.4cta Neurol. Srandinav. 56, 483-507, 1977

Ophthalmology Department, St. Elisabcth Hospital, Tilhurg, Ncuropathology Section of the Neurology Department, St. Radboud Hospital, Nijmegen, Department of Submicroscopic Morphology, St. Radboud Hospital, Nijmegen, and Neurology Department, “De Goddelijke Voorzicnigheid” Hospital, Sittard, Holland.

CHRONIC PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA IN A HEREDO-ATAXIA : NEUROGENIC OR MYOGENIC? A Clinical, Neuropathological and Submicroscopic Sfudy I,. 4 . K. BASTIAENSEK, H. H. J. JASPAR, A. M. STADHOUDER~S, G. J. &I. EGBERINK and J. J. KORTEN ABSTRACT

A patient with Friedreich’s disease and chronic progressive external ophthalmoplegia is described. An investigation was performed into the nature of the ocular motor disorders, which appeared clinically to be supranuclear. The EMG of t h e ocular muscles suggested myopathy. A specimen of ocular muscle was obtained by biopsy and examined with the light microscope and-for the first time-under the electron microscope. Signs of mitochondria1 myopathy were found alongside neurogenic features. Postmortem examination of the central nervous system confirmed the diagnosis of Friedreich’s disease with lesions of t h e motor cells in the anterior horn of the spinal cord. No evidence was found f o r a supranuclear or internuclear origin of the ocular palsies, but 2 0 3 0 per cent of t h e neurons i n the nuclei 111 and I V were atrophic. Lesions of the non-medullated motor nerve fibres were also visible under the electron microscope. That the origin of the c. p. e. o. in this heredo-ataxia is neurogcnic-nuclear is postulated on the grounds of the neuropathological and electronmicroscopic findings. Rescmblances to the microscopic and submicroscopic appearance of many types of “ocular myopathy” and “ophthalmoplegia-plus” throw doubt upon t h e myogenic character of these conditions. Possibly chronic, slowly progressive atrophy i n the nuclear areas of the ocular motor nerves must i n these cases also be held responsible for the c. p. e. 0. Perhaps Moebius’s Kern-Schwund theory may be revived after 85 years.

Progressive external ophthalmoplegia in association with various forms of ataxia has been known for a long time. As early as 1878 Galexowski described lesions of ocular muscles associated with ataxia; 32’

484 Fraser ( 1880) described progressive strabismus with cerebellar degeneration; Dtjerine ( 1884) described ptosis with ataxia; Schultrc (1888) described ophthalmoplegia externa combined with ataxia (autopsy: combined posterior tract degeneration). Sanger Brown (1892) published an article on a family with hereditary ataxia, in which a few cases of ptosis and/or ophthalmoplegia externa occurred. Ornierod (1892), in the discussion following Brown’s paper, mentions a family with practically the same lesions including nystagmus, atrophy of the optic nerve and delayed pupil reactions. Pierre Marie (1893) describes the impairment of the ocular movements in his classic description of the disease which is named after him. Ophthalmoplegia externa can also be associated with Friedreich’s ataxia according to Ma{gnus ( 1899). Nonne ( 1890) describes familial cerebellar ataxia with anomalies of the eye muscles (in 1905 autopsy: cerebellar atrophy). In the so-called “locomolor ataxia”, which can occur alone, ophthalmoplegia is often the result of syphilis (Hutchinson 1879, Hri.~touw1885, Gowers 1888). In the twentieth century the number of publications on the combination of ophthalmoplegia externa and the heredo-ataxia’s increases greatly. Many authors concern themselves about the origin of the oculomotor disturbance, based on detailed clinical and/or autoptic studies, especially of the cerebral areas involved in ocular motility. In Table 1 a survcy is given of studies of the combination heredo-ataxia and progressive external ophthalmoplegia. I n Table 2 the literature about the combination heredo-ataxia-progressive external ophthalmoplegia-retinal degeneration has been taken together (See Andrt van Leeiiwen et al. (1948) and Barnafter e f al. (1961) for surveys of the already for several decades known combination of heredo-ataxias and tapetoretinal degenerations). The autoptic findings of Lelong et al. (1941), Devos (1957), Gerstenbrand & Weingarten (1962), Brion & De Recondo (1967) and W o o d s & Schauiriburg (1972) point to a nuclear genesis of the ophthalmoplegia. On the other hand, Stephens e f al. (1958), in a case very similar to our patient, did not find any anomalies in the oculomotor nuclei and claimed, supported by a ocular muscle biopsy, a myopathic genesis for the ophthalmoplegia, in accordance with the theory of Kiloh & Nevin (1951), for chronic progressive external ophthalmoplegia sensu strictu. Jarnpel et aZ. (1961) and Koeppen & Hans ( 1966), also could not find lesions in the nuclear areas of the oculomotor nerves (and oculomotor nerve resp. fasciculus longitudinalis medialis) and claimed a supranuclear origin for the ophthalmoplegia in their patients because of the clinical picture.

