Oculopharyngeal muscular dystrophy (OPMD)

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  • Neuro-ophthalmology o I 65- 8107/97/US$12.00

    Neuro-ophthalmology- 1997, Vol. 17, No. 4, pp. 189-200 0 Eolus Press Buren (The Netherlands) 1997

    Accepted 8 November 1996

    Oculopharyngeal muscular dystrophy (OPMD)

    A. Neetens J. J. Martin

    B. Brais2 B. Wein3

    B. Dreuw4 C.C.Xjssen5 C. Ceuterick

    Born-Bunge Institute Neurosciences, University of Antwerp, Belgium

    Neuro-Sciences Research Institute, McGill University, Montreal, Canada

    Departments of Radiology and 4Surgery, R W H Aachen, Germany Department of Neurology, Elisabeth GH, Tilburg, The Netherlands

    Abstract Six OPMD families (one of five generations) confirm that the disease is autosomal dominant; mapping on chromosome 14 has been de- scribed. There is obvious anticipation of the cardinal symptoms ptosis and dysphagia. Hutchinson face is a hallmark of chronic progressive external ophthalmoplegia (CPEO), the correct diagnosis of which relies on careful history-taking and histopathology of a girdle muscle showing the rimmed vacuoles and the specific intranuclear filaments. Diet, fluid food, and early swallowing training is advised, as is the easy, hardly invasive Guyton- Friedenwald surgery for ptosis, which is adaptable during the evolution of the disease.

    Key words OPMD; ptosis; dysphagia; Guyton-Friedenwald ptosis pro- cedure; videofluorography

    Introduction The commonest and earliest hallmark of chronic progres- sive external ophthalmoplegia (CPEO) is blepharoptosis of the upper eyelid. Progressive blepharoptosis is overcome by contraction of the frontalis mus- cles and extension of the head backwards: Hutchinson face* (Fig. I).

    Although subclinically extraocular muscles are also involved, pupil motil- ity always remains normal. In about 50% of cases, the underlying myogenic disease process may affect other muscles: facial, cranial, upper and lower girdle, proximal and distal extremities, and, rarely, the cardiac muscle. I Reti- nal pigment epithelium may be involved (disturbed electro-oculography with normal electroretinography ).

    CPEO is actually a sign, which may be either isolated or a part of compli-

    Correspondence to: Prof. Dr. A. Neetens, Born-Bunge Institute Neurosciences, c/o Rubenslei 32, B- 201 8 Antwerp, Belgium

    Acknowledgements: The authors were supported by FGWO grant G. 3009.94.

    *J. Hutchinson, caricatured in Vanity Fair (September 27, 1890). retired from Moorfields in 1878 before completion of office; overwhelmed by the upcoming refractive work, he preferred to dedicate his life to the study of Neuro-Ophthalmology .

    Oculopharyngeal muscular dystrophy (OPMD) 189

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  • cated neurodegenerative disorders such as ophthalmoplegia plus in mito- chondrial cytopathy (Keams-Sayre syndrome, KSS) and in oculopharyngeal muscular dystrophy (OPMD).2-4 OPMD, described for the first time in 1915 in a French Canadian family by T a y l ~ r , ~ is relatively rare although distrib- uted worldwide, as appears from the

    Historically, there has been considerable confusion in the understanding of the CPEO sign, but the palpebro-pharyngeal form is a fairly well-defined category of rather purely muscular dystrophy. It is characterized by: I. late onset ptosis: during the 5th or 6th decade with subclinical anticipa-

    2. followed, accompanied, but seldom preceded by dysphagia, experienced

    3. with minimal mostly subclinical involvement of the extraocular muscles;

    4. a variable amount of skeletal muscle weakness.

    tion in younger generations;

    at first only with solid food and later on with liquids;

    and

    Material and methods Six families, one of them covering five gen- erations, were searched (Figs 2 and 3).

    Fig. I . Hutchinson caricatured in 'Vanity fair' (September 27, 1890). Note the reading glasses in his hand.

