Oculopharyngeal dystrophy diagnostic problems and possibilities

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  • Documenta Ophthalmologica 46,2: 391-401, 1979



    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 malnutrition 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


  • muscles. The disease has a descending course and the proximal muscles are more affected than the distal ones, 'oculopharyngeal skeletal myopathy' (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 condition 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 addition 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 condition 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 dystrophy 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 myopathy 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 dystrophy (Teasdall et al. 1964, Ellis et al. 1966, Levy & Scaff 1974).

    A completely different hereditary pattern makes the diagnosis of oculopharyngeal dystrophy 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 dystrophy 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


  • 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.


  • 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 myopathy 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 addition specific features appear (Dubowitz & Brooke 1973): small angular fibres which, on histochemical examination, stain dark in oxidative enzyme reactions, and so-called 'rimmed 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 condition (Schotland & Rowland 1964, Roberts & Bamforth 1968, Weitzner 1969, 1971, Fournier et al. 1974, Satoyoski & Kinoshita 1977).

    The moti l ity 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


  • 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 manometric 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


  • 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 condition 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 patient's swallowing difficulties.


  • 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 retinopathy 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 pattern (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.


  • 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 dystrophy 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 treatment either; surgery of the cricopharyngeal muscle in extreme cases of dysphagia is the only treatment to be considered (Peterman et al. 1964, Montgomery & Lynch 1974).


    Aarli, J.A. Oculopharyngeal muscular dystrophy. Acta neurol.scand. 45:484-492 (1969).

    Alberca, R., Coca, M.C., Gil Peralta, A., G6mez Bosque, P. & Navarro, A. Miopatia


  • ocular familiar (Estudio immunoelectrofor6tico y de microscopfa electr0nica). Rev.clin.esp. 123:45-52 (1971).

    Arnould, G., Tridon, P., Thiriet, M., Floquet, J., Andre, J.M. & Andr&Brichet, B. Myopathie oculo-pharyngo-squelettique. Apropos de trois cas. Rev.Oto-neur~- ophtal. 41:228-240 (1969).

    Barbeau, A. The syndrome of hereditary late onset ptosis and dysphagia in French Canada. In: Symposium fiber progressive Muskeldystrophie - Myotonie - Myas- thenie. 1965. Ed. by E. Kuhn, Berlin, Springer-Verlag, 102-109 (1966).

    Barbeau, A. Oculopharyngeal muscular dystrophy in French Canada. Presidential address. In: Progress in Neuro-Ophthalmology. Vol. 2. Proceedings of the 2nd International Congress of Neuro-Genetics and Neuro-Ophthalmology, 1967. Ed. by J.R. Brunette and A. Barbeau, Amsterdam, Excerpta Medica Foundation, International Congress Series 176:3 (1969).

    Campanella, G., Filla, A., Serlenga, L., Federico, A. & Buscaino, G.A. Myopathie oculo-pharyng6e. Observations histochimiques musculaires et dosage des immuno- globulines du s~rum dans une famille italienne. Rev.neurol. 131:615-628 (1975).

    Champion, P. Oculopharyngeal muscular dystrophy. Proe.roy.Soc.Med. 64:45 (1971). Cogan, D. (Chairman), Burian, H.M., Osserman, K. & Walton, J.N. Classification of

    primary ocular myopathies. A panel. In: Progress in Neuro-Ophthalmology, vol. 2. Proceedings of the 2rid International Congress of Neuro-Genetics and Neuro-Ophthal- mology, 1967. Ed. by J.R. Brunette and A. Barbeau, Amsterdam, E Medica Foundation, In ternational Congress Series 176:44-49 (1969).

    Crone, R.A. Chronic progressive external ophthalmoplegia. In: Diplopia. Ed. by R.A. Crone, Amsterdam, Excerpta Medica, 369-374 (1973).

    Dotsenko. S.N. O bul'barno-oftal' moplegicheskoi trome miopatii. Zh. Neuropat. Psikhiat. 64:811-815 (1964).

    Dubowitz, V. & Brooke, M.H. Ocular and oculopharyngeal dystrophies. In: Muscle biopsy: A modern approach. Ed. by V. Dubowitz and M.H. Brooke. (Major problems in neurology, vol. 2., ed. by J.N. Walton). Philadelphia, IY.B. Saunders Company, 231-241 (1973).

