Progressive dystrophy of the external ocular muscles (ocular myopathy). By L. G. Kiloh and S. Nevin (From the Neurological Department, King's College Hospital.) Brain 1951: 74; 115–143.
Cambridge
Making the point that subsequent involvement of the ocular muscles rarely complicates the regional or generalized weakness with which progressive muscular dystrophy presents, and then only in cases of Landouzy-Dejerine myopathy (facioscapulohumeral dystrophy) or myotonic dystrophy, (Leslie) Kiloh (1917–1997) and (Sam) Nevin (1905–1979) have noted ‘a number of cases of myopathy ... in which ocular involvement was the primary and predominant feature’. ‘In some ... only the levators of the upper lids were affected, but in others a complete external ophthalmoplegia developed over many years. The question arises whether these cases constitute a clinical group justifying the title ocular myopathy or whether they are merely rare atypical forms of muscular dystrophy ... the pathology of those cases described as chronic progressive external ophthalmoplegia [is] considered by most authors to result from degeneration of the oculomotor nuclei, although no clear pathological anatomy has been established ...’. They describe five cases.
S.S. developed progressive ptosis and ophthalmoplegia in his early 40s retaining only a few degrees of eye movement in any direction; he also shows facial, neck, scapular and upper limb weakness and has retained tendon reflexes (Fig. 1A). R.S. noticed drooping lids in his early 20s followed later by generalized limb weakness; eye movement is limited to 10° in any direction and he has generalized facial, girdle and limb weakness with reduced but preserved tendon reflexes. C.N. developed asymmetrical ptoses in his early 40s; he has partial ophthalmoplegia and weak neck muscles. F.C. developed asymmetrical ptoses from the age of 30; he has slight ophthalmoplegia and facial weakness. W.F. has complained of progressive drooping of the eyelids since her mid-20s but has no other symptoms or signs. She has been examined electrophysiolgically; muscle action potentials are weak with no evidence for denervation and no response to electrical stimulation (although oral lemon juice improves the ptoses for around 15 min unless the throat is anaesthetized with amethocaine: Fig. 1B–D).
|
Tissue taken at surgery to correct the ptoses is available in four patients and has been examined with assistance from Prof. (Henry) Magnus (1909–1967). Samples of the orbicularis oculi and medial rectus, and to a lesser extent the vastus lateralis, in S.S. show atrophy, variation in surviving fibre size and fibrosis: affected fibres are eosin rich and have centrally placed dark staining nuclei; some surviving fibres show proliferated sarcolemmal and pyknotic nuclei; striatal staining with Heidenhain's iron haematoxylin is generally reduced and nerve twigs caught up in the biopsy are normal (Fig. 2). Muscle removed from the deltoid of R.S. shows scattered fibre abnormality with granular and vacuolar degeneration, increased sarcolemmal nuclei and loss of striatal features using stains for haemotoxylin. Superior rectus muscle taken from C.N. proves not to be an adequate sample from which to draw any useful conclusions. In W.F., the affected ocular muscles show atrophy with hyaline changes and intense eosinophilia; striatal patterning is absent. A sixth case is briefly mentioned in a footnote (to page 132) as having ocular myopathy based on biopsy of the right inferior oblique muscle, but this is not described in any detail. Kiloh and Nevin are not in doubt that these patients all have muscle disease. But can any nosological precision be adduced from the histological appearances, or more rigorous survey of the existing literature?
|
Correcting authors such as Bristow (1885) and Gowers (1888) who concluded that their patients presenting with ophthalmoplegia followed by limb weakness had Landouzy-Dejerine dystrophy manifesting the rare complication of ophthalmoplegia, and citing material described by Fuchs (1890) and Silex (1897), Treacher Collins (1909), McMullen and Hine (1921), Desogus (1923), Pelnar (1924), Sterling (1929), Poe (1933), Elliot (1939), Martin (1936) and Thiébaut et al. (1941) [see original paper for citations]—in which primary and slowly progressive external ophthalmoplegia began in childhood or early adult life with or without later involvement of other muscles many nevertheless showing sarcolemmal abnormalities—Kiloh and Nevin feel comfortable classifying their cases as having a muscular dystrophy restricted to the levator muscles that can best be dubbed ‘ocular myopathy’. But still they have a nagging doubt whether or not it is valid to separate ocular myopathy from cases described as ‘chronic progressive external ophthalmoplegia’, or ‘chronic progressive "nuclear" ophthalmoplegia’ in which the clinical evolution is remarkably similar to that seen in their five patients. Are these all examples of the same primary muscle disease?