    Results

    FAMILY I (five generations) (Fig. 2 ) (EM: Fig. 3). Twenty-three members were clinically manifestly affected: nine with ptosis and dyspha- gia, six with ptosis, and eight with dysphagia. The nine members afflicted with ptosis and dysphagia were all older than 50 years of age.

    c.

    Fig. 2. Family tree of family 1.C.

    Family 1

    7" I I1 dl

    Palpebral ptosis + dysphagia (full blown OPMD) a Dysphagia

    Palpebral ptosis * Muscle biopsy 2

    190 A. Neetens et al.

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  • Generation I and I1 members were documented from history-taking. In generation 111, symptoms initially started at about 50 years (patients range from 55 to 73 years of age) (2 biopsies). Of the 6 ptosis patients in genera- tion IV, five were under 40 years of age. Of the eight dysphagia patients in generation IV, six were under the age of 40 years (3 members, ranging from 54 to 59 years, started symptoms at about age 45; 10 members, ranging from 3 I to 40 years, started symptoms at about 30 years of age). In generation V, all members were under 27 years of age, and one of them (25 years old) showed a beginning unilateral ptosis.

    All deltoid muscle biopsies confirmed the diagnosis. Infrared oculography in generation I11 members demonstrated (Fig. 4) a significant decrease in the maximum velocity of visually guided saccades, also present, but moderately affected in asymptomatic generation IV members (Fig. 5). Diplopia was al- ways absent and associated moving of yoke muscles seemed well-balanced. Electromyography of proximal muscles showed generalized low or moderate noncharacteristic muscular type weakness.

    25 .r 0 . 0 .

    T 25 or 0 . S

    Fig. 3. EM deltoid muscle biopsy (Family I .C.). Rimmed vacuoles (V) consisting of numerous autophagic vacuoles with multiple concentric pseudo-myelinic figures, multilamel- lated membranous structures and heterogenous dense bodies in an atrophic muscle fiber (Standard EM techniques. Scale = I pm).

    Fig. 4. Infrared reflection oculo- graphy. The eye movement record- ings show a severe decrease in the maximum velocity of the visually guided saccades to both sides (about 200 dg/l).

    Fig. 5. Infrared reflection oculograpy. Asymptomatic younger generation IV member of family I .C. The eye movement recordings show a moderate decrease in the maximum velocity of the visually guided saccades to both sides.

    2s or 0 . 0 1

    Oculopharyngeal muscular dystrophy (OPMD) 1 9 1

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  • 1.2. C.R. '16.06.1929, sister of C.H., generation 111. At age 52, this patient showed ptosis, nasal speech, dysphagia, and proximal and distal amyotro- phic muscle weakness. EMG confirmed myogenic potentials in the deltoid muscle. Biopsy of the latter showed rimmed vacuoles and a lack of baso- philia in part of the nucleoplasm. Immunohistochemistry demonstrated the presence of ubiquitin, amyloid 4, tau protein, and tubulin at the level of the rimmed vacuoles. Intranuclear 7-9 and I 8 nm filaments were demonstrated by EM. The rimmed vacuoles contained I 8 nm sarcoplasmic filaments.

    1.2. C.H. "15.10.1936, sister of C.R., generation 111. Ptosis had occurred since age 51, one year later dysphagia and Hutchinson face; infrared oculography confirmed extraocular muscle involvement. ERG was within normal limits. Light microscopy of the deltoid muscle biopsy on semithin sections revealed small rimmed vacuoles. EM demonstrated 7-9 nm intranu- clear filaments with palissade structure, typical rimmed vacuoles, and a few cores and rods.

    Fig. 6. Pathognomonic Hutchinson face.

    1.3. C.J. "07.og.rg33, brother of C.R. and C.H., generation 111. Ptosis pre- ceding dysphagia was present since about the age of 50 years; Hutchinson face (Fig. 6). Infrared oculography (Fig. 4) confirmed extraocular muscle involvement. Videofluorography demonstrated serious impairment of swal- lowing. Patient underwent successfully a Guyton-Friedenwald ptosis proce- dure (see Fig. 16).