Progressive ophthalmoplegia externa with ataxia and pigmentary anomalies of the retina are found in various conditions such as BassenKornzweig disease, Refsum’s disease and some forms of ophthalmoplegia-plus as Kearns syndrome. We had the possibility of examining a patient with Friedreich ataxia, retinal pigment degeneration and progressive external ophthalmoplegia. -4 submicroscopic examination of an external eye muscle (the first to o u r knowledge) and an extensive post-mortem neuropathologic research were established. CASE HISTORY Mrs. P., born i n 1935, had disturhances of gait from her youth, characterized by

uncertain and jerky movements. Since the age of 25 she suffered from increasing nervousness and trembling hands, vague disturbances of sensibility in the cxtremitics and visual complaints, sometimes diplopia. The motor abnormalities i n t h e legs became more severe after the first, and more markedly so after the second pregnancy (28 years), with pain in the legs and disturbances of equilibrium. When the patient was tired left-sided ptosis occurred. On her first clinical examination stigmata of degeneracy were observed (high instep, car lobule attached, high palate) and further choreiform movements, generalized hypotonia without obvious paresis, marked ataxia, disturbances of sensibility in the legs and hyporeflexia. Ophthalmological examination revealed a gaze palsy to t h e left and upwards and nystagmus in laterorersions. E.N.T. invcstigation showed slight perceptive deafness and insensitive labyrinths with spontaneous and positional nystagmus. Vertebral angiography showed no anomalies. The clinical diagnosis was Friedreich’s ataxia. In the family history a sibling of the same generation was found with the sarhe clinical picture. One of the patients children had hydrocephalus. Three members of the family had Parkinsons disease. The patient was subsequcntly admitted four times with a progressivc clinical picture: increasing loss of strength i n t h e extremities, increasing anomalies of peripheral sensibility, the appearance of pathological foot-sole reflexes, increasing extrapyramidal disturbances (choreiform movements, later severe myoclonus). Progressive dysarthria, dj-sphagia and dementia developed. Ophthalmological examination showed severe limitation of t h e eye movements with a moderate ptosis, which however disappeared in sursumversion; Bell’s phcnomenon was clearly intact. On both sides deorsumduction was least affected. In the fundus coarsening of the peripheral pigmentation was seen with some black clumps of pigment and peripapillary atrophy of the choroid. The visual acuity of both eyes was reduced to 0.7 after correction; perimetry, adaptometry, electroretinography, clectro-oculographg, and examination of colour vision revealed no abnormalities. Electromyographic examination of the superior, inferior and external rectus muscles of the right eye indicated myopathy (good recruitment of motor unit with very slight motor effect and low amplitude of A.P.: 150 micron V). The EMG of muscles of the leg showed no abnormalities a t first, later some signs of neuropathy appeared without active denervation symptoms. The conduction of the posterior tibia1 nervc was 47 m/sec. Laboratory investigations indicated progressivc EEG

486

Figure 1 . Transverse section of a nerve fibre m a i n l y composed o f non-myelinated axons. The great variation in diameter o f the axons is noteworthy, some of which are considerably larger than the one visible myelinated axon. Some slight swelling of an unmyclinated axon is visible. The perineurium s h o w s n o abnormalities. X 6,000.

anomalies culminating in generalized epilepsy, slight vitamin B, deficiency, a rather flat oral GTT curve and a basal metabolic rate 11 per cent below normal. The ECG was normal. Transaminases i n t h e blood and creatine excretion i n the urine were normal. Tests f o r hypo-b,eta-lipoproteinaemia and phytic acid i n the blood showed no anomalies. erum reactions for lues was negative. The CSF showed no abnormalities except a slightly raised total protein level (63.3 mg). In 1969 biopsy was performed on the left superior rectus muscle, f o r the purpose of examination under the light- and electron-microscopes; the findings a r e described below. The epileptic manifestations became more severe and were added to the progressive character of the other symptoms. The patient finally died a t t h e age of 36 years in status epilepticus. Directly after death a portion of the sural nerve was removed f o r examination; t h e conclusion was indecisive because of acute signs of neuropathy.

Histological examination of ocular muscle The specimen removed from the left superior rectus muscle was examined under the light- and electronmicroscopes. Lightmicroscopy: HE staining shows many degenerative muscle cells and marked variability in the diameter of the fibres: granular and

487

Figure 2. Portion of a “Felderstruktur” fibre, in which, between the contractible elements, which are cut nearly transversely, numerous abnormal mitochondriu appear. X 10,500.

hyalinelike degeneration and even complete necrosis of muscle cells ; some cells have preserved their structure in some parts and in other parts show degenerative features. The muscle cells contain much fat and lipofuscin. There is more interstitial connective tissue than normal. Electron-microscopy. Preparation of specimens : fixation i n 3 per cent glutaraldehydJ0.1 M ~Na-cacodylatebuffer pH = 7.3, rinsing i n 0.1 M Na-cacodylate buffer pH = 7.3, second fixation i n 2 per cent OsO, i n Palade buffer, rinsing i n Palade buffer, dehydration in alcohols of increasing strengths, embedding i n Epon 812 and staining with saturated uranium acetate solution and lead citrate (Reynold’s method). The sections were cut with a glass knife i n t h e LKB ultramicrotome I11 and examined with the Philips 300 electron microscope.

488

Figure 3. Electron micrograph of a subsarcolemmul agglomerate of aberrant mitochondria. Some mitochondria show clearlg a concentric arrangement of the crisfae, in others the cristae haue changed to a tubular a n d / o r vesicular structure. X 16,500.

Findings. In the muscle fibres which are still reasonably intact the Z-lines are often slightly irregular in torm (zig-zag) o r ,show the beginning of streaming. In some areas completely disorganized fibres are seen (with complete loss of orientation of myofilaments which otherwise apear to be intact), in which a great number of rods are present. In the clearly atrophic muscle fibres in which the myofilaments are extensively affected, the Z-lines are no longer recognizable. Under the sarcolemma protuberances of sarcoplasm occur, in which many glycogen granules, clusters of mitochondria and membranous bodies are seen, in addition to Zebra bodies and sometimes filamentous cytoplasmic bodies. The mitochondria have increased greatly in number, especially under

489

Figure 4 . In a large proportion o f the muscle f i b r e mitochondria the cristae are abnormal: between the membrancs o f the cristde there is an osmiophilic, finelu structured substance, an initial stage in the formation o f pseudocrustals. X 32,000.

the sarcolemma, and show various degrees of abnormality: we can subdivide these anomalies into four groups: 1. The mitochondria seem to be hardly affected (especially in the “Felderstruktur” muscle fibres) ; they are very swollen, the cristae are absent in some cases or have an irregular, concentric form. 2. Concentric laminated bodies, occurring as clusters in the sarcoplasm of atrophic muscle fibres, often containing glycogen: the membranes are arranged concentrically at regular intervals. 3. Mitochondria in which the cristae have a tubular and/or vesicular structure, mainly to be seen under the sarcolemma; transitional forms between types 2 and 3 occur. 4. Mitochondria with intracristal crystalline inclusions. The nuclei show no obvious anomalies. In the interstitial tissue calcium is sporadically seen in the vessel walls. The intramuscular nerves, in which both myelinated and nonmyelinated axons are found, exhibit no obvious pathology, although a few non-myelinated fibres have a swollen appearance. Between the axons fibrous long-spacing collagen apears sporadically.

