- Email: [email protected]
Infantile and juvenile spinal muscular atrophy
269
Journal of the neurological Sciences
Elsevier Publishing Company, Amsterdam- Printed in The Netherlands
Infantile and Juvenile Spinal Muscular Atrophy* I, H A U S M A N O W A - P E T R U S E W I C Z , W. ASKANAS, B. BADURSKA, B. EMERYK, A. FIDZIAlqSKA, W. GARBALII~ISKA, L. H E T N A R S K A , H. JEDRZEJOWSKA, Z. K A M I E N I E C K A , I. NIEBROJ-DOBOSZ, J. P R O T AND E. SAWICKA Department of Neurology (Head: Prof. L Hatlsmanowa-Petrusewicz), School of Medicine, Warsaw (Poland)
(Received 25 June, 1967)
INTRODUCTION The classical form of infantile spinal muscular atrophy described by Werdnig and Hoffmann is an acute disease, usually fatal in the early years of life. Cases of initially classical type in which the disease ran a protracted course have been described formerly, but the concept of spinal muscular atrophy in early life has been essentially changed by the work of Kugelberg and Welander. They have clearly established the existence of a mild form, apparently resembling muscular dystrophy in its clinical picture. This is immensely important for practical clinical purposes, because it changes the prognosis in some of the cases. On the other hand, it raises a fundamental theoretical question: are the two forms nosologically distinct entities, or two variants of essentially the same disease? Both views have their advocates. MATERIALAND METHODS We tried to arrive at a conclusion by analyzing 105 cases observed in the course of the past 10 years in the Neurological Department of Warsaw School of Medicine**. In Table 1 the material is divided into three groups according to clinical criteria. Group 1 comprises children who have never walked: here it is possible to distinguish (a) the acute form corresponding to the classical description of Werdnig and Hoffmann, and (b) cases less rapidly fatal, with survival till the fourth year of life. Group 2 comprises children in whom the disease appeared later. However deceptive a criterion time of onset may be, the important fact that distinguishes this group from the previous one is that the children had initially walked unaided. The disease ran a * Summary of a symposium held in the Department of Neurology, 14 January, 1967. These studies are part of a research project, supported by N. I. H., Bethesda, Md. (U.S.A.), under agreement No. 227702. ** The Department operates a consulting centre for muscular diseases, and serves patients from all parts of Poland. J. neurol. Sci. (1968) 6:269-287
I
~D
°,
16 (1 fatal)
31
3. Pseudodystrophic benign spinal atrophy
18 (llfatal) 40 (6fatal)
Number o f cases
2. Spinal atrophy of late childhood (intermediate)
(b) chronic
I. Spinal atrophy of early childhood (a) acute
Clinical type
TABLE 1
4-17 years
2-5 years
O-12months (never walked) 0 12months (never walked)
Onset o f illness
proximal atrophy only in lower extremities, pseudohypertrophy of calf and gluteal muscles (65 ~), fasciculations (50 ~), knee-jerk areflexia, other reflexes present, benign course not leading to immobilisation
delayed motor development, proximal atrophy, arefiexia, fasciculations, considerable skeletal deformation (immobilisation from about age of 10)
flaccidity, proximal paresis, muscle atrophy masked by fat, areflexia, no fasciculation flaccidity, proximal paresis, muscle atrophy, areflexia, fasciculations, skeletal deformation
Clinical picture
C H A R A C T E R I S T I C S OF T H E C L I N I C A L T Y P E S OF S P I N A L M U S C U L A R A T R O P H Y OF E A R L Y O N S E T
average 16.7
average 13.9
death usually in 1st year average 7.05
Age o f patient at time o f examination (years)
N
-t
0
:Z
to O
INFANTILE AND JUVENILE SPINAL MUSCULAR ATROPHY
271
more protracted course than in group lb, but was nevertheless severe and it was not therefore classified as Kugelberg and Welander's type but as an intermediate form. Finally, we included in group 3 typical cases of the benign pseudodystrophic form of spinal muscular atrophy.
