathy. B. Forms occurring at an earlier age C. Forms with a different hereditary pattern

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Table 3. Differential Diagnosis

1. Myasthenia gravis 2. Progressive bulbar paralysis 3. Dystrophia myotonica 4. Polymyositis 5. Tumours and inflammation of the brain stem, meninges and base of the skull 6. Senile ptosis with organic stenosis of the oesophagus 7. Lues 8. Cachexia with extreme atrophy of the cranial muscles. 9. Ocular myopatny and ophthalmoplegia-plus.

includes several very serious conditions, whereas oculopharyngeal dystrophy

usually runs a benign course (Table 3). As it is a rather uncommon

condition the symptoms of the various forms and the possible further

diagnostic aids may not be known in general hospitals. The clinical

symptoms are summarized in Table 4. In classical cases (the

~ form) the diagnosis is not difficult, given the

characteristic autosomal dominant hereditary combination of ptosis and dysphagia in later life. When the disease appears at an early age or the

hereditary pattern is not clear additional investigations will be necessary

(Table 5). In the first place the myopathic character of the condition must be

demonstrated. In the early stages the C.P.K. level is usually slightly or

moderately raised (Barbeau 1966, 1969, Murphy & Drachman 1968). EMG examination of the levator palpebrae muscle is very easy to perform by the

transcutaneous route; the registration shows typical myopathic features: a rapidly attained interference picture associated with absent or very slight

motor effect, low voltage (normal 400-600 micronV) and short duration

(normal 1-3 millisec.).

A Tensilon test under EMG control is very desirable for the exclusion of

myasthenia. Biopsy of an ocular muscle is usually not necessary; a resected

Table 4. Symptoms of Oculopharyngeal Dystrophy

1. Autosomaldominant heredity 2. Usually occurring after the age of 50, often after the age of 60 years 3. Ptosis 4. Dysphagia 5. Involvement of other cranial muscles: dysphonia, rhinolalia aperta, dysarthria,

dysmasesia, facies myopathica 6. Often: involvement of other external ocular muscles 7. Sometimes: involvement of other skeletal muscles from cranial to caudal, proximal

more than distal 8. Rarely: distal muscles of extremities more affected than proximal muscles.

3~J

Table 5. Diagnostic Aids

I. Demonstration ofmyopathic character 1. Raised C.P.K. in blood 2. E.M.G. 3. Biopsy of ocular and skeletal muscle - light microscopy - histochemistry - electron microscopy (4. Autopsy)

II. Examination of the swallowing disorder 1. E.N.T. examination of pharynx and larynx 2. X-ray examination - motility of velum - act of swallowing with contrast - cineradiograpliy 3. Manometric examination

III. Examination of immuno-proteins in blood

piece of levator palpebrae muscle (obtained at a ptosis operation) usually only shows fibrosis. A biopsy specimen from a skeletal muscle is easier to

examine, even in cases where there is clinically only slight involvement of the skeletal muscles. On light-microscopy slight non-specific signs of

myopa thy are seen - centralisation of nuclei, increased variation in fibre diameter, fibrosis, myophagia and basophilia (El/is et al. 1966, Lewis 1966,

1969, Champion 1971, Fernandez-Martin et al. 1971, Lessell 1975). In addit ion specific features appear (Dubowitz & Brooke 1973): small angular

fibres which, on histochemical examination, stain dark in oxidative enzyme reactions, and so-called ' r immed vacuoles' (see Fig. 1), vacuoles with a

sharply punched-out edge surrounded by basophilic material. Angular fibres alone are not specific (Morgan Hughes & Lambert 1974).

On electron-microscopical examination only atypical anomalies have been described without indications of a mitochondrial myopathy (Rebeiz et al. 1969, Alberca et al. 1971, Johnson & Kuwabara 1974, Fournier et al. 1974, Man et al. 1976). These indications are to be seen in other forms of c.p.e.o. in particular in ophthalmoplegia-plus. Crystalline inclusions in the mitochondria are only described in one publication (Julien et al. 1974). Post-mortem examination has so far corroborated the primarily myogenic character of the condit ion (Schotland & Rowland 1964, Roberts & Bamforth 1968, Weitzner 1969, 1971, Fournier et al. 1974, Satoyoski & Kinoshita 1977).

