Olivopontocerebellar atrophy

Journal O/the Neurological Sciences, 1982, 53: 253- 272

253

Elsevier Biomedical Press

OLIVOPONTOCEREBELLAR ATROPHY A Review of 117 Cases

JOS[~ BERCIANO

Section q! Neurolo~v, Celltro Mddico Nacional "Marqu~s de Vaktecilla", Sanlander /Spain) (Received 8 April, 198l) ( Revised, received l 1 June, 1981 ) (Accepted 9 July, 1981)

SUMMARY

Fifty-four cases of familial OPCA (FOPCA) and sixty-three cases of sporadic OPCA (SOPCA) have been gathered from the literature. The data concerning age at onset, duration of the disease, frequency of symptoms and the various localizations of lesions have been evaluated. In comparison with SOPCA, the disease begins earlier in FOPCA and lasts longer ( P < 0.001). The differences in the percentages of clinical manifestations and associated lesions are also significant with regard to the greater frequency in FOPCA of abnormal movements, ophthalmoplegia, spinal symptoms and lesions located in the dentate nucleus and spinal cord, except for the pyramidal tract. The clinical signs and symptoms are reviewed, special emphasis being given to dysphagia and urinary incontinence, their relevance having been underestimated in previous studies. After a critical analysis of the classifications in current use, I conclude that that of Greenfield (1954) remains the most appropriate.

INTRODUCTION

Olivopontocerebellar atrophy (OPCA) is a term created by Ddjerine and Thomas (1900) which comprises a series of heterogeneous diseases whose only common factor is the loss of neurons in the ventral portion of the pons, inferior olives and cerebellar cortex (Petito et al. 1973). Nowadays the OPCA's are included under the general heading of multiple system atrophy (Oppenheimer 1976).

Address for correspondence: Josd Berciano, Seccidn de Neurologia, Centro M~?dico Nacional "'Marq u6s de Valdecilla', Santander, Spain. 0022-510X,82/0000-0000/$02 75 © Elsevier Biomedical Press

254 The nosology of OPCA has been the subject of several reviews (Scherer 1933a,b; Welte 1939; Rosenhagen 1943; Crichtley and Greenfield 1948; Greenfield 1954, Ule 1957; Bullo 1960; Escourolle and Masson 1967; Veron 1968; Becker 1969; Konigsmark and Weiner 1970; Eadie 1975a,b,c), in spite of which certain aspects have not been studied thoroughly enough. Firstly, although data concerning onset and duration of the disease are mentioned by Veron (1968) and Eadie (1975a,b), it has not been established whether the differences in these respects between familial OPCA (FOPCA) and sporadic OPCA (SOPCA) are significant. Secondly, except with regard to extrapyramidal symptoms and lesions of the substantia nigra and striatum (Rosenhagen 1943), the frequency of the clinical manifestations and of the localization of the associated lesions is unknown. Thirdly, and as a consequence of the last point, the relevance of certain symptoms (namely, dysphagia and urinary incontinence) has been underestimated. And fourthly, a critical analysis of the classifications in current use is necessary in order to determine which of them is the most suitable. The object of this study is to deal with these aspects alter a thorough review of the literature. REVIEW O F T H E L I T E R A T U R E

Anatomically confirmed cases of OPCA reported up till December 1979 are numbered in Tables 1 and 2, following the chronological order of publication. I have therefore excluded cases published as OPCA but lacking anatomical proof (Guillain et al. 1928 : Skoog 1936: Padovani 1950: Boudin and Pepin 1956 : Nielsen and Hyman 1958 ; Ryan and Smith 1971 : Landis et al. 1974). Likewise the following observations have been excluded: that of Davison and Wechsler (1938) because the findings described are not of a systematized atrophy, but of a lesion of indeterminate nature: that of Verhaart (1963) because the author only describes the bulbar lesions: that of Perrero (1906), quoted by Bullo (t960) as OPCA. because it was a case of pontocerebellar hypoplasia: those of Fraser (1880), Lelong et al. (1941) and Jampel et al. (196t) and the pedigrees of Nonne (Nonne 1891. 1905), Brown (Brown 1892: Meyer 1897; Barker 1903), Klippel and Durante (Klippel and Durante 1892: Switalski 1901 : Thomas and Roux 1901 : Rydel 1904: Guillain et al. 194l) and of Gerstman (Gerstman et al. 1936: yon Braunmiihl 1954: Seitelberger 1962), accepted by other authors as OPCA (Hassin and Harris 1936: Welte 1939: Rosenhagen 1943: Destunis 1944: Pratt 1967 : Konigsmark and Weiner 1970: Eadie 1975c), given the non-existent, doubtful or minimal involvement of the ventral portion of the pons: and those of von Cramon and Kelemen (1973) and Jetlinger and Tarnowska-Dziduszko (1971} because some of their cases have been previously published. In agreement with Neimann et al, (1976), I have interpreted as OPCA of early onset the cases reported by Norman and Urich (1958) and Gross and Kaltenb~ick (1959).

I

D R D

I 1 D I D

23. 24. 25. 25a. 26. 27. 28. 29. 30.

D R. D

D D

18. 19. 19a. 19b. 20. 21. 22.