[]
o÷
9
D+
0
Do
[]
[]
8
7
DO
00o
.~ 6
4
o+
3 D÷
[]
2
o
o÷
[]
0 []
D+D+Fq + D+
0
I [3+0+0 + 0 group I
Fig. 1. Occurrence of different clinical types in individual families. Key: tZ: male; o : female; -t- : deceased.
In spite of the considerable differences in clinical picture and course, our material suggests two manifestations of one disease. The fact is that we have seen different clinical pictures in different members of the same family (Fig. 1), and this intrafamilial variability lends support to the theory of a single disease, which becomes manifest in various forms under the influence of some obscure factor (?genetic ?environmental). Occasionally it is suggested in the literature that the two forms are differently transmitted (ARMSTRONG et al. 1966; BECKER 1966; TSUKAGOSHI et aL 1966). T~LE2 DISTRIBUTION BY SIBSHIP OF 7 6 I N D I ~ D U A L S W I T H S P ~ A L ATROPHY
Size of sibship S
Number of sibships Ns
Number of children S × Ns
Number affected R
2 3 4 5 6 7 8 9 12 Totals
16 12 7 7 2 3 1 1 1 50
32 36 28 35 12 21 8 9 12 193
18 17 12 11 5 4 1 3 5 76
J. neurol. Sci. (1968) 6:269-287
272
i. HAUSMANOWA-PETRUSEWICZet al. GENETIC INFORMATION
We have made a thorough analysis of the pedigrees of 90 of our patients, who belong to 64 families. In 14 families the patient was the only child, and this group was not further considered. In the remaining 50 families (Table 2) there were 76 patients (36 girls, and 40 boys), and 117 healthy sibs. The material was analysed by the method of propositi, the sibship, the a priori methods, and the method of Lejeune, whereby the genetic ratios of 18 ~o, 26~o, 25 ~ , and 2 7 ~ , were respectively obtained. This ratio shows that spinal muscular atrophy in our material is transmitted as a recessive autosomal trait with full penetrance. Consanguinity of the parents was established in 2 families. We have not found any case of spinal muscular atrophy among the cousins of our patients. The incidence rate seems to be higher than Brandt's estimate (one per million per year). For instance, we recorded 4 children born in 1958 in the District of Warsaw (population 3.5 million), but our material accounts for only a relatively small proportion of infants with the typical acute form of spinal muscular atrophy, most of whom are admitted to hospital paediatric departments. Karyotype studies of patients with spinal muscular atrophy (by the Moorhead method - - culture of peripheral blood lymphocytes) have yielded normal findings.
LABORATORY STUDIES
The great variability of the clinical picture should be reflected in laboratory results. Histology In the first place we analyzed the histological picture. Our analysis involved 59
Fig. 2. The acute form of Werdnig-Hoffmann disease. Uniform atrophy of whole bundles of fibres in the quadriceps femoris muscle. Haematoxylin-eosin, × 100. J. neurol. Sci. (1968) 6:26%287
INFANTILE AND JUVENILE SPINAL MUSCULAR ATROPHY
273
muscle specimens t a k e n f r o m 56 patients representing the whole range o f clinical pictures. The differences between the i n d i v i d u a l cases were m a n i f e s t e d in the degree o f the a t r o p h i c process a n d the changes in the n o n - a t r o p h i c muscle fibres. I n the acute f o r m o f W e r d n i g - H o f f m a n n , a t r o p h y usually involved m o s t o f the
Fig. 3. Werdnig-Hoffmann disease running a slower course. Beside the atrophic bundl~e of fibres, a well-preserved one is seen. Deltoid. Haematoxylin-eosin, × 400.
Fig. 4. Kugelberg-Welander type. A small group of atrophied fibres is seen (to the left) within a bundle of normal muscle fibres. Deltoid. Haematoxylin-eosin, x 100. J. neurol. Sci. (1968) 6:269-287
274
I. HAUSMANOWA-PETRUSEWICZel al.
fibre bundles (Fig. 2) whereas in the chronic cases (groups lb and 2), well preserved bundles were often seen beside the atrophic ones (Fig. 3); in Kugelberg and Welander's form of spinal muscular atrophy, not infrequently only a part of the fibres in a bundle were atrophic (Fig. 4).