    Ellis, J.G., Dalessio, D.J. & Lowe, H.M. Ocular myopathy. Disease of muscle in the elderly. Amer. J. Ophthal. 61:167-169 (1966).

    Felden, E. & Mikl6s, A. [m Erwachsenenalter sich entwickelnde heredit/ffe Ptose. Klin.Mbl.Augenheilk. 153:47-52 (1968).

    Fernandez-Martin, F., Peres Serra, J., Juan, P. de, Grau Veciana, J.M., Bueno, J. & Barraquer-Bordas, L. Distrofia muscular oculofarfiagea. Rev.clin.esp. 139:525-532 (1975).

    Finkel, N., Vaz Ribeiro, A.R. & Rodriques Sampaio, M.C. Miopatia ocular descendente. Arch.Neuro-psiquiat.{S.Paulo) 30:148-157 (1972).

    Fournier, M., Vital, C., Vallat, J.M., Le Blanc, M., Coquet, M., Pourrat, A., Bouvier, E. & Jeanneau, M. Etude d'une famiUe atteinte de myopathie oculo-pharyng~e avec examen anatomique et ultrastructural d'une observation. Bord.m~d. 8:1185-1189 (1974).

    Freitas, M.R.G. de, & Nascimento, O.J.M. Miopata ocular descendente. Arch. Neuro- psiquiat. (s. Paulo) 33:161 -167 (1975).

    Fried, K., Arlozorov, A. & Spira, A. Autosomal recessive oculopharyngeal muscular dystrophy. J.med.Genet 12:416-418 (1975).

    Goto, I., Kanazawa, Y.. Kobavashi, T., Murai, Y. & Kuroiwa, Y. Oculopharyngeal myopathy with distal and cardiomyopathy, d. Neurol. Neurosurg. Psychiat. 40: 600-607 (1977).

    Graf, K. Myopathia oculo-pharyngealis tarda hereditaria. Pract.oto-rhino-laryng. (Basel) 33:203-208 (1971).

    Johnson, C.C. & Kuwabara, T. Oculopharyngeal muscular dystrophy. Amer.J.Ophthal. 77:872-879 (1974).


  • Julien, J., Vital, C., Vallat, J.M. Vallat, M. & Le Blanc, M. Oculo-pharyngeal muscular dystrophy. A case with abnormal mitochondrial and 'fingerprint' inclusions. J.neuroLSci. 21:165-169 (1974).

    Lessell, S. Chronic progressive external ophthalmoplegia. In: Neuro-Ophthalmology, vol. 8. Symposium of the University of Miami and the Bascom Palmer Eye Institute, December 1975. Ed. by J.S. Glaser and J.L. Smith. St. Louis, The C.V Mosby Company, 216-236 (1975).

    Levy, J.A. & Scarf, M. Distrofia muscular progressiva. Forma oculofarfngea. Rev.Hosp.Clin.Fac.Med.S.Paulo 29:224-226 (1974).

    Lewis, I. Late-onset muscle dystrophy: oculopharyngoesophageal variety. Canad.med.- Ass.J. 95:146-150 (1966).

    Lewis, I. Oculopharyngeal muscular dystrophy. A family study. In: Progress in Neuro-Ophthalmology. Vol. 2. Proceedings of the 2nd International Congress of Neuro-Genetics and Neuro-Ophthalmology, 1967. Ed. by J.R. Brunette and A Barbeau. Amsterdam, Excerpta Medica Foundation, International Congres Series 176:4-11 (1969).

    Lundberg, P.O. Ocular myopathy with hypogonadism. Acta neurol.scand. 38:142-155 (1962).

    Man, H.X., Mikol, J., Guillard, A. & Boudin, G. (1976): Etude anatomoclinique d'une myopathie ocu!o-pharyng6e. Bull.Soc.Ophtal.Fr. 76:23-30 (1976).

    Manigand, G., Lucsko, M. & Deparis, M. Les myopathies oculaires. Apropos d'une observation familiale de dystrophie musculaire oculo-pharyng6e et squelettique d~but tardif. Sem.Hdp.Paris 45:2803-2808 (1969).

    Matsunaga, M., Inokuchi, T., Ohnishi, A. & Kuroiwa, Y. Oculopharyngeal involvement in familial neurogenic muscular atrophy. J. Neurol.Neurosurg.Psychiat. 36:104-111 (1973).

    Millefiorini, M. & Fifippini, C. Distrofia muscolare oculofaringea. Riv.Neurol. 37: 327-337 (1967).