D

-

reference

Ley (1947): Gallemaerts el al. (1939) M a r b u r g and Riese (1947) Gray and Oliver (1941) Schut and H a y m a k e r (1951), patient 1 Ibid, patient II Havener (1951) N e u m a n n and Cohn (1955) Carter and Sukavajana (1956), paticnt I1 Chandler and Bebin (1956) N o r m a n and Urich (1958), patient 1 W o o d w o r t h et al. (1959), patient I lbid, patient 11 Locke a n d Foley (1960) A d a m s et al. (1961), pal'iel~t IV Gerstenbrand and Weingarten (1962) Sigwald et al. (1964) K r a u s - R u p p e r t (1964), patient Frida

Transmission

17.

Case No.

'~ These numbers are used for all references to cases throughout this article. D = autosomal dominant: R = autosomal recessive: 1 = indeterminate.

15. 16.

7a. 8. 9. I0. I1. 12. 13. 14.

7.

D Menzel (1891) R R a y m o n d (1910), patient Mclie R Flicker (1911), patient IV I - WincHer (1923) D Keiller (1926), patient JA lbid, patient W m lbid; Hassin and Harris (1936), patient JE D Mathieu and Bertrand (1929), patient BrouJll D - Jakob et al. (1934) Bullo (1960) D Waggoner el. al. (1938) R Aring (1940) D - Rosenhagen (1943), patient V D lbid, patient VII D [bid, patient VIII 1 lbid, patient X R - /bid, patient IX: Welte (1939), patient IV D Destunis (1944) R Titica and van Bogaert (1946)

1. 2. 3. 4. 5. 5a. 5b.

reference

Transmission

Case No)'

H E R E D I T A R Y O P C A : R E P O R T E D CASES (N = 54)

1 ABLE

40a. 41. 41a. 42. 43.

34a. 34b. 34c. 35. 36. 37. 38. 39, 40.

32. 33. 34,

31.

Case No.

Carpenter and Schumachcr (1966), patient 1. D - Weiner et al. (1967) D Petlegrini and Scarlato (1969) D - K o n i n g s m a r k and Lipton (1971), patient III-2 lbid, patient 11-1 Ibid, patient 1I-2 lbid. patient II1-1 I Petito et al. (1973), patient I D Alberca et al. (1973) D M a l a m u d and Hirano (1974) D Bonduelle et al. (1976) D K o e p p e n and Hans (1976) D Koeppen et al. (1977), family 1 patient 11-2 /bid, patien~ III-3 D - Perry el al. (1977), patient I lbid, patient 11 D Wadia (1977), patienl PSJ D Berciano (1978)

D

Transmission - reference

bo k./i

Ibid, patient 8/30 lbid, patient 2728 Maas and Scherer (1933) Dimitri and Victoria (1934) Noica et al. (1936) Hassin (1937) Aranovich (1939) Guillain et al. (1942); Guillain (1939) Rosenhagen (1943) and Welte (1939), patient I Rosenhagen (1943), patient 11 Ibid, patient III Ibid, patient IV Ibid, patient numberless lbid, patient VI Luque and Pucheta Morcillo (1945) Lambie et al. (1947) Critchley and Greenfield (! 948). patient I lbid, patient II Tans (1952) T6bel (1952)

Reference

l'he,~e numbers are used for all references to cases throughout this article.

83. 84. 85.

75. 76. 77. 78. 79. 80. 81. 82.

66. 67. 68. 69. 70. 71. 72. 73. 74.

44. 45, 46. 47 48. 49. 50. 51, 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65.

Pierret (1871) Schultze (1887) Royet and Coltet (1893) Arndt (1894) Reddlieh (18%) Thomas (1897), patient IV Ibid. patient V l~jerine and Thomas (1900) Thomas (1903) Schweiger (1906) Flicker (1911), patient 1 Stauffenberg (1918) Schuster (1924) Bakker (1924) Parodi and Ricca (19251 Ley 0925) Guitlain et al. (1933~. patient I Van Bogaert and Bertrand t1929) Messing (1930) Guillain et al. (1933) Scherer (1933a, b), patients 72/29 Ibid. patient 1789

Case No.

Case No. ~ Reference

SPORADIC OPCA: REPORTED CASES (N = 63)

TABLE 2

89. 90. 91. 92. 93. 94, 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106.

86. 87. 88.

Case No.

Guerra and Antunes (1953) Geary el al. (1956) Liithy and Mumenthaler (1958), patient I lbid, patient I1 Gross and Kaltenb/ick (1959) Isida et al. (1962) Popp and Gruner (1962) Esser (1964) Veron (t%8), patient 1 Ibid, patient It Ibid, patient llI Ibid, patient IV Ibid, patient V Kulawik et al. (1972) lonel (1972) Petito et al. (1973), patient I1 Ibid, patient III Kaiya (1974) Drobisheva et al. (1974) Neumann (1977) Lapresle and Anna bi (1979)