The moti l i ty of the pharynx and larynx should also be examined. The absence of the pharyngeal reflex and weak movements of the soft palate, tongue and larynx can be demonstrated by the ENT specialist. X-ray

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Fig. 1. Rimmed vacuole in atrophic angular (skeletal) muscle fibre

examination of the velum reveals the myogenic origin of the rhinolalia

aperta which may be present; contrast examination shows stagnation in the piriform sinuses or even a false passage. Cine-radiography of the act of

swallowing can provide information about the degree of paresis of the pharyngeal muscles and the coordination between the contraction of the

lower pharyngeal muscles and the associated relaxation of the oesophageal sphincter. This reflex relaxation, which occurs when the rise in pressure in

the lower part of the pharynx is sufficient, is absent when the pharyngeal muscles are dystrophic (rise in pressure insufficient); this is the most

important cause of the dysphagia. On manometr ic examination (Van

Overbeek & Betlem 1977) this insufficient rise in pressure in the hypo- pharynx can be demonstrated.

Anomalies of the immuno-proteins in the blood have been described occasionally: a rise in gamma-globulin (Finkel et al. 1972, De Freitas &

Nascimento 1975), in particular a rise in IgA and IgG (Barbeau 1966, 1969, Russe et al. 1969, Campanella et al. 1975).

It is often unnecessary, and undesirable in older patients, to perform drastic diagnostic tests; this is certainly true in classical cases. The hereditary combination of ptosis of late onset with dysphagia is sometimes met by

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Fig. 2. Patient with marked ptosis and facies myopathica ('Hutchinson face')

chance in patients who are admitted to hospital for quite different conditions. Knowledge of the various forms of oc.ph.d, and the scope of quite simple diagnostic aids will often be sufficient to determine the correct diagnosis, even when the family history is deficient on account of the late

age of onset (no knowledge of the occurrence of the condit ion in relatives who live at a distance) and poor memory. A good example of the diagnostic

problems and possibilities is given by the patient to be described here.

A 72-year-old woman suffering from arterial hypertension, diabetes

mellitus, aorta sclerosis and slight dementia has had increasing bilateral ptosis for 7 years, recently followed by dysphagia with nasal regurgitation (Fig. 2). The family history was reported negative, but on an old family photograph ptosis was seen by the patient 's morner and a cousin on the mother ' s side (Fig. 3) had ptosis with dysphonia. Further investigation

of the family was not possible. No organic cause was found for the pat ient 's swallowing difficulties.

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Fig. 3. Patient's cousin: moderate ptosis

On ophthalmological examination pronounced bilateral ptosis with intact eye movements was found. To compensate the ptosis there was marked

contraction of the frontalis muscles and a backwards tilt of the head. The orbicularis oculi muscles were weak on both sides. Diabetic re t inopathy was seen in the fundus. On neurological examination dysphagia, dysarthria and dysmasesia were observed; there was weakness of the lingual and pharyngeal muscles, and also of the sternocleidomastoid and the trapezius. The muscles of the arms and legs showed some loss of power without atrophy. On examination of the blood a raised CPK level was found: 143 U/L (normal up to 110 U/L). The protein spectrum showed a rise in alpha-globulin and gamma-globulin; on immuno-electrophoresis a raised level of IgA globulin

was found. EMG examination of the levator palpebrae muscle produced a typically myopathic pat tern (Fi.g. 4). The ECG indicated bundle-branch block, the EEG was slightly slower than normal. LPEG revealed enlarged

ventricles and slight cortical atrophy. The patient refused all further exa- mination, such as ENT examination, Tensilon test and muscle biopsy.

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Fig. 4. EMG of levator palpebrae muscle. On maximum effort there was no motor effect but the EMG showed a full and rapidly achieved interference picture (high frequency discharges). The separate action potentials have an average duration of 1-2 millisec. (low normal) and an amplitude of 250 micron-Volt (low normal). Conclusion: myopathic picture.

In spite of the missing information, due to these refusals, and in spite of

the incomplete family history, we made the diagnosis of oculopharyngeal

dyst rophy on the basis of the ptosis of late onset and dysphagia, in

combination with slight weakness of other cranial muscles and muscles of

the extremities. The diagnosis was supported by the myopathic EMG of the levator palpebrae muscle, the raised levels of CPK and IgA globulin in the

blood and the very suggestive family history. We did not press this elderly patient to further examination; a muscle biopsy would probably have

provided too little specific information to be considered necessary for the diagnosis. The result of the diagnostic investigations would not affect the t reatment either; surgery of the cricopharyngeal muscle in extreme cases of dysphagia is the only t reatment to be considered (Peterman et al. 1964,

Montgomery & Lynch 1974).

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Authors' addresses: L.A.K. Bastiaensen Ophthalmological Department St. Elisabeth Hospital Tilburg The Netherlands

B.P.M. Schulte Neurological Department St. Elisabeth Hospital Tilburg The Netherlands

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