Fig. 5. Kugelberg-Welander type. Hypertrophic fibres (diameter 110/z) with centrally-placed sarcolemmal nuclei, showing hyaline necrosis and a tendency to disintegrate, beside atrophic fibres represented by chains of sarcolemmal nuclei only. Biceps brachii. Haematoxylin-eosin, x 200.
@
@
Fig.6. Pattern of the muscle fibre atrophy. 1, groups of "fascicular" atrophy of muscle fibres; I1, a single non-atrophic muscle fibre is seen within a group of atrophic ones; IIl, a group of several atrophic fibres lie within a normal bundle; IV, thinly-scattered non-atrophic fibres are seen among atrophic ones; V, uneven atrophy of muscle fibres; hypertrophic fibres are present. J. neurol. Sci. (1968) 6:269-287
INFANTILE AND JUVENILE SPINAL MUSCULAR ATROPHY
275
In the chronic cases (group 3) we observed gradual proliferation of the endomysial connective tissue, blurring of the fascicular pattern of atrophy and also structural changes in the non-atrophic muscle fibres. Furthermore, there were hypertrophied fibres (Fig. 5). Changes of this type were seen to be most pronounced in the pseudodystrophic form of the disease. Incidentally, various authors have described structural changes in the non-atrophic fibres in spinal muscular atrophy as well as in other forms of chronic neurogenic atrophy of muscle. Variations in the arrangement of atrophic muscle fibres is shown in the diagram in Fig 6. Patterns I, II and III were met with in all the clinical forms of the disease, but pattern IV was exclusively found in Werdnig-Hoffmann's acute form, and pattern V was seen chiefly in the pseudodystrophic form of Kugelberg and Welander. It appears that pattern III may be explained by muscle fibre atrophy withinsubunits. An explanation for the irregular distribution of atrophic fibres, i.e. the mixed pattern of narrower and broader fibres, might be thought to lie in reinnervation of denervated muscle fibres, or a variable reaction to muscle fibre denervation within a single motor unit, or both. The reasons for the degenerative changes in the non-atrophic muscle fibres and their hypertrophy are, in our view even less clear. We feel unable to propose any convincing explanation, having the choice of three speculative hypotheses: (1) that functional overloading of the muscle fibres which are spared leads to their functional hypertrophy with secondary degeneration; (2) that hypertrophy is due to a change in the mode of innervation of muscle fibres; and (3) that, as appears from some experimental work, such degenerative changes and hypertrophy may represent an early stage of denervation (GUTMANN AND ZELENA 1962). In some cases of spinal muscular atrophy the muscle spindles show the following changes: a thickening of the capsule, proliferation of connective tissue within spindles
Fig. 7. Transverse section through the sarcolemmal bag region of a musclespindle in the deltoid. Thickening of capsule, oedema of intracapsular space. Haematoxylin-eosin, × 200. I. neurol. Sci.
(1968) 6:269-287
276
I. HAUSMANOWA-PETRUSEWICZe t al.
(Fig. 7), and, rarely, degenerative changes in the intrafusal muscle fibres. These changes are non-specific (they have been observed in various cases of myopathy) and are not very pronounced. The changes we found in intramuscular m o t o r nerve fibres and in the end-plates in the acute form of Werdnig-Hoffmann disease resembled those described by other authors. Changes in the intramuscular terminal nerve bundles were seen in all cases under consideration (Fig. 8). In cases with diffuse muscle atrophy in the biopsy specimens, there was loss of terminal motor innervation. In others, collateral reinnervation was occasionally found. In the Kugelberg-Welander form, numerous collateral, terminal, and subterminal sprouts were seen in areas of non-atrophic muscle fibres
Fig. 8. Marked loss of nerve fibres from an intramuscular nerve bundle comprising exclusively large sensory fibres. Biopsy specimen from the deltoid muscle. Intravital methylene blue staining, x 600. (Fig. 9). Branching was more profuse than in the acute form of the disease, and besides collateral reinnervation of some muscle fibres, there appeared also to be hyperneurotization of a few others. Hence, it is possible that the benign and the acute form of spinal muscular atrophy differ somewhat in the abnormalities of terminal motor innervation which are observed. The problem of the innervation of the non-atrophic muscle fibres seems to deserve further study, notably in connexion with research on the hypertrophy of some muscle fibres and certain electromyographic changes. U l t r a s t r u c t u r a l s t u d i e s . Electron microscopy showed changes to be more pronounced in the acute form of Werdnig-Hoffmann disease. The continuity of the myofibrils was preserved, but they were narrowed, and the interfibrillar spaces were enlarged. Their number was distinctly reduced in some muscle fibres, which resulted in a pattern of "teased" myofibrils (Fig. 10). In other muscle fibres the myofibrils followed an irregular J. neurol. Sci. (1968) 6:26%287
INFANTILE AND JUVENILESPINAL MUSCULARATROPHY
277
and chaotic course, with filaments of a density resembling that of the Z-band running the whole length of the sarcomere or through part of it (Fig. 11). The mitochondria showed changes involving chiefly swelling of the matrix and disintegration of the mitochondrial cristae (Fig. 10). Occasionally there were osmiophilic inclusions (Fig. 11).