490

Figure 5. Two filamentous bodies lie under the sarcolemma. The numerous mitochondria are swollen, the cristae are either partially absent or very irregular in shape. There is excessive glycogen between the mitochondria. X 10,500.

Neuropathological examination Macroscopic. On postmortem examination the weight of the brain was 1235 gram (normal). There is no obvious atrophy, in particular the pons and cerebellum do not appear atrophic. In the spinal cord the lumbosacral posterior roots are thin and too grey in colour. Microscopic. Demyelinisation and loss of axons are observed in the posterior roots and the posterior tracts, particularly in the fasciculi graciles. At the high thoracic and cervical levels there is also partial demyelinisation of Burdach’s tracts. The demyelinisation is associated with gliosis, but catabolic fatty products are absent. In the posterior roots the demyelinisation chiefly affects the thicker myelinated fibres.

491

I'igure 6. An area in a slightly affected muscle f i b e r s h o w s complete disarrangement of m y o f i l a m e n t s and numerous rods. X 3250.

In the spinal ganglia a few large neurons in regression and foci of sheath cells are found. In the spinal cord Clarke's columns are atrophic. Demyelinisation is also seen in the area of the dorsal spinocerebellar fibres and possibly to a lesser degree in other lateral tract systems. The lateral and ventral pyramidal tracts are unaffected. Above the spinal level demyelinisation is encountered ,in the extension of the spinocerebellar tracts. Other systems, including the lemnisci mediales and laterales, the brachia conjunctiva and on the right side the hilus nuclei dentati exhibit dubious demyelinisation. In the cerebellum the number of Purkinje cells is probably reduced. The pons, cerebellum and olivae are otherwise intact. With regard to the optical systems the tractus opticus, corpora geniculata and colliculi superiores are intact. No fibre loss or other structural anomaly is seen in the pretectal and collicular areas. The large number of corpora amylacea in and around the aqueduct and roof of the mesencephalon is striking. No abnormalities are found in the fasciculus longitudinalis medialis on both sides. The fibres of the oculomotor and trochlear nerves are well myelinated, at least in their intracerebral course. Fibres of the abducent nerve

492

Figure 7 . ( W e i l ) . Low thoracal segment. Widening o f central canal: complete demyelinization of funiculi graciles, lesser demyelinization of funiculi cuneati and o f dorsal spinocerebellar tracts. N o obvious affection o f pyramidal tracts. x 12.

Figure 8. (Kluuer) Nucleus nerui I I I , left anterior part dorsal nuclear group. X 115.

493

Figure 9. (Kluver) Nucleus nerui 111, left anterior part. Magnification of photograph 8 (left o f centrum). Small atrophic neurons especially i n the lateral part of the nucleus. X 360.

Figure 10. (Kluoer) Nucleus nervi 111, apterior part. Ventral nucleus; here also a number of small neurons are visible. X 110.

494

are only found in a few sections, a fact which might indicate that the number of fibres is decreased. We have no transverse sections of nerves 111, IV and VI. In the nuclei of the oculomotor and abducent nerves atrophy of a number of neurons can be seen: 20-30 per cent of the neurons (identified by their nucleolus) are too small and have too little cytoplasm without Kiss1 bodies. The anomalies in the oculomo-tor nuclei are most obvious in the lateral parts of the anterior dorsal nuclear group. There is no reactive gliosis. The trochlear nuclei were not found in our sections ; the Edinger-Westphal nucleus is intact. X o abnormalities are seen at levels above €he mesencephalon or in the cerebral cortex, in particular the precentral and occipital areas. DISCUSSION

The clinical diagnosis in our patient was Friedreich disease with some features of Charcot-Marie disease, chronic progressive external ophthalmoplegia with “benign” pigmentdegeneration of the fundus (no tapetoretinal degeneration) and increasing abnormalities in the EEG. The ophthalmoplegia appears to be supranuclear on the grounds of thc paradoxical ptosis and the positive Bell’s phenomenon. The neuropathological diagnosis confirms the diagnosis, although the cerebellar abnormalities are slight and lesions of the pyramidal tract-present clinically-are absent. No anatomic evidence could be found for a supranuclear orogin of the disorders of ocular movements: the frontal and pontine motor eye fields, in particular, were intact, and the occipital fields and the colliculi superiores also. The subcortical connections with these areas also appeared to be intact. The internuclear connections via the fasciculus longitudinalis medialis were also unaffected. Examination of the ocular motor nuclei reveals unmistakeable lesions in 20-30 per cent of the neurons in the nuclei I11 and VI. The atrophy is not associated with pyknosis, gliosis or spongiosis, and the number of cells does not appear to be diminished. This partial neuron atrophy must be considered as a significant factor in the development of the ocular muscle palsies. The intracerebral fibres of nerve I11 appear to be intact, but cannot be assessed satisfactorily as crosssections are lacking; the same is true of the decussating fibres of nerve IV, while nerve VI appears to be atrophic. We found a few small motor branches in the light- and electronmicroscopic examination of the left superior rectus muscle : the medullated fibres (alpha motor neuron fibres) are completely intact. A