    FAMILY 2 D.W. (Fig. 7) (EM: Figs 8-1 I).

    2.1. D.WA. '14.11.1928, twin sister of D.W.R. Ptosis, nasal speech, and dysphagia started at about 45 years of age. EMG showed slight myogenic involvement of the facial muscles. Deltoid muscle biopsy showed rimmed

    Family 2 Family 3

    Family 4

    m OPMD Fig. 7. Family trees of families statusunknown

    2.D.W., 3.T.T., 4.B.M, and 5.P.G. * Muscle biopsy

    Family 5

    'I" 7

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  • vacuoles and typical 7-9 nm intranuclear filaments, in part parallel building bundles or palissades. Nuclei of normal looking fibers contained dito fila- ments, not present in the sarc~plasm.~

    2.2. D.WR. '14.11.1928, twin sister of D.W.A. Father, paternal uncle, and cousin were similarly OPMD-affe~ted.~ Same slow development of symp- toms from about 45 years on. EMG was within normal limits. Rimmed vac- uoles were seen, mainly in small atrophic fibers, and somewhat enlarged nuclei with central decrease of basophilia. Tau protein, tubulin, and ubiquitin (to a lesser extent) were present in rimmed vacuoles. EM con- firmed the presence of 7-9 nm intranuclear filaments, 18 nm sarcoplasmic filaments, and rimmed vacuoles.

    FAMILY 3 T.T. '26.1 1.1921 (Fig. 7). Familial ptosis and dysphagia were manifest in the patient since the age of 55 years. EMG at age 65 was within normal limits. Important variations were seen in the size of muscle fibers, rimmed vacuoles, and nuclei with clearer central chromatine. Immunohisto- chemistry demonstrated very small amounts of amyloid precursor protein, tau protein, and tubulin in or around a few rimmed vacuoles. EM confirmed typical 7-9 nm filaments in the nuclei and in rimmed vacuoles and also I 8 nm sarcoplasmic filaments.

    FAMILY 4 B.M. O31.07.1932 (Fig. 7). Familial ptosis and dysphagia was present since age 50 (sister "1933, mother since her ~ O S , and maternal grand- father were also OPMD-affected). EMG showed mild myogenic changes in upper extremity muscles. Single fiber EMG ruled out any disturbance of the neuromuscular transmission. Many rimmed vacuoles and eosinophilic changes were seen in enlarged subsarcolemmal nuclei. The rimmed vacuoles

    Fig. 8. EM deltoid muscle biopsy (Family 2.D.W.). Characteristic 7-9 nm filaments with a typical palissade structure (arrowheads) in a sub- sarcolemmal nucleus (Standard EM techniques. Scale = I pm).

    Fig. 9. EM deltoid muscle biopsy (Family 2.D.W.). Higher magnifica- tion of the 7-9 nm intranuclear filaments (Standard EM techniques. Scale = I pm).

    Oculopharyngeal muscular dystrophy (OPMD) 193

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  • Fig. 10. EM deltoid muscle biopsy (Family 2.D.W.). Many bundles (arrows) of I 8 nm sarcoplasmic filaments close to the rimmed vacuoles (V). (Standard EM techniques. Scale = I pm).

    Fig. XI. EM deltoid muscle biopsy (Family 2.D.W.). Higher magnifica- tion of the 18 nm sarcoplasmic twist- like pattern filaments (arrowhead). (Standard EM techniques. Scale = I pm).

    contained amyloid precursor protein, amyloid A4, ubiquitin, and tau protein. EM confirmed 7-9 nm intranuclear filaments, rimmed vacuoles, and 18 nm sarcoplasmic filaments.

    FAMILY 5 P .J . "15.12.1924 (Fig. 7) (EM: Fig. 12). Father presented with bilateral ptosis and patient developed ptosis about the age of 50, soon fol- lowed by dysphagia. Paresis of facial and proximal upper and lower extrem- ity muscles was found. EMG showed mixed mild neurogenic and myogenic features. Numerous atrophic fibers contained many rimmed vacuoles. Very large subsarcolemmal nuclei were seen, with sometimes a less basophilic center (H and E stain). Immunohistochemistry demonstrated amyloid pre- cursor protein, tau protein, and ubiquitin in and around rimmed vacuoles. EM confirmed 7-9 nm intranuclear filaments, often building palissades, and 18-20 nm sarcoplasmic filaments were observed.