    Montgomery, W.W. & Lynch, J.P. Oculopharyngeal muscular dystrophy, treated by inferior constrictor myotomy. Trans.Amer.Acad.OphthaLOtolaryng. 75:986-993 (1971).

    Morgan-Hughes, J.A. & Lambert, C.D. Chronic progressive external ophthalmoplegia. Trans.Amer.neuroLAss. 99:35-38 (1974).

    Murphy, S.F. & Drachman, D.B. The oculopharyngeal syndrome. J.Amer.med.Ass. 203:1003-1008 (1968).

    Myrianthopoulos, N.C. & Brown, I.A. A genetic study of progressive spinal muscular atrophy. Amer.J.hum.Genet. 6:387-411 (1954).

    Noyes, A.P. A case of myasthenia gravis with certain unusual features. R.I.med.J. 13: 52-59 (1930).

    Overbeek, J.J.M. van & Betlem, J.C. Myotomie van de faryngo-oesofageale sphincter bij hypopharynxverlamming op geleide van drukregistraties. Ned.T.Geneesk. 121: 705-709 (1977).

    Petit, H. Myopathie oculo-pharyng6e. Rev. Oto-neuro-oph tal. 43: 303-310 (1971). Peterman, A.F., LiUington, G.A. & Jamplis, R.W. Progressive muscular dystrophy with

    ptosis and dysphagia. Arch.Neurol.(Chic.) 10:38-41 (1964).i, Rebeiz, J.J., Caulfield, J.B. & Adams, R.D. Oculo-pharyngeal dystrophy - a presen-

    escent myopathy. A clinico-pathologic study. In: Progress in Neuro-Ophthalmo- logy. Vol. 2. Proceedings of the 2nd International Congress of Neuro-Genetics and Neuro-Ophthalmology, 1967. Ed. by J.R. Brunette and A. Barbeau. Amsterdam, Excerpta Medica Foundation, International Congress SeNes 176:12-31 (1969).

    Roberts, A.H. & Bamforth, J. The pharynx and esophagus in ocular muscular dystrophy.Neurology (Minneap.) 18:645-652 (1968).

    Russe, H., Busey, H. & Barbeau, A. Immunoglobulin changes in oculopharyngeal dystrophy. In: Progress in Neurogenetics. Vol. 1. Proceedings of the 2nd


  • International Congress of Neuro-Genetics and Neuro-Ophthalmology, 1967. Ed. by A. Barbeau and J.R. Brunette, Amsterdam, Excerpta Medica Foundation, h2ternational Congress Series 175:62-65 (1969).

    Satoyoshi, E. & Kinoshita, M. Oculopharyngodistal myopathy. Report of four families. Arch.Neurol.(Chic.) 34:89-92 (1977).

    Scbotland, D.L. & Rowland, L.P. Muscular dystrophy. Features of ocular myopathy, distal myopathy and myotonic dystrophy. Arch.Neurol. (Chic.) 10:433-445 (1964).

    Taylor, E.W. Progressive vagus-glossopharyngeal paralysis with ptosis: A contribution to the group of family diseases. J.nerv.ment.Dis. 42:129-139 (1915).

    Teasdall, R.D., Schuster, M.M. & Walsh, F.B. Sphincter involvement in ocular myopathy. Arch.Neurol. (Chic.) 10:446-448 (1964).

    Thiel, J.H. Chronic progressive ophthalmoplegia with extra-ocular extension (ocular myopathy). Folia psychiat.neerl. 57:554-563 (1954).

    Victor, M., Hayes, R. & Adams, R.D. Oeulopharyngeal muscular dystrophy. A familial disease of late life characterized by dysphagia and progressive ptosis of the eyelids. New Engl.J.Med. 267:1267-1272 (1962).

    Weinstein, I.H. Dos familias con miopatia ocular. Estudio clinico, gen~tico, histo- 16gica y electromiogr~fieo. Rev. neurol. B. Aires. 22:143-149 (1964).

    Weitzner, S. Changes in the pharyngeal and esophageal musculature in oculopharyngeal muscular dystrophy. Report of two cases.Amer.J.dig.Dis. 14:805-810 (1969).

    Weitzner, S. The histopathology of the pharynx and esophagus in oculopharyngeal muscular dystrophy. Case report and literature review. Amer.J.Gastroent. 56: 378-382 (1971).

    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