495 remarkable number of nonmedullated nerve fibres were seen running with the medullatcd fibres. These fibres arc probably branches of nerve 111 to the eyemuscle cells with multiple innervation (Teriiviiinen et al. 1969) and not demyeliniscd nerve fibres: some of them appeared swollen. Motor end plates were not found in the specimen, which had probably been taken too distally. Light-microscopic examination of the ocular muscle obtained by biopsy shows varying degrees of granular and hyaline degeneration and also intact muscle fibres. This so-called “myopathic” picture can, however, also be found in chronic neurogenic muscular disease (Drachmann et al. 1968, 1969) ; the EMG of the extra-ocular muscle, which also gave a myopathic picture, is not sufficient evidence either. Submicroscopic examination produces some evidencc for neurogenic involvcment (Z-line-streaming and zigzagging) alongside dystrophic features such as atrophic muscle fibres with myofilament damage and marked mitochondria1 anomalies, which suggest mitochondrial myopathy. Some completely intact fibres are seen and others which arc completely disorganized with total loss of orientation of the-otherwise intact-myofilaments, in which many rods are seen; we also saw atypical cytoplasmic inclusion bodies, membranous bodies and Zebrabodies ( = leptofibrils), accumulations of glycogen, fat and lipofuchsin: These anomalies can also be found in normal ocular muscle tissue (Mukuno 1966, 1968, 1969, Martinez e f al. 1976). The crystalline inclusions in the cristae of the mitochondria resemble closely the linear intracrystalline inclusions found by Melined et al. ( 1975) following the experimental uncoupling of oxidative phosphorylation, and Ihe inclusions seen in ischaemic muscle fibres (Karpati et al. 1974). Similar mitochondrial anomalies, often associated with crystalline inclusions, have been described in combination with dystrophic changes in the contractile elements in the ocular muscles of patients suffering from “ocular myopathy” and ophthalmoplegiaplus” (Molbert & Doden 1959, Zintz 1965, Alberca et al. 1971, Koerner & Schlote 1972, Adachi et al. 1973, Bastiaensen et al. 1974, Koerner & Probsf 1975, Croft e f al. 1977). Mitochondrial changes were also seen in the skeletal muscles in many patients with the “descending” and “plus” forms of “ocular myopathy”. Little is. known of the submicroscopic appearance of a neuropathic ocular muscle, but Minodu (1971) in the mouse and Cheng-Minoda e f al. (1968) in the rabbit found the principle anomalies in the sarcomeres, in particular in the Z-lines, where Schlote & Korner (1975) in the man found chiefly loss of myofilaments. Mitochondria1 lesions

496 Table 1. Heredo-ataxia and

Author

Type of heredo ataxia

Eye motility disturbance

Best 1909 Barrett 1927 Mollarct 1929 Matthieu cs 1929 Kipmanowa 1934 Piton cs 1939

M. Friedreich. M. Friedreich. M. Friedreich. Cerebellar heredo ataxia. M. Friedreich. Cerebello-pyramidal heredo-ataxia (probable M. Friedreich). Pyramidal-cerebellar syndrome. M. Friedreich. M. Pierre Marie. Olivo-pontoccrebellar degeneration. M. Pierre Marie.

C. p. e. 0. c. p. e. 0. Opht halmoplegia. Diplopia, vertical palsy. Ophthalmoplegia externa. Vertical motility-disturbance.

Monier-Vinard cs 1939 Sjogren 1943 Rosenhagen 1943 Franceschetti cs 1945 Meycr 1918 Richter 1950

Degeneratio optico-cochleoden tata. Hereditary late cortical cerebellar atrophy (M. Marie-FoixAlajouanine?) Family with heredo-ataxia type Friedreich, type P. Marie, spastic paraplegia. M. Pierre Marie. M. R O U S S ~ - L C V Y . M. Pierre Marie.

Ptosis and ophthalmoplegia cxt erna. Ptosis, gazepalsies. Ptosis, gazepalsies. Ptosis, VI-paresc, gazepalsy. Ptosis, disturbance of voluntary movements, c. p. e. 0. Ptosis, slow eye movements. Gazepalsy.

.

Schut 1950

Euziirre cs 1952 Mutrux cs 1953 Barraquer-Bordas cs

Ptosis, vertical motility disturbance, slow eye movements.

Gazepalsies. Ptosis, vertical gazepalsy. Gazepalsies.

1954

Devos 1957

M. Marie-FoixAlajouanine

Ptosis, concentric limitation of movement "ataxie des yeux".

Stephens cs 1958

Combination of Fricdreichs ataxia and neural amyotrophia (Charcot-Marie-Tooth).

Ptosis, progressive ophthalmoplegia cxterna.

Hariga 1959

Spastic heredo-ataxia.

Ptosis, c. p. e. 0.

497 exiernal ophthalmoplegia. ~

Eye muscle histology

Autopsia

Characteristic spinal cord signs.

Location of eye motility disturbance (acc. to author) ? ? ? Supranuclear. ? Supranuclear.

“Nevraxi te”. ?

Spongiosis C. N. S.

Disappearance of neurons, gliosis, “senile plaques” in CNS.

Nuclear and supranuclear. Supranuclear. ?

Supranuclear.

Uncertain.

Supranuclear? Supranuclear? Supranuclear?

Atrophy, hypertrophy, and normal musclecells randomly; desintegration muscle cells; intramuscular nerves: no abnormalities.

Affection of nuclei nn 111-IV and Perlia; affection of cerebellum, periaquaductal formatio, nuclei retic.pontopedunculares, globus pallidum. Nuclei of nn 111, IV and EdingerWestphal, no abnormalities; nervus I11 : normal. Spinal cord : affection of posterior columns, Clarke’s column; cervical level : loss anterior horn cells. Peripheral nerves : demyelinisation, swelling, fragmentation.