    FAMILY 6 V.B.J. '23.04.1932. Ptosis and dysphagia occurred at age 52. His brother presented with the symptoms at age 57 as did their father, sug- gesting autosomal dominant transmission. Light microscopy (LM) of a del- toid muscle biopsy revealed type I fibers, larger than type I1 fibers, some of them atrophic, with nonspecific rimmed vacuoles (Fig. I 3). Infrared oculography also confirmed in this family the saccadic delay of extraocular muscles, although no diplopia.

    Genetics The disease is autosomal dominant with minimal variability in expression and 100% penetrance. The age of onset can vary in a given fam- ily, but this may be only apparent because increased awareness detects obvi- ous anticipation with subclinical symptoms, as demonstrated in family I .C.

    194 A. Neetens et al.

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  • The locus of OPMD maps to the region of the cardiac alpha- and beta- myosin heavy ch in genes (one cardiac involvement)' on chromosome 14 Q

    A package of genomic DNA from family I .C (members of generation I11 and IV) was submitted for genetic typing. Although it was too small for link- age analysis (maximum lod score of 0.29 with MYH7.24), it is clear that the affected siblings share an area of chromosome I 4 in the region of the OPMD gene. This suggests that family 1.C is also linked to the same locus as French Canadian families. Furthermore, this family shares a small region (i.e., haplotype for markers DrqSggo, MYH7.24, and MYH7.r) with at least one larger European family, making it even more probable that they are linked to the same region and share an ancestral mutation with other Euro- pean families.

    I I.2-913.'0

    Histopathology KSS is characterized by ragged red fibers and by widespread mitochondrial cytopathy. Several uncommon and still incom- pletely defined syndromes that also affect extraocular, pharyngeal, and skel- etal muscles are believed to be myopathic: ragged red fibers are not a char- acteristic feature nor are mitochondrial abnormalities.

    Histological data support a genuinely muscular origin in OPMD.9*' The presence of typical but not specific rimmed vacuoles (LM) (Fig. I 3) and characteristic OPMD-type nuclear filaments in all muscle fibers (electron microscopy) has been demonstrated (deltoid muscle biopsy), as have small angular fibers which stain directly with oxydative enzyme reactions (ATP- ase). The rimmed vacuoles have a sharply out-punched appearance: they stain red with trichrome stain and basophilic with H and E stain.

    Electron microscopy confirms that the rimmed vacuoles correspond to areas of focal destruction (autophagic nature) (Figs 3,8-I 2). Ultrastructural features were similar in all biopsies. Characteristic 7-9 nm filaments were

    Fig. 12. EM deltoid muscle biopsy (Family 5.P.J.). Subsarcolemmal nucleus with 2 clear central zones (arrows) of characteristic 7-9 nm filaments. (Standard EM techniques, fixation in glutaraldehyde, postfixation in osmium tetroxide, embedding in araldite, staining with uranyl acetate and lead citrate. Scale = I pm).

    Fig. zj. LM deltoid muscle biopsy (Family 5.P.J.). Rimmed vacuoles (H and E) (oc.40bj.10).

    Oculophatyngeal muscular dystrophy (OPMD) 195

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  • found in subsarcolemmal nuclei from normal-looking muscle fibers (Figs 8,9,12). These filaments were not present in the sarcoplasm. They could be grouped parallel to each other, building a typical interwoven palissade struc- ture. Rimmed vacuoles were prominent and consisted of numerous autopha- gic vacuoles with pseudo-myelinic figures, multilamellated membranous structures, and heterogenous debris (Fig. 3). Many bundles of 18 nm sarco- plasmic filaments were observed in the neighborhood of the rimmed vacu- oles (Figs IO,II ) . Some 18 nm filaments appear twisted. These filaments were not membrane-bound and can be distinguished from the typical 7-9 nm intranuclearfilaments. A few cores and rods were also found in one case.