‘The conception that this group of cases results from degeneration of the oculomotor nuclei has no pathological basis’. For Drs Niloh and Nevin, this formulation is an error initiated by Moebius (1900) and by Willbrand and Sanger (1900) and perpetuated uncritically by many others. In fact, the problem dates from 1868 [reported by (Albrecht) von Graefe (1828–1870)] and they tabulate details of 100 cases (some already mentioned) to 1948 in which the same mistake has been made: ‘they resemble closely ... [the] general clinical features . of ocular myopathy already described ... [but] it is improbable that two distinct pathological processes would give rise to such similar clinical findings and ... there is no satisfactory evidence of an isolated nuclear degeneration as the cause of this condition’. That said, autopsy in one case (Langden and Cadwalader, 1928) has revealed neuronal loss in the brainstem oculomotor nuclei with apparent axonal attrition in the dependent cranial nerves although no abnormalities were seen in surviving fibres. But Kiloh and Nevin find this case, not adequately controlled and without examination of the ocular muscles, unconvincing. Nor is much to be made of one other autopsied case reported to show neuronal abnormalities and ocular muscle atrophy judged to be ‘of a secondary type ... [but] not very revealing’. Kiloh and Nevin challenge those who espouse the neuronal doctrine of chronic progressive external ophthalmoplegia to prove that the muscle changes are secondary to neurodegeneration and not, as they themselves believe, part of a primary disease process. In a sweeping statement they conclude that ‘all cases listed in the appendix are considered by us to be cases of progressive dystrophy of the external ocular muscles’. But they concede that ‘ ... it is not denied that the [oculomotor] nuclei may be involved in degenerative conditions affecting the central nervous system ... external ophthalmoplegia [may be] associated with widespread muscular atrophy and signs of pyramidal tract disturbance. Such cases appear, however, to be extremely rare’. Thus, for these commentators writing in 1951, chronic progressive ophthalmoplegia clearly constitutes an appreciable proportion of cases showing progressive muscular dystrophy. Typically, onset is before the age of 30 with ptosis followed within 5 years by symmetrical or asymmetrical external ophthalmoplegia that progresses slowly over several decades, often with periods of apparent stability. Males and females are equally affected and 50% of patients have a family history. The demeanour is characteristic: the forehead wrinkled; the head tilted backwards; the face impassive due to muscle weakness and the shoulders not infrequently dropped. The separation from dystrophia myotonica is clear and ‘ocular myopathy appears to approach most closely in its general characteristics to the Landouzy-Dejerine type of this disease. It is not our intention to separate it rigidly from other types of myopathy, as the pathological changes found in the muscles are not in any way distinctive’. And so they leave it, with muscle biopsies that have not been stained to reveal their mitochondrial secrets.
Within a few years, Kearns and Sayre described ‘Retinitis pigmentosa, external ophthalmophegia, and complete heart block: unusual syndrome with histologic study in one of two cases’ (1958) and the phenotype of progressive external ophthalmoplegia started to expand, with unambiguous evidence provided from 1968 for involvement both of muscle and nerve. With the introduction of the Gomori trichrome stain for ragged red fibres in 1972, it became clear that many examples of ocular myopathy have abnormal mitochondria; and so emerged the concept of the mitochondrial cytopathies. Writing with the benefit of hindsight in the 1992 edition of the Handbook of Clinical Neurology (Vol. 18) L.P. (Bud) Rowland confessed to having placed his earlier (1971) account of progressive external ophthalmoplegia in a chapter on brainstem neuronal degenerations akin to amyotrophic lateral sclerosis (motor neurone disease): ‘but the world changed in 1988 when [Ian] Holt et al. described mutations of mitochondrial DNA and it was soon shown that these deletions were restricted to syndromes that included ophthalmoplegia ... we still have to determine how much of a syndrome is due to a muscle disorder, or one of neurones or peripheral nerves, but the challenge now is to determine how a mutation of mtDNA leads to a biochemical abnormality that causes the clinical symptoms.’ The present issue of Brain maintains that process with our inclusion of papers implicating mutations of OPA1 in a mitochondrial cytopathy having a syndrome dominated by chronic progressive external ophthalmoplegia, and on which one of the pioneers of the field, Massimo Zeviani, now comments (page 314).
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||