Nuclear.

Myopathy.

Nuclear?

33

ACTA NEUROL. SCAND. 56, 6

498 Table 1.

Author

Type of heredo ataxia

Eye motility disturbance

Fotopulos, Schulz 1962

M. Friedreich.

Ptosis, c. p. e. 0.

Gerstenbrand cs 1962

Olivo-pontoccrebellar degeneration ; “encephalitis”.

Gazepalsy. n 111parese prclethaal.

Schut, Book 1963

Hereditary ataxia.

External oph4halmoplegia.

Mahloudji 1963 Heck 1964 Brown cs 1966

Hereditary spastic ataxia. M. Friedreich. Hereditary spastic paraplegia with ataxia.

Gazepalsics. Ophthalmoplegia externa. Pscudo-ophthalrnoplegia.

Brion cs 1967

M. Pierre Marie.

C. p. e. o., ptosis; afterwards pupil disturbances.

Ricker cs 1970

Probably M. Friedreich.

Renz 1972

Friedreich ataxia with myotrophy.

Ptosis, c. p. e. 0. EMG of eye muscle: “myopathic”. Ptosis, c. p. e. 0 . sluggish pupils, EMG of eye muscle :no abnormalities.

are not mentioned, apart from some decrease in number (Minoda 1971). The material however was from ocular muscles which had been abruptly denervated.

499 (continued).

Eye muscle histology

Location of eye motility disturbance (acc. to author)

Autopsia

Nuclear.

Musc. orbic. oculi: grouped atrophy; intramuscular nerves : no abnormality. Encephalitis-signs i n nucleus n 111 besides signs of ,an old degenerative process. Further anomalies conform olivopontocerebellar atrophy.

Nuclear and prabably supranuclear.

Supranuclear. Nuclei nn 111-IV-VI : not described; anomalies of cerebral grey matter, demyelinisation of white matter; affection of cerebellum, nucleus dentatus; demyelinisation of spinocerebellar tracts. Nuclei n 111, IV, VI and Perlia affected; nucleus Edinger-Westphal : normal; nervi I11 and IV: demyelinisation; F. L. M. : demyelinisated areas; corpora quadrigemina: normal; cerebral hemispheres : normal; discrete demyelinisation of genu capsulae internae and fasciculus fronto- and temporopontinus. Cerebellum, cerebellar projections, nucleus, dentatus, olivae, pontine nuclei, nucleus Cajal and nucleus Darkschewitz : affected.

Supranuclear.

Nuclear, internuclear and probably supranuclear.

Myopathy. Uncertain.

CONCLUSION

A sufficient cause for the progressive ophthalmoplegia externa in our patient is to be found in the lesions in the ocular motor nuclei. The 33'

500 Table 1.

Type of heredo ataxia

Eye motility disturbance

Woods cs 1972

Degeneratio nigro-striato-dentato.

Ptosis, ophthalmoplegia externa.

Singh cs 1973

Spinocerebellar degeneration.

Koeppen cs 1976

Olivo-pontocerebellar degeneratioa.

Slow eye movements; disturbance of horizontal saccades and pursuit movements. Pseudo-ophthalmoplegia.

Author ~~~~~~~~~~

~

anomalies in the non-medullated axons also suggest a neurogenic origin. In addition Z-line anomalies (streaming and zig-zagging) are regularly visible in the submicroscopic picture, indicating a neurogenic process. The frequent areas of myofilament disorientation and rod accumulation suggest a neurogenic cause too strongly to be regarded merely as R variant of the appeanance of normal ocular muscle (not in accord with Mukuno and Martinez). Considered in this light, serious doubt must be thrown on the “myogenic” character of the lesions in ocular muscles seen under the electron microscope in various forms of “ocular myopathy”. Even in our patient, in whom the neurogenic-nuclear origin of her chronic progressive external ophthalmoplegia is clear, a mitochondrial myopathy of the external ocular muscle examined appears to be present. Probably the mitochondrial anomalies reflect metabolic disturbances in various neuromuscular disorders of the external eyemuscles, varying (possibly in smooth transition) from “pure” ocular myopathy to ophthalmoplegia-plus and external ophthalmoplegia with heredoataxias. Enzym-histochemic studies are needed for further differentiation. REFERENCES Adachi, M.,J. Torii, B. W.Volk, P. Briet, A. Wolintz BE L. Schneck (1973) : Ele-ctronmicroscopic and enzym-histochemical studies of cerebellum, ocular and skeletal muscles in chronic progressive ophthalmoplegia with cerebellar ataxia. Acta Neuropathol. 23, 300-312.

501 (continued).

Ex e muscle histology

Autopsia

Grouped atrophy : denervation.

Nucleus n I11 : severe loss of neurons; FLM: no abnormalities; affection of cerebellar connections and nuclei, vestibular nuclei, nuclei dentati, nuclei pontini, nuclei medullares, anterior horncells. Affection of substantia nigra and connections.

Location of eye motility disturbance (acc. to author) Nuclear.

Supranuclear.

Nuclei IV-V-VI intact, FLM intact, central tegmental tracts intact, signs of olivo-pontocerebellar degeneration.

Supranuclear.

Alberca, H., M. C. Coca, A. Gil Peralta, P. Gomez, Bosque & A. Kavarro (1970): Miopatia ocular familiar (estudio immunoelectroforetico y de microscopia electronica). Rev. Clin. Esp. 123, 45-52. Andre, M. van Leeuwen, J. Babel, L. van Bogaert, A. Franceschetti, D. Klein & Montandon (1948) : HCredo-ataxies par dbgenerescence spino-ponto-cCrCbelleuse. Leurs manifestations retiniennes, optiques et cochlhaires. Rapport du 16e Congris de L’ONO. Revue d’Oto-Neur-Ophth. 20, 1-230. Bamattcr, F., A. Franceschetti & D. Klein (1961): Les Abiotrophies neuroretiniennes, Les Phacomatoses. 18e Congres de PCdiatres de Langue Francaise, Genive. Tome 2, pag. 85-91. Edit. K a g e r , Basel. Barraquer-Bordas, L., J. Mari-Batllo, J. Ruiz-Lara, J. Talayero (1954) : Herbdoataxie cerebelleuse avec paralysie du regard. Conf. Neurol. 24, 203-210. Barrett, Th. M. (1927): Friedreichs ataxia. Clinical and postmortem study of two cases i n brothers a t different stages of the disease. Arch. Neurol. Psych. 27, 28-43.

Bastiaensen, I,. A. K., 0. R. Hommes & A. M. Stadhouders (1974) : Ocular myopathy. A case history with electronmicroscopy, biochemistry and review of literature. Ophthalmologica 168, 325-347. Best, F. (1909) : Die chronische progressive Ophthalmoplegia. Kurzes Handbuch der Ophthalmologie, pag. 504-505. Ed. F. Schieck, A. Briickner. Springer-Verlag, Berlin. Boudin, G., J. Barbizet & M. Y. Le HBnaff (1952) : Heredo-ataxie cBr6belleuse avec amblyopie et paralysie de la verticalit6 du regard chez la mere et l’enfant. Rev. Neurol. 87, 330-335. Brion, S . & J. de Recondo (1967) : OphthalmoplCgie nucleaire progressive et hiredodbgenerescence spinocCr6belleuse; 6tude d’un cas anatomo-clinique. Rev. Neurol. lf6, 383-400. Bristowe, J. S. (1885) : Cases of ophthalmoplegia, complicated with various other affections of t h e nervous system. Brain 8 , 313-344.

502 Table 2. Heredo-ataxia, external ophthalrnoplegia

Author

Type of heredo ataxia

Eye motility disturbance

Rimbaud cs 1932

M. Pierre Marie.

C. p. e. 0.

Zonca 1937

M. Pierre Marie.

Palsies.

Stewart 1937

Diplegia spastica cerebellaris familiaris. Cerebellar ataxia with affection of anterior horncells of spinal cord.

Ptosis.

Casus 1 en 2 : Pierre Marie. Hereditary ataxia, with signs of Friedreichs ataxia, olivo-pontocerebellar degeneration and muscular atrophy.

Ophthalmoplegia externa.

Jampel cs 1961

Familiar spinocerebellar ataxia.

C. p. e.

Chabot 1963

Heredo-ataxia of Roussy-Levy.

C. p. e. 0.

Hamard cs 1965

Pontocerebellar degeneration.

Ptosis, “viscositk des mouvements oculaires”.

De Marco 1968

Spinocerebellar heredo-ataxia.

Ophthalmoplegia.

Lelong cs 1941

Boudin cs 1941 Woodworth cs 1959

C,p. e. 0. without ptosis.

Lagophthalmus with possible disturbance of eye elevation.

0.

without ptosis.

Brown, J. & R. Coleman (1966): Hereditary spastic paraplegia with ocular and extra pyramidal signs ( a clinical and pathological study of a family). Bull. Los Angeles New. SOC.31, 21-34. Cheng-Minoda, K., T. Ozawa & G. M. Breinin (1968): Ultrastructural changes in rabbit extra-ocular muscles after oculomator nerve section. Invest. Ophthal. 7,

599-616.

and retinal pigmentary degeneration. Retinal anomaly

Autopsia

Uncertain.

Typical retinitis pigmentosa. Retinal pigmentdegeneration. Retinal pigmentations. Typical aspect of retinitis pigmentosa.

Tapetoretinal degeneration. Tapetoretinal degeneration.

Peripheral and central pigment disturbances. ERG: subnormal.

Retinal pigment degeneration : ERG subnormal. Atypical pigment degeneration : ERG subnormal. Tapetoretinal degeneration : ERG subnormal.

Location of eye motility disturbance (acc. to author)

Uncertain. Uncertain. Nucleu’s n I11 affected; affection of some motor nuclei i n cerebro and i n spinal cord. Besides classical aspects of heredoataxia, atrophy of cerebellum and its connections, olivae, nuclei dentati : nuclei of t h e pons: normal.

Nuclear.

Uncertain. Affection of cerebellum, olivae, pons, optic nerves, globus pallidum, spinal cord (posterior and lateral columns) ; loss of anterior horncells; other patient: some cerebral cortical atrophy; nuclei of eye muscle nerves not observed. Nuclei n I11 and nerveroot I11 : normal; affection of Purkinje cell-layer, cortex cerebelli, cerebral trunc; demyelinisation of spinocerebellar tracts; opticatrophy; extra-ocular muscle : normal.

Uncertain.

Supranuclear.

Uncertain.

Uncertain.

Uncertain.

Croft, P. B., J. C. Cutting, E. C. 0. Jewesbury, W. Blackwood & W. G. Mair (1977): Ocular myopathy (progressive external ophthalmoplegia) w i t h neuropathic complications. Acta neurol. scand. 55, 169-197. Dkjerine (1884) : Paralysis bilaterale des releveurs de la paupiCre chez u n ataxique. Progr. Med. 12, 850.

504 Devos, J. 11957) : Atrophie cCrCbelleuse corticale tardive, a hCr6ditC dominante avec paralysies oculaires. Psychiat. Neurol. 133, 46-62. Drachman, D. A. (1968) : Ophthalmoplegia plus. Arch. Neurol. f8, 654-674. Drachman, D. A., N. Wetzel, M. Wasserman & H. Naito (1969): Experimental denervation of ocular muscles. A critique of t h e concept of ocular myopathy. Arch. Neurol. 21, 170-183. Euzikre, J., R. Lafon, C. R. Mercadier & P. Bayon (1952) : HBrCdo-ataxie cthbelleuse et paralysie familiale de la verticalit6 d u regard. Rev. Neurol. 87, 323-329. Fotopulos, D. & H. Schulz (1962) : Isolierte chronisch-progressive Ophthalmoplegia externa als Friihzeichen einer spinocerebellaren (Friedreichsen) Ataxie. Psychiat. Neurol. Med. Psychol. 14, 286-293. Franceschetti, A., G. de Morsier & D. Klein (1945) : Ueber e i n e n e u e mit ophthalmoplegia cxterna progressiva kombinierte infantile Form von zerebellarer Heredoataxic (Pierre Marie) bei vier Geschwistern. Arch. Julius Klaus Stiftung f. Vererbungsf., Sozialanthr., Rassenhygihe 20, 59-81. Fraser, D. (1880): Defect of the cerebellum occurring in a brother and sister. Glasgow Med. J. 23, 199-210. Galezowski (1878): Paralysie de tous les muscles de l’oeil dans l’ataxie. Rec. d’ophthalmol. 1, 88-90. Gerstenbrand, F. & K. Weingarten (1962): Beitrag zum Problem der Systematrophien des Kleinhirns. Wien Klin. Wschr. 74, 702-705. Gowcrs, W.R. (1880): A family affected with locomotor ataxia. Transact. of the Clin. SOC.London 14, 1-5. Gowers, W.R. (1880) : A manual of diseases of the nervous system. Pp. 183-186. Churchill, London. Greenfield, J. G. (1954) : The spino-cerebellar degenerations. Blackwell Scientific Publications, Oxford. Hamard, H. & P. Bregeat (1967) : Limitation des mouvements volontaires et rCtinopathie pigmentaire a u cours d’une dCgCnerescence ponto-cCr6belleuse. Bull. Mem. Soc. Frans. Ophth. 80, 567-577. Hariga, J. (1959) : HCrCdo-ataxie du type spastique avec ophthalmoplegie chronique progressive. J. Gen. Hum. 8, 61-71. Heck, A. I;. (1964): A study of neural and extraneural findings in a large family with Friedreich’s ataxia. J. Neurol. Sci. I , 226-255. Hutchinson, J. (1879) : On ophthalmoplegia externa o r symmetrical immobility (partial) of the eyes, with ptosis. Medico-chirurg. Trans. London 62, 307-329. Jampel, R. S., H. Okazaki & H. Bernstein (1961) : Ophthalmoplegia and retinal degeneration associated with spinocerebellar ataxia. Arch. Ophthalmol. 66, 247-259.

Karpati, G., S. Carpenter, C. Melmed & A. A. Eisen (1974): Experimental ischemic myopathy. J. Neurol. Sci. 23, 129-161. Kiloh, L. & S. Nevin (1951) : Progressive dystrophy of the external ocular muscles. Brain 74, 115-135. Kipmanova, I,. (1934): In Neurol. Polska 16/17, 348; cited b y Franceschetti e t al. Koeppen, A. H. & M. B. Hans (1976) : Supranuclear ophthalmoplegia in olivopontocerebellar degeneration. Neurology 26, 764-768. Koerner, F. & W. Schlote (1972) : Chronische progressive ophthalmoplegie mit atypischen Netzhaut-pigmentierungen. Ber. Deutsch. Ophth. Gesellsch. 71, 503-510.

Koerner, F. & J. Probst (1975) : Typische retinopathia pigmentosa bei chronisch

505 progressiver Ophthalmoplegie. Albr. van Graefes Arch. Klin. Ophthalmol. 195, 195-200.

Lelong, M., J. Bertrand & J. Lereboullet (1941): Affection dkgknerative proche de l’hkrkdo-ataxie ckrkbelleuse avec atteinte du neurone moteur pkriphkrique. Rev. Neurol. 73, 360-363. Magnus, W. (1899) : In Norsk Magasin f. Lagevidensk. H. R. XIII, 3, 265; cited by Franceschetti e t al. Mahloudji, M. (1963) : Hereditary spastic ataxia simulating disseminated sclerosis. J. Neurol. Neurosurg. Psych. 26, 511-513. Marco, P. de (1968) : Degenerazione retinica e oftalmoplegia associate a eredoatassia cerebellare. Riv. Pat. Neur. Ment. 89, 34-36. Marie, P. (1893) : In Semaipe Medicale 13, 444; cited by Franceschetti et al. Martinez, A. J., S. Hay & W. McNeer (1976) : Extra ocular muscles. Light microscopy and ultrastructural features. Acta Neuropathol. 34, 237-253. Mathieu, P. & L. Bertrand (1929) : Etude anatomoclinique sur les atrophies ckrkbelleuses. Rev. Neurol. 1, 721-781. Melmed, C., G. Karpati & S. Carpenter (1975): Experimental mitochondria1 myopathy produced by i n vivo uncoupling of oxidative phosphorylation. J. Neurol. Sci. 27, 305-318. Meyer, J. E. (1949): Ueber eine kombinierte System Erkrankung i n Klein-, Mittclund Endhirn (Degenerescence systematiske optico-cochleo-dentalke). Arch. Psych. New. Krh. 182, 731-758. Minoda, K. (1971) : Histochemical and eleotron microscopic studies of extraocular muscles IV. Fine structure of neuropathic extra-ocular muscles. Acta Soe. Ophthal. Jap. 75, 54-65. Molbert, E. & W. Doden (1959): Die chronische progressive oculare Muskeldystrophie i n electronenmicroscopische Bilder. Ber. Deutsch. Ophth. Gesellsch. pag. 392-307. Mollaret, P. (1929) : Maladie de Friedreich. Etude physio-elinique. Ed. AmkdBc Legrand, Paris; cited by Renz. Monier-Vinard, Velter & G. Offret (1939) : Fixetk total et permanent d u regard par hypertonie des muscles oculomoteurs. Rev. Neurol. 2, 172-179. Mutrux, S., F. Martin & Y. Shesni (1953) : Ataxie congenitale et familiale associbe i des malformations somatiques, B des troubles oculaires et B des troubles mentaux. J. Gknkt. Hum. 2, 103-116. Mukuno K. (1966): The fine struoture of the human extra ocular muscles. A “laminated” structure in the muscle fibers. J. Electron. Micr. (Tokyo) 25, 227-236.

Mukuno, I(. (1969) : Electron microscopic studies o n the human extra ocular muscles under pathologic conditions. J a p Journal of Ophthalmol. 13, 35-45. Mukuno, K. (1970) : Fine structure of the human extra ocular muscles with special reference to ringband, rod like structures and satelite cells. Adv. Neurol. Sci. 14, 508-514. Nonne, M. (1890) : Ueber cine eigcnthiimliche familiare Erkrankungsform des Centralnervensystems. Arch. Psych. Nerv. Krh. 22, 283-316. Nonne, M. (1905) : Ein weiterer anatomischer Befund bei einem Fall von familiarer Kleinhirnataxic. Ueber die Berechtigung des Morbus Friedreich i n eine spinale und cerebellare Form. Casuistische, Klinische Beitrage zur congenitale Form dcs Klein-hirnataxie zur acuten Ataxie. Arch. Psych. Nerv. Krh. 39, 1225-1251. Ormerod (1892) : Remarks on Dr. Sanger Browns cases. Brain 15, 268-278.

506 Piton, J. & R. Tiffenau (1939): Maladie familiale du type de l’hkrkdo-ataxie. Rev. Neurol. 72, 774-777. Renz. F. J. (1972) : Myatrophische Form der Friedreichsen Ataxie mit ophthalmoplegie. Praxis 62, 1232-1236. Richter, R. (1950) : Late cortical cerebellar atrophy: a form of hereditary cerebellar ataxia. Amer. J. Hum. Genet. 2, 1-29. Ricker, K. & W. Gruninger (1970) : Okulare myopathie und spino-cerebellare ataxie. Klin. Monatsbl. Augenhlk. 157, 233-239. Rimbaud, L., H. Viaillefont & A. Balmes (1932): In Rev. Oto-Neuro-ophthal. 20, 697-700; cited by Franceschetti e t al. Rosenhagen, H. (1943): Die primare Atrophie des Briickenfusses und der unteren Oliven (dargestellt nach klinischen und a n a t o m i s c b n Beobachtung). Arch. Psych. Nerv. Krh. f16, 163-228. Sanger Brown (1892): On hereditary ataxy with a series of twenty-one cases. Brain 15, 250-268. Schlote, W. & F. Korner (1975) : Chronic progressive external ophthalmoplegia a neuromuscular disorder? Basic mechanisms of ocular motility and their clinical implications. Werner Gren Symposium 1974. Pag. 549-553. PergamonPress, Oxford. Schultze, F. (1888) : Ophthalmoplegia externa eigenthiimlicher Art : Ataxie der unteren Extremitaten m i t gesteigerten Patellar-reflexen bei einem 28-jahrigem Mannc (Bei einem alteren Bruder Mikrophthalmus, ausserdem Colobome der Iris und Choreoidea). Neurol. Central blatt. VIII, 26, 460. Schut, J. W. (1950) : Hereditary ataxia; clinical study through six generations. Arch. Neurol. Psychiat. 63, 535-568. Schut, J. W. & J. A. Book (1963) : Hereditary ataxia. Difference between progeny of male and female affected members and a definition of certain signs useful i n detecting the disease prior to onset of clinical symptoms. Arch. Neurol. Psychiat. 70, 169-179. Singh, B. M., H. Iramoto & R. J. Strobos (1973): Slow eye movements i n spinocerebellar degenerations. Am. J. Ophthalmol. 76, 237-240. Sjogren, T. (1943) : Klinische und erbbiologische Untersuchungen iiber die Heredoataxien. Acta Psychiatr. (Kbh.), Suppl. 27. Ed. Munksgaard. Stephens, J., M. Hoover & J. Denst (1958): On familial ataxia, neural amyotrophy and their association with progressive external ophthalmoplegia. Brain 81, 556-566.

Stewart, R. Bl. (1937) : Amentic familial cerebellar diplegia and retinitis pigmentosa. Proc. Roy. SOC.Med. 39, 849-850. Teravlinen, I€. & H. Huikuri (1965) : Effect of oculomotor and trigeminal nerve section o n t h e ultrastructure of different neuromuscular junctions in the r a t extra-ocular muscle. Z. Zellforsch. f 02, 466-482. Woods, B. T. & H. H. Schaumburg (1972) : Nigro-striato-dentatal degeneration with nuclear ophthalmoplegia. J. Neurol. Sci. 27, 149-166. Woodworth, J. S., R. S. Beckett & M. G. Netsky (1959): A composite of hereditary ataxies : a familial disorder with features of olivopontocerebellar atrophy, Lebers optic atrophy and Friedreich ataxia. A. M. A. Arch. Int. Med. 104, 594-606.

Zintz, R. (1965) : Neue elektronenmikroskopische Befunde bei der chronisch p m gressiven ocularen Muskeldystrofie. Ber. Deutsch. Ophth. Gesellsch. 67, 113-1 18.

507 Zonca, G. (1937): In Atti 34e Congr. SOC.Ottalm. Ital. 1937, pag. 721; cited by Andre van Leeuwcn et al.

Received June 26, accepted August 9, 1977

L. Bastiaensen, M.D. St. Elisaheth-Ziekenhuis Tilburg Holland