A
B
[
"'
Fig. 9. A: collateral branching. Biopsy specimen from the deltoid. Intravital methylene blue staining, × 600; B: drawing from Fig. 9A.
The sarcoplasmic reticulum showed dilatation of its canals with vacuolization (Fig. 12). In the more chronic forms of spinal muscular atrophy the changes were similar; the myofibrils were narrowed with clearing and obliteration of Z-bands, the mitochondria were swollen and disintegrating and the canals of the sarcoplasmic reticulum were dilated with the formation of giant vacuoles (Fig. 13) containing osmiophilic substances. Only in 1 case of the Kugelberg-Welander type, of 20 year duration and late onset, J. neuroL Sci.
(1968) 6:269-287
278
I. HAUSMANOWA-PETRUSEWICZ et al.
Fig. 10. Acute Werdnig-Hoffmann type. Biceps brachii. Longitudinal section. The continuity of myofibrils is preserved. The reduced number of myofilaments creates the impression of "teased" myofibrils (Mf). Z-band is pale. Disintegration of mitochondrial (Mi) cristae with paling of the matrix, X 45,000.
Fig. 11. Acute Werdnig-Hoffmann type. Biceps brachii. Longitudinal section. Chaotic, irregular destruction of myofibrils (Mf). Filaments resembling Z-band in density extend throughout the whole or a part of the length of a sarcomere, x 48,000. Z neurokSci. (1968) 6:269-287
INFANTILE AND JUVENILE SPINAL MUSCULAR ATROPHY
279
Fig. 12. Acute Werdnig-Hoffmarm type. Biceps brachii. Longitudinal section. The myofibrils (Mf) are showing the characteristic cross-striations (Z,M-band). The canals of the sarcoplasmic reticulum (SR) are excessively dilated. Mitochondria (Mi) with clear matrix and numerous short cristae. Nucleus (Nu) is unchanged on periphery of muscle cell, x 48,000.
Fig. 13. Chronic Werdnig-Hoffmarm type. Biceps brachii. Longitudinal section. Paling and disappearance of Z-band. The canals of the sarcoplasmic reticulum (St), are excessively dilated and filled with an osmiophilic substance, × 45,000. J. neuroLSci. (1968) 6:269-287
280
I. HAUSMANOWA-PETRUSEWICZel al.
there were also, besides the changes characteristic of neurogenic atrophy, others which resembled the changes seen by us in muscular dystrophy. They consisted in discontinuities of myofibrils due to focal destruction of myofilaments in different parts of sarcomeres with preservation of the Z-band and with large areas devoid of myofibrils (Fig. 14). The canals of the sarcoplasmic reticulum showed little dilatation, and there were no changes in the mitochondria.
Fig. 14. Kugelberg-Welander type. Deltoid. Longitudinal section. Marked widening of the interfibrillary spaces. Continuity of myofibrils patchily interrupted (Mf). Irregular destruction of myofilaments. Z-band well preserved. Mitochondria (Mi) and their cristae are normal, × 36,000.