    Dysphagia Recent pharyngeal manometric and imaging methods2' al- low a correct diagnosis and detect preclinical, possibly later life-threatening, hypotonic esophageal sphincter activity, which may be relieved by train- ingllogopedic treatment in early stages.22

    Videofluorography was performed by examining patients in an upright position in lateral and frontal view during the swallowing of small amounts (8- I 2 ml) of water-soluble contrast media (Ultravist 370,370 mg iodine/ml, Schering, Berlin, Germany). All images were recorded on magnetic tape (Umatic Sony, Cologne, Germany) for further evaluation. The images were reviewed on a videorecorder and afterwards digitized with a matrix of 256 * 256 pixels with 8 bit grey level (Mipron, Kontron, Munich, Germany).

    Movement of epiglottis, contraction of the pharynx and propulsion of the tongue, opening of the upper esophageal sphincter as well as the movement of the esophagus were assessed qualitatively, and afterwards partly quantita- tively by computer analysis. The time course and the amount of movement of the swallowing act was assessed using a dedicated image analysis C-pro- gram running on an Atari TT computer (Atari Corp, Soden, Germany). This program returns the amount of grey level changes in up to 49 subsquares of the original image during the time course by giving the mean of the subtrac- tion of the corresponding pixel values of successive images for a specific section of the image (Figs I 4, I 5).

    Fig. 14. Radio-anatomical distribu- tion of the analyzed videofluoro- graphy image segments. The grid demonstrates the segments used in the movement analysis program for evaluation of the pharyngeal bolus passage. The numbers of the segments run from I (upper left) to 49 (lower right) columnwise. Obviously some segments e.g. 7 and 14) will not show any movement, because lack of contrast dye.

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  • Fig. 15. Analysis of the movement of the pharynx and upper esophagus. Graphs show the results of automatic movement analysis of two examined generation I11 members and two examined generation IV members of Family I .C., derived from Ultravist 370 (Iopromid) swallow X-rays. All scaling factors are the same: time in abscissa and relative extent of movement in arbitrary units in ordinate. Younger member generation IV (upper left). Sharply defined double-swallow act (2 and 4.5 seconds); pharynx clearance: no contrast changes and is complete within 1 . 1 seconds (normal). Older member generation IV (upper right). Slight pharynx clearance deficiency, resulting from slight weakness of the pharyngeal constrictor muscles (curves 26 to 28 from bottom in the time range between I .o to 6.0 seconds). However, the swallowing act itself presents with normal delay (0.0 to 0.9 seconds). Younger member generation 111 (lower left). Obvious clearance deficiency ( I .3 to 3. I seconds); slow pharynx movement is visible ( I .o to I .4 seconds). No aspiration. Older member generation III (lower right). Most pronounced dysphagia: no clearance at all with all time segments involved. Delayed tongue motion (curves 26 to 32 from bottom, I .4 to 2.6 seconds). No normal swallowing act. Dysphagia causes intermittent aspiration.

    Time curves revealed the amount of movement in the specific sections of the viewing field during the swallowing act. A younger patient of generation IV (3 I years) showed normal movements of the upper tract, while her older sister (41 years) presented with a slightly reduced motility of the esophagus, but no impairment of swallowing. The movements of an older patient of generation I11 (59 years) were more severely impaired, demonstrating a lack of emptying of the lateral recessi. Most severe impairment of the swallowing act was observed in a patient of generation I11 (65 years) with nearly no ac- tivity in the esophagus and multiple aspirations of contrast media.

    The examination disclosed that only the two older patients showed aspira- tion of severe amounts of contrast media during their swallowing efforts.

    Oculopharyngeal muscular dystrophy (OPMD) 197

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  • The oldest patient showed very severe aspiration, suggesting the need for percutaneous enterogastrostomy (PEG). However, this depends on the clini- cal appearance of possible aspiration pneumonia. The younger patient of generation 111 demonstrated no significant aspiration, but emptying of the pharynx did not occur optimally. More severe complications may be ex- pected later on.