Reference

t~

257 Clinical &~ta Sex. age O/OnSet and duration 0 / the dis'ease The male/female ratio is 1.9 : 1 (34/20) in FOPCA, and 1 : I (31:32) ira SOPCA. In FOPCA after discounting the pedigrees with uncertain inheritance a similar sex ratio remains, 1.8:1 (31/17); nevertheless the frequency of males affected, 64.5"., is not significantly different from the 50" o expected ira an autosomal inheritance (P = 0 . 1 ) . The age of onset of the disease ranges between 2 months (Case 24) and 53 years (Case 35) ira FOPCA and from a congenital onset (Case 90) to 66 years (Cases 47. 105 and 106) in SOPCA. The average age of onset is 28.35 + 1.18 (mean + SEM) years for FOPCA and 49.22 _+ 1.64 years tk~r SOPCA. the difference is significant (t = 8.11 ; P < 0.001). The duration of the disease varies between 3 months (Case 24) and 38 years tCase 32) in FOPCA and between 4 months (Case 78) and 20 years (Case 50) in FOPCA. The average duration is 14.88 _+ 1.22 years for FOPCA and 6.31 _+ 0.53 years for SOPCA; the difference is also highly significant (t = 6.43; P <0.001). tferedil r" In 1944, Destunis gathered together 45 cases of OPCA of which 16 were hereditary, with an autosomal dominant transmission in 11 cases and autosomal recessive in the remainder. In the revised case histories (Table 1) FOPCA represents 46" o, inheritance being autosomal dominant in 30 families, autosomal recessive it1 7. and uncertain due to lack of information in 6. lnitk// ,~3"nTplonls

As other authors have already indicated (Critchley and Greenfield 1948: Bullo 1960: Escourolle and Masson 1967; Veron 1968; Eadie 1975a,b), the clinical picture usually begins with cerebellar ataxia, especially involving gait (Table 3). When dementia or extrapyramidal rigidity are found among the first manifestations they will always be important symptoms throughout the course of the disease. It is frequently reported that the lower limbs are easily tired: the pathogenesis is uncertain, but perhaps it should be linked with cerebellar asthenia or extrapyramidal rigidity as it is not associated with pyramidal or anterior horn cell signs. In all FOPCA cases with a severe visual defect, the deficit is usually an early symptom: in 2 cases (Nos. 25a and 32) blindness preceded, and in another 2 (Cases 25 and 31) accompanied the other initial symptoms. Generalized spasticity and psychomotor retardation constituted the whole clinical picture in OPCA of early onset (Cases 24 and 90). Spastic paraparesia preceded by some time the remainder of the clinical picture in Cases 53 and 76, although in Schweiger's patient a destructive lesion of the dorsal spinal cord, which probably accounted for the pyramidal signs, was discovered. In Titica and van Bogaert's patient (Case 16) the disease started with abnormal moeements, and in the patient reported by Adams et al. (Case 27) nansicnt dysphagia and paroxysmal disturbances of balance were the first symptoms.

25S TABLE 3 INITIAL SYMPTOMS No, of cases ('!,) Cerebellar Gait ataxia Gait ataxia with limb ataxia or dysarthria Limb ataxia or intentional tremor Dysarthria Parkinsonian Mental abnormalities Tiredness Other symtoms Cramps and lightning pain Involuntary movements Myoclonus Spasticity Sphincter disturbances Dysphagia Reduced vision Psychomotor retardation Disturbances of the equilibrium Indeterminate

90 (76.9) 67 11 9 3 11 (9.4) 4 (3.4) 16 (13.6) 19 (16.2) 3 1 1 3 I I 4 I 4 10 (8,5)

Other initial symptoms which accompany those already mentioned are summarized in Table 3.

Establ&hed clinical picture The frequencies of signs and symptoms F O P C A and SOPCA appear in Table 4. The differences between them are significant where ophthatmoplegia. dyskinesias and non-pyramidal spinal symptoms are concerned. Cerebellar disturbances are the most outstanding clinical features of the disease. In fact, as well as being almost constantly present, it is the dominant group of symptoms in 88.8~o of F O P C A and in 84,1% of SOPCA. In contrast with the greater frequency of ataxic gait in the early stages, as the disease progresses the cerebellar syndrome always becomes static and kinetic. With the exception of Case 29 where its absence is specifically reported and of 10 patients ICases 7a. 20, 24, 28, 44, 64, 90, 92, 95 and 105) in which it is not mentioned, dysarthria is also a constant symptom, frequently being early and at times so severe that speech becomes an unintelligible sequence of sounds. The type o f dysarthria varies, having been described as scanning, bulbar or pseudobulbar_ slow and monotonous, or as mixture of these. In 15 patients (Cases 1. ! 1-14, 17.45~ 54. 56, 58.70, 72.79. 82 and 83) the description of dysarthria fits that of spastic dysphonia (Critchley t939). Parkinsonian symptomatotogy is reported in 25 of the 45 cases reviewed by Rosenhagen (1943) and in 40°/o of the patients of Jetlinger and Tarnowska-Dziduszko

259 (1971). These frequencies are similar to those found in this review (Table 4). In accordance with Recondo (1964), the extrapyramidal symptomatology can either be combined with the cerebellar syndrome, lessening or masking it. or constitute one of the initial symptoms and in the latter case, as Rosenhagen (1943) indicated, the parkinsonian symptoms do not evolve into cerebellar symptomatology. In some patients (Cases 64, 65, 79 and 81) with an early extrapyramidal history there are severe striatal lesions, it being impossible consequently to differentiate them from striatonigral degeneration. Abnormal movements considered as a whole are significantly more frequent in FOPCA (Table 4). These may be myoclonus, spasmodic torticollis, choreoballismic jerks, and choreiform or athetotic dyskinesias. These are always not very obvious manifestations usually appearing late, except in Cases 1, 12, 16, 38 and 105. The patient of Bonduelle et al. (Case 38) was diagnosed clinically as dissynergia cerebellaris myoclonica because of the important myoclonic postural syndrome. but post-mortem examination revealed OPCA with an intact dentate nucleus. In Rosenhagen's eighth patient (Case 12) the triad of choreilbrm movements, dementia and ataxia led to a diagnosis of Huntington's chorea: nevertheless no lesions of the striatum or cerebral cortex were found. A noteworthy clinical feature in patients of Menzel (Case 1) and Neumann (Case 105) was spasmodic torticollis. Neumann postulates that the underlying anatomic basis of her case report might be atrophy of the vestibuloreticular system. In Menzel's patient one might think of an associated atrophy of the subthalamic nucleus of Luys, because the author found "very flattened and reduced subthalamic nuclei", but unfortunately he does not give a microscopic description. The choreo-ballismic dyskinesias in the patient of Titica and van Bogaert (Case 16) are the expression of advanced atrophy of the pallidum and subthalamic nucleus of Luys, Various studies have alluded to the not infrequent mental deterioration found during the course of the OPCA (van Bogaert and Bertrand 1929: Critchley and Greenfield 1948: Veron 1968; Koningsmark and Weiner 1970; Eadie 1975a,b,c). Percentages in Table 4 supports this view, but are far from those reported by Jellinger and Tarnowska-Dziduszko (1971) in whose series 16 of 20 patients suffered from dementia to some degree. Dementia is a dominant feature in 22.2'! o of FOPCA and 11.1'~,, of SOPCA. It can appear in any phase of the disease, but especially in the middle to late period. When mental deterioration is early in appearance it becomes an outstanding symptom liable to lead to errors of diagnosis (general paresis, Case 75; Huntington's chorea, Case 12). Descriptions of the mental state are usually very sparse, there being a systematic lack of an adequate neuropsychological examination. As Greenfield (1954) pointed out, the clinico-pathological correlation is poor (Tables 4 and 5). The pyramidal signs are in the majority of the reports a mere semeiological finding in the form of enhanced muscle stretch reflexes and/or extensor plantar responses. In 13 patients (Cases 21, 24, 30, 31, 36, 61, 76, 77, 86, 90, 91, 97 and 102) spastic paralysis and/or pseudobulbar dysarthria were reported and 5 (Cases 7. 14, 63, 80 and 83) developed the complete pseudobulbar syndrome. The pyramidal

55 (87.2) 35 (55) 11 (17.4) 22 (34.9) 29 (46) 14 (23.8) 30 (47.6) 3 (4.7) 20 (31.7) 1 (1.5) 15 (23.8)

No. (o)

No. ('~i) 52 (96.2) 21 (38.8) 21 (38.8) 31 (57.4) 27 (50) 27 (50) 21 (38.8) 14 (25.9) 10 (18.5) 7 (12.9) 18 (33.3)

SOPCA (N = 63)

FOPCA (N = 54)

NS NS <0.05 NS NS < 0.05 NS <0.01 NS NA NS

P*

* P was obtained using the ~(2-test (with Yates" correction) excluding the cases pointed out as not mentioned, NA = not applicable (2 expected values below 5); NS = not significant. (+ + ) = dominant sign; ( + ) = secondary sign; ( - ) = absent sign; (NM) = not mentioned.

Cerebellar Parkinsonian Involuntary movements Dementia Pyramidal Spinal except pyramidal Sphincter disturbances Opfithalmoplegia Nystagmus Reduced vision Dysphagia

Signs or symptoms

FREQUENCY OF NEUROLOGICAL FINDINGS IN OPCA

TABLE 4

48/53 10/17 4/1 12/7 1/6 1/0 0/0 0/0 0/0 5/0 1/2

(+ + ) 4/2 11/18 17/10 19/15 26/23 26/14 21/30 14/3 10/20 2/1 17/13

(+ ) 1/7 21/18 26/39 15/27 21/26 18/31 11/4 26/41 19/17 33/43 6/9

(-)

FOPCA/SOPCA (No. of Cases)

l/1 12/10 7/13 8/14 6/8 9/18 22/29 14/19 25/26 14/19 30/39

(NM)

37 (68.5) 31 (57) 7 (12.9) 30 (55.5) 26 (48.1) 12 (22.2) 17 (31.4) 25 (46.2) 8 (14.8)

No. (%)

F O P ( ' A (N = 54)

13 (20.~ 17 (28 10 (15.8 17 (26.9 14 (22.2 24 (38) 10 (15.8 30 (47.6 14 (22.2

No. I".)

SOPCA (N = 63)

< 0.01 < 0.01 NS < 0.02 < 0.01 NS NS NS NS

P*

* P was obtained by the same method indicated in Table 4. NS = not significant. ( + + ) = severe lesion; ( + ) = mild to moderate lesion; ( - ) = no lesion detectable; (NM) = not mentioned.

Posterior white columns Spinocerebellar tracts Corticospinal tracts Anterior gray horn Dentate nucleus Corpus striatum Cerebral cortex Substantia nigra Locus coeruleus

Localization

F R E Q U E N C Y O F M A I N A S S O C I A T E D LESIONS WITH O P C A

TABLE 5

15/3 3/0 1/0 10/1 14/4 4/3 3/2 14/9 I/5

(++)

22/10 28/17 6/10 20/16 12/10 8/21 14/8 I 1/21 7/9

I+~

)

11/37 13/33 33/36 16/26 21/41 25/29 26/35 18/I1 10/6

(

F O P C A : S O P ( ' A (No. of Cases)

6/13 10/13 14/17 8/20 7/8 17/10 I 1/18 11/22 3643

(NM)

bo

262

signs are not particularly late in developing as has been claimed (Critchtey and Greenfield 1948; Veron 1968; Eadie 1975a), but on the contrary are almost always found at the first clinical examination. Along the same lines as that observed in the pedigree of Currier et al. (1972), serial examinations in some patients have made it possible to demonstrate that hyperactive reflexes can become hypoactive (Cases 32, 34, 70, 76 and 87) or on the contrary can become enhanced after an initial normality (Cases 54 and 7t). Degeneration of the pyramidal tract has only been reported in 17 cases (Table 5) in 8 of which there were no or doubtful pyramidal signs. This gross clinico-pathological disassociation had been pointed out earlier (Nathan and Smith 1955). Non-pyramidal spinal symptoms are not absent in SOPCA as Becker (1969) affirms, but they are significantly less frequent than in FOPCA (Table 4). They may be amyotrophy, fasciculations without amyotrophy, hypopallaesthesia in lower limbs, lightning pains, arreflexia, kyphoscoliosis, and pes cavus. Spinal symptoms are usually of little importance. Nevertheless, in 3 patients (Cases 2, 17 and 18) a clinical diagnosis of Friedreich's ataxia was made. In this connection, it is timely to remember the reflexion made by Raymond (1910) about the anatomical findings m his patient (Case 2): "Je m'6tais cru autoris6 ~ porter d6s le d6but le diagnostique de maladie de Friedreich; et l'6volution de la maladie semblait bien m'avoir donnd la raison". ECG's were always normal (Cases 25a, 26. 32-34, 35, 43 and 73) and an association between OPCA and myocardiopathy has never been reported. There is an obvious dissociation between the frequency of lesions of the posterior white columns and anterior gray horns and that of corresponding clinical malfifestations (Tables 4 and 5). Since Bakker's study in 1924, disturbances of the sphincters in OPCA have not received sufficient attention. Percentages in Table 4 seem to coincide with the "frequent bladder disturbances" observed by Jellinger and Tarnowska-Dziduszko (1971) in their series, Except in 8 patients (Cases 27. 51. 56. 84. 86. 99. t05 and 106) in which it was an early symptom, urinary incontinence appears m the advanced stages of the disease. Double incontinence may develop (Cases 40a. 42a, 50-52.68. 81 and 82). Urinary retention is uncommon (Cases 6. 71 and 103). A cystometrogram was carried out in only 1 patient (Case 31) showing an atonic bladder. The pathogenesis of this urinary incontinence has led to various hypotheses: according to Bakker (1924) it is due to an interruption of the control of the cerebellum over the sympathetic nervous system ~Gray and Oliver (1941) considered it to be secondary to destruction of cells in Clarke's column ; and more recently Eadie (1975a) affirms that the disturbance cannot be explained by pathological findings and therefore "'it does seem possible that the symptom is a consequence of dementia". Among the 51 patients with urinary incontinence the following features were observed: dementia in 28, posterior column syndrome and/or degeneration in 27. and pyramidal signs or degeneration of the tract in 7. Only 4 patients (Cases 56, 57. 59 and 971 were free of clinical signs or anatomical lesions which theoretically could cause sphincter disorders. These data indicate that various factors are probably involved in the pathogenesis of the urinary incontinence.

263 During the course of heredoataxia nuclear or supranuclear ophthalmoplegia may occur (Recondo 1964). Ophthalmoplegia is mainly associated with FOPCA (Table 4). Nuclear ophthalmoplegia occurred in only 1 patient (Case 33) in whom. together with bilateral palpebral ptosis, a severe limitation of conjugate lateral and vertical eye movements was found. Histological examination showed neuronal loss and severe gliosis of the lIIrd and IVth cranial nerves. Supranuclear ophthalmoplegia due to deficiency of the saccadic movements OPCA has recently been singled out (Koeppen and Hans 1976). However, this disturbance had been marvelously described by Thomas (1903) (Case 52): "Novembre 1898: Le nystagmus transversal existe fi l'6tat de repos. Mars 1899:I1 n'y a pas de nystagmus A l'6tat de repos, il existe une diminution de la motilit6 des globes oculaires dans routes les directions, mats surtout en haut. Le malade ne peut regarder de c6t6 sans d6placer au m~me temps la tare". Later, apraxic ocular movements were described in 10 patients (Cases 28, 29, 38, 39, 41-43, 73 and 78); furthermore, they were observed by Landis et al. (1974) and Sears et al. (1975) in follow-up studies in patients from the pedigrees of Schut (1950) and Carter and Sukavajana (1956), respectively. Gallemaerts et al. (1939) (Case 17) demonstrate an almost total abolition of the quick phase of vestibular nystagrnus. The low percentages of nystagmus (Table 4) or its disappearance during the course of the disease could indicate that the disturbance in saccadic movements is not as rare as one migh! think from the infrequent occurrence of ophthalmoplegia. The descriptions of eye movements in the remaining patients (Cases 32, 34, 34a, 34b, 52 and 68) are of little value; nevertheless the absence ofptosis and of lesions of the oculomotor nuclei leads one to suppose that the ophthalmoplegia was of the supranuclear type in all of them. With the exception of peripheral tapetoretinal degeneration, OPCA is associated with all the varieties of visual defect described as occurring in the course of heredoataxia (Recondo 1964): macular degeneration in the father of Havener's propositus (Case 20), diffuse pigmentary degeneration (Cases 31 and 32), slow progressive optic atrophy (Case 68), retrobulbar optic neuritis (Case 19b), severe optic atrophy (Cases 21, 25 and 25a) and cataracts (Case 16). Visual disturbances usually occur in FOPCA, Case 68, a sporadic case, being an exception. Dysphagia has been considered an infrequent symptom in OPCA (Bullo 1960: Escourolle and Masson 1967: Veron 1968; Eadie 1975b,d). In contrast, this review indicates that it is a relatively frequent manifestation (Table 4). The similar incidence in FOPCA and SOPCA does not supports the hypothesis that the dysphagia is of genetic origin (Bell and Carmichel 1939). Swallowing disorders are characteristic of the intermediate and advanced stages of the disease, except for occasional early appearance (Cases 25, 25a, 27, 31, 63, 74, 93 and 106). Several patients (Cases 19a, 19b, 25, 25a, 27, 33, 34, 42, 43, 59, 60, 64, 74 and 106) suffered repeated choking spells or starvation or needed nasogastric intubation. Three patients (Cases 19a, 19b and 106) had associated laryngeal paralysis. Bulbar palsy (Bell and Carmichel 1939: Gray and Oliver 1941; Schut 1950; Veron 1968)and pseudobulbar syndrome (GuiIlain et al. 1933: Luque and Pucheta Morcillo 1945: Critchley and Greenfield

264 1948) have been cited in order to explain the dysphagia which occurs in OPCA or heredoataxia. There is clear evidence of bulbar palsy in only 4 patients (Cases 19a. 19b, 33 and 106), and of pseudobulbar syndrome in the 5 patients quoted above. That is to say, the pathogenesis of the dysphagia is uncertain in the majority of the reports. Dysphagia in OPCA is frequently transitory, recurrent and accompanied by choking and regurgitation, calling to mind the description of oropharyngeal dysphagia due to disturbances of motility in the superior oesophagea[ sphincter (Palmer 1976; Hurwitz et al. 1979). Functional examination of the cricopharyngeal muscle appear to be called for in future patients with dysphagia.

Pathology The nature and characteristics of the degenerative process have been sufficiently studied in previous works which dealt with the pathology of OPCA as a whole (Welte 1939; Critchley and Greenfield 1948; Greenfield 1954; Ute 1957. Escourolle and Masson 1967; Veron 1968; Eadie 1975a,b,c; Oppenheimer 1976) or concentrated on lesions of the striatum and substantia nigra (Scherer 1933a.b: Rosenhagen 1943; Recondo 1964; Jellinger 1968; Gray 1972). of the thalamus (Martin 1970), and of the reticular formation (Varela 1969). Electron microscopy has been used by Petito et al. (1973) on post-mortem material and by Landis et al (1974) on cerebellar biopsies in patients suspected of having OPCA. On this point. as said previously, the frequencies of the various lesions have yet to be established. The fundamental lesions are those located in the structures derived from the bands of Essick (Winckler 1923): the arcuate, pontine, inferior olivary and pontobulbar nuclei. The cortical cerebellar lesions are traditionally linked with the fundamental lesions according to D~j~rine and Thomas (1900). but they are the result of an anterograde transsynaptic degenerative phenomenon eVan Bogaert and Bertrand 1929). Olivary atrophy was absent in Cases 69 and 85. as was demyelinization of the olivocerebellar fibres in Cases 7a and 103. The lesion of the pontine nuclei was constant, while that of the middle cerebellar peduncle was not seen in 2 patients (Cases 16 and 103). The arcuate nuclei or the external arcuate fibres were reported to be involved in 61 cases and intact in 7 (Cases 1, 16. 19. 22.45.71 and 103). Atrophy of the pontobulbar body is mentioned only by Bakker 11924) (Case 57) and Tans (1952) (Case 84). The cerebellar cortex was normal in e, patients (Cases 20, 36, 37, 76, 77 and 90). Atrophy of the cerebellar cortex fundamentally involves Purkinje cells. Reduction of the thickness of the molecular layer or a decrease in the number of parallel fibres or stellate cells was seen m 27 instances: these same characteristics were also seen in granular layer in 48 patients. There was always demyelinization in the white matter of the cerebellum which was sometimes more marked on the axis of the laminae. Predominance of atrophy in the neocerebellum is reported in 54 instances. In the few patients (Cases 21.36. 59 and 63) where the atrophy of the vermis is greater than that of the hemisphere, like Ley (1925), I would question whether there is not an associated corticocerebellar atrophy. From the studies with more detailed histological descriptions 1 conclude that

265 the associated lesions are constant. Jelliner and Tarnowska-Dziduszko (1971) did not find pure OPCA among their series. The main associated localizations are shown in Table 5 ; differences between FOPCA and SOPCA are significant concerning those of'the dentate nucleus and the spinal localizations except for those of the corticospinal tract. The frequencies of atrophy in Clarke's column and the superior cerebellar peduncle are slightly inferior to those of the spinocerebellar tracts and dentate nucleus, but the differences between FOPCA and SOPCA are significant to a similar degree. Atrophy of the posterior root ganglia is only mentioned in Cases 1 and 70. Occasionally, paleness of the corticopontine tracts is noted (Cases 5, 7, 54, 70, 73, 74 and 93). In accordance with the nomenclature of Varela (1969), atrophy of the reticular formation of the brain stem in OPCA is partial, affecting the following nuclei: lateral reticular (Cases 24, 27, 52, 57 and 61), reticularis gigantocellularis (Cases 27 and 93), vestibular (Cases 29, 86, 96 and 105), interpeduncular (Case 17), superior central (Cases 17 and 27), and reticularis pontis oralis and caudalis (Cases 29, 87, 94 and 105). In addition, gliosis or neuronal loss is reported in the reticular area, without other details, in 9 patients (Cases 1, 18, 21, 33, 49, 51, 54, 61 and 93). Although it has been suggested that degeneration of the paramedian reticular formation might be the underlying anatomical cause of the saccadic anomalies in patients with heredoataxia (Zee et al. 1976: Murphy and Goldblatt 1977), this lesion was not observed in any of the OPCA cases with apraxic eye movements. The uncertain pathogenesis of the ocular disorder in OPCA is extensively reviewed by Wadia (1977). Atrophy of the pallidum is reported in 13 instances, but except for Cases 16, 22 and 27 the descriptions given do not make it possible to ascertain whether the pallidal atrophy is subordinate to the striatal. The role of the thalamus in the degenerative process has been the subject of an exhaustive study in the Thesis of Martin (1970). Other associated localizations of the lesions are divided among the following structures: nucleus ambiguus (Cases 33 and 106), hypoglossal nucleus (Cases 1, 19b, 33, 38, 76 and 104), dorsal motor nucleus (Cases 2, 29, 74-76 and 84), accessory cuneate nucleus (Case 16), nucleus of the mesencephalic tract of the trigeminal nerve (Cases 16 and 74), nucleus gracilis or nucleus cuneatus (Cases 48 and 73), central tegmental fasciculus (Cases 26, 27, 47 and 63), retina (Cases 25a and 32) and red nucleus (Cases 8, 9, 16, 77, 79, 85, 93 and 102). In Case 12a demyelinization of the IXth and Xth cranial nerves in their intramedullary course was observed and similar lesions of the hypoglossal nerve were seen in Case 19b. Demyelinization of the central tegmental fasciculus was accompanied by olivary pseudohypertrophy in Cases 26 and 63. Finally, atrophy of the red nucleus was not li)und with lesions of the dentate nucleus in Cases 8, 9, 77, 85 and 93, a litct which supports the primary nature of the atrophic process.

Classf/ication The initial work of Dejerine and Thomas (1900) and later Loew's Thesis (1903 1904). under the tutelage of Ddjerine himself, considered cases of OPCA

266 previously published to be atypical when there existed a hereditary factor or lesions which extended beyond the olivopontocerebellar framework, or a clinical picture which was not limited to cerebellar symptoms. The concept of atypical O P C A fell into disuse with the recognition of FOPCA (Keiller 1926- Hassin and Harris 1936) and of the many combinations of lesions which frequently accompany olivopontine degenerations ( Welte 1939). Greenfield (1954) divides the underlying anatomical basis ot" heredoataxia into two groups: type A (Menzet), which would enter into the general category of OPCA. and type B (Holmes). He studies OPCA separately, a genuine example of which would be D6jerine and Thomas's observation (1900). Hence OPCA is divided into a hereditary type (Menzel) and a sporadic type (D6jerine-Thomas). The publication of cases with uncommon clinico-pathotogic findings d.c. dementia, blindness or severe amyotrophy) leads to the identification of a new type of OPCA called "special" (Becker 1969) or "variant" (Eadie 1975c)L Using geneuc. clinical and pathological data, Konigsmark and Weiner f1970) classify OPCA into 5 categories (type I. dominant: type II, recessive: type IlI, with retinal degenerauon : type IV, Schut and Haymaker type; type V. with dementia, ophthalmoplegia and extrapyramidal signs). They add a further 2 categories for sporadic observations and for those which do not fit into the previous 5. although in their opinion such cases probably belong to type II This review has demonstrated the enormous clinico-pathological complexity of OPCA. which makes it difficult to sustain any classification based on clinical and pathological criteria. Thus. for example, the creation of "'types" or "variants" with dementia or amyotrophy ignores the fact that mental deterioration or atrophy of the anterior gray horn are seen in half the cases of FOPCA. Certain omissions m the study of Konigsmark and Weiner (1970) make the borderlines of their " ' t y p e s somewhat hazy. Gray and Oliver's patient 11941), type I. should be transferred to type IV because he belongs to Schut's pedigree (1950). The cases of Destunis (1944) and Rosenhagen (1943: pauent VIII), which are also included in type I. could fit into type V judging by the profound dementia described in both of them. The absence of spinal lesions or symptoms in type II. which differentiates it from type I according to Konigsmark and Weiner. ~s not confirmed by other repor-ts on recessive cases not included by the latter authors (Raymond 1910: Neumann and Cohn 1955: Rosenhagen 1943; patient IX). The great number o f sporadic observations compiled in my series leads me to consider their statement that "some or all belong to the recessively transmitted OPCA'" to be of doubtful validity. An additional drawback in the clinico-pathological classification is that it gives rise to the progressive creation of variants, such as the OPCA with slow eye movements (Wadia 1977). Koeppen et al (1977) have pointed out that hereditary ataxia should not be subdivided and should be classified simply on the basis of onset and mode of transmission, either dominant or recessive. Along similar lines. 1 believe that the most suitable classification of OPCA is still that proposed by Greenfield in 1954.

267 ACKNOWLEDGEMENTS

I am grateful to Prof. Raymond Escourolle for permission to review the anatomical material of the Cases 38, 49 52, 59, 60, 63, 73 and 94-98, to Dr. Federico Monsalve for statistical assistence, and to Ms. Carmen Sainz for secretarial help. REFERENCES Adams, R., L. van Bogaert and H. Van der Eecken (1961) Degen&escences nigro-striaes et cerebellonigro-slriees (Unicite clinique et variabilit6 pathologique des degenerescences preseniles 'a forme de rigidit~ extrapyramidale), P.sTchiat. el Neurol. (Basel), 142:219 259. Alberta, R., M.T. Garcia, A. Gil Peralta and G. Miranda (1973) Heredodegeneraci6n espinocerebelosa tipo Menzel Sobre las formas fundamentalmente cordonales, Arch. Neurohiol. (Madrid). 36: 313 324. Aranovich, J. (1939) Contribucion al estudio de las atrofias olivopontocerebelosas, Sere. m~;d. (Buenox Aires), 2:10 32. Aring, C.D. {1940) Degeneration of the basal ganglia associated with olivo-ponto-cerebellar atrophy, J. nerv. ment. Dis., 92: 448-470. Arndt. M. (I 894) Zur Pathologie des Kleinhirns, Arch. Psyehiat. Nervenkr., 26: 40z~429. Bakker. S. P. (1924) Atrophia olivopontocerebellaris, Z. ,~'es. Neurol. Psvchial., 89:213 244. Barker, L.F. 11903) A description of the brains and spinal cords of two brothers dead of hereditary ataxia Cases XVII1 and XX of the series in the family described by Dr. Sanger Brown, Tran.~. Ass. Amer. Ph)'cn.~'., 18: 637--709. Beckcr, P. E. (1969) Enfermedades de localizaci6n preferente en el sistema espmocerebeloso. In: S.A. f o r a y (Ed.), Gen&ica Humane, Vol. V,'I, Barcelona, pp. 233 320. Bell, J. and E.A. Carmichel (1939) On hereditary ataxia and spastic paraplegia, In: R.A. Fisher (Ed.). The Treasury ol Human Inheritance, Vol. IV, Part HL Cambridge University Press, London. pp. 163 281. Berciano, J. 11978) Nuevas Contrihuciones al Conocimiento Clinieo v Patole,~ieo de la Atro/ht O/ivopontoeerehelosa, Thesis, University of Bilbao. Bogaert, L. van and I. Bertrand 11929) Une verier6 d'atrophie olivo-pontine a evolution subaigu6 avec troubles dementiels, Rev. neurol., 1: 165-178, Bonduelle, M., R. Escourolle, P, Boygues, G. Lormeau and F. Gray (1976) Atrophie olivo-pontocerebelleuse familiale avec myoclonies Les limites de la dyssinergie cerebelleuse myoclonique (Syndrome de Ramsay-Hunt), Rev. neurol., 132:113 124. Boudin, G. and B. Pepin 11956) Atrophie de type olivo-ponto-c&ebelleuse et syphilis nerveuse. Rev. neurol., 94 : 295- 297. Braunmfihl, A. yon 11954) (Jber eine eigenartige hereditfi.r-familifi.re Erkrankung des Zentralnervensystems, Arch. P.~vehial. Nervenkr., 191:419 449. I'h-m~n. S. IIS!)2)On hereditaryataxia w i t h e scriesoftwenty-onecascs, Brain. 15:250 268. Bullo, J. (196(}) Sobre la atrofia olivo-ponto-cerebclosa primitiva y la variedad familiar. Rev. neurol. (Buenos Aires), [8:189 214; 259-297. Carpenter. S. and G. A. Schumacher 11966) Familial infantile cerebellar atrophy associated with retinal degeneration, Arch. Neurol. (Chic.), 14:82 94. Cartcr, H. R. and C. Sukavajana (1956) Familiar cerebello-olivary degeneration with late development of rigidity and dementia, Neurolo
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