This electron microscopic pattern deserves special attention because it shows changes characteristic of neurogenic lesions (loss of the Z-band, reduction of the myofibril diameter, and widening of interfibriUar spaces) together with some changes met with in muscular dystrophy. Histochemistry. Histochemical investigation of muscle specimens* demonstrated changes commonly observed in neurogenic lesions: viz. (1) the difference between type I and II muscle fibres was blurred; (2) enlarged groups of fibres of a single type (Fig. 15), and (3) target fibres were present. FENICnI~L AND ENGEL (1963) reported that in Werdnig-Hoffmann disease, atrophy * The activity of the following enzymes was tested in the sections: succinic dehydrogenase after Pearse's method, lactic dehydrogenase after Novikoff's method, cytochrome oxidase after Burstone's method, in a few cases dehydrogenases, glycerophosphate and glucose-6-phosphate after Barka's method, phosphorylase a and b after Takeuchi and Kuriaki's and Cuh-Wegman's methods, myofibrillar ATP-ase after Padykula's method, acetylcholinesterase after Koelle-Gerebtzoff'smethod. J. neurol. Sci. (1968) 6:269-287
INFANTILE AND JUVENILE SPINAL MUSCULAR ATROPHY
281
and hypertrophy concern only fibres of type I. Our material fails to confirm this view; usually we saw atrophy of fibres of both types (I and II), whereas occasionally blurring of the difference between them made it impossible to establish which type was atrophic or hypertrophic. In a few cases only, there are strikingly selective lesions of the fibres
Fig. 15. Kugelberg-Welander type. Enlarged groups of uniform fibre type. Biceps brachii. Succinic dehydrogenase, x 120.
Fig. 16. Werdnig-Hoffmarm type. Atrophy of type II muscle fibres. Biceps brachii. Myofibrillar ATP-ase, x 100.
of a single type, either I or II (Figs. 16 and 17), as if fibres of the other type had resisted the morbid process longer. This finding deserves further study; it might be indicative of differences in response to the disease between fibres of particular types, or of selective lesions of the anterior horn cells innervating only a single metabolic type of fibre. Much J, neurol. ScL
(1968) 6:269-287
282
I. HAUSMANOWA-PETRUSEWICZet al.
Fig. 17. Kugelberg-Welandertype. Atrophy of type II muscle fibres. Deltoid. Myofibrillar ATP-ase, x 200.
Fig. 18. Werdnig-Hoffmann's form. Group of motor end-plates, some of them having a simplified structure. Biceps brachii. AChe, × 120.
as in other cases of neurogenic atrophy, we saw in spinal muscular atrophy some normal motor end-plates and also large numbers of small ones, some of them having a simplified structure (Fig. 18), and others with acetylcholinesterase activity in foci which were broken up into granules.
BIOCHEMICALSTUDIES The biochemical methods were those commonly used in muscle disease. Even if the physiological creatinuria of children is taken into account, we found the level of urinary creatine in spinal muscular atrophy to be raised in the form of WerdnigHoffmann more so than in that of Kugelberger and Welander. Increased serum aldolase and pyruvic transaminase activity was a finding in 66 ~o of the cases in the clinical groups 1 and 2 taken together, and in 56 ~ of those of the KugelbergWelander type, but the "scatter" of activity values was much larger in the latter condition. Oxalacetic transaminase activity in the serum behaved somewhat differently, rising to the highest relative levels in the more acute cases. Serum creatine kinase aetivJ. neurol. Sci. (1968) 6:269-287
283
INFANTILE AND JUVENILE SPINAL MUSCULAR ATROPHY
ity (Fig. 19) was elevated in many cases of the Kugelberg-Welander type (in 70 of the cases). It was highest in 5 patients with clinically distinct pseudodystrophic features and with a histological pattern which in certain respects resembled that of progressive muscular dystrophy (HETNARSKA e t al. 1968). The cause of this finding is
40
30"
20.
10-
.-.'. ~-~*, . 2r Acute form of WerdnigHoffmann disease
.....
o-~--
.....
2T
//2-
Spinalatrophy of lore childhood 'intermediate rarer
KugelbergWe[ander form
Fig. 19. Mean values of creatine phosphokinase in serum in various types of spinal muscular atrophy.
A W/./,• R
]!
Fig. 20. Immunoelectrophoresis performed with rabbit anti-Werdnig-Hoffmarm serum (AWHS~). The