    The swallowing act of the younger patient in generation IV showed a pretty well-defined double swallow, whereas the older member of generation IV showed delayed movements in the pharyndesophagus, with late clearing. The subject had a protruded double swallow, not showing complete rest be- tween both parts of the swallowing act, while the older patients of generation 111 performed multiple swallowing acts in the pharyngeal/esophageal area, demonstrating inability to clear the tract sufficiently.

    Liquid videojluorography has conjirmed that the dysphagia is caused by affected muscles of the hypopharynx and the upper third of the esophagus. Severe complications may arise: aspiration pneumonia, inanition, and ca- chexia are indications for PEG. Younger patients do not need any treatment, in spite of their slight movement handicaps. Adaptation of the diet (liquid food) in less severe cases of dysphagia may be necessary. Swallowing train- ing by specially educated logopedics is the next step.

    Discussion The correct neurornuscular diagnosis of a Hutchinson-face patient rests mainly on careful history-taking (family, relatives, ptosis, dys- phagia) and a biopsy of a proximal girdle muscle, even in the subclinical state. Actual histopathology with several stains (H and E, modified Gomori- trichrome, histochemical stains for mitochondria1 oxydative enzymes, ATP- ase) and electronmicroscopic studies are decisive for diagnosis (intranuciear 7-9 nm $laments and less speciJc rimmed vacuoles). Electromyography of an extraocular muscle may establish the diagnosis of an ocular myopathy, but the procedure is not routinely done. Histopathological evaluation of ex- traocular muscles remains controversial as already mentioned by Daroff et al. ,23 who described spongiform encephalopathy with CPEO, mimicking ocular my~pathy.~.~

    Recently (1993)~ Hardiman et al.26 described neuropathic findings in OPMD with involvement of the muscles of the extremities and advanced muscular wasting, but more pronounced extraocular muscle participati~n.~~ Long-standing denervation of skeletal and EO muscles as well may produce characteristic changes of m y ~ p a t h y . ~ . ~ ~ - ~ Only one of our patients (family C, generation 111) presented with mental disturbances, dysphagia, and seri- ous muscular wasting of all four extremities while ptosis appeared only min- imally and manifest extraocular muscle involvement was absent.

    Nevertheless, infrared oculography has demonstrated in our cases a signif- icant decrease of the maximum velocity of visually guided saccades indicat- ing that the extraocular muscles are also affected, although ocular motility and yoke-muscular activity do not seem to be clinically impaired and never give rise to diplopia. Further neurological investigations showed no pathog- nomy: proximal muscle weakness may be present but is not pathognomo- nic.

    Incoordination of the pharyngeal muscles during swallowing leads to pull- ing of material in the piriform sinuses. The progressive weakness ofthe pha- ryngeal muscles is further complicated by incomplete relaxation of the upper

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  • esophagus sphincter. This relaxation is caused by an insufficient buildup of pressure in the hypopharynx. Efficient cooperation between hypopharyngeal contractions and sphincter relaxations is lost when the muscular activity of the hypopharynx decreases. This insufficient buildup of pressure in the hy- popharynx and the concurrent insufficient relaxation of the sphincter with abnormal pressure in the upper esophagus can be studied accurately by pha- ryngeal manometric and imaging methods. They allow correct earlypreclin- ical diagnosis of later perhaps life-threatening hypotonic esophageal sphinc- ter activity, which may be relieved by adapted diet and specialized logopedic training treatment in early stages. To avoid severe complications such as aspiration pneumonia, percutaneous enterogastrostomy may be indicated.

    Ptosis may best be approached by the Guyton-Frieden wald technique: no muscle is resected and a nylon thread 2/0 may pull up or lower the upper eyelid as required depending on the evolution of the disease. As there is no diplopia, the procedure improves vision considerably allowing patients to see without problems, normalizing head posture and releasing the frontalis muscle contractions (Fig. 16). Even in advanced cases, there is no diplopia and eye movements are hardly limited.

    Fig. 16. Hutchinson face treated by Guyton-Friedenwald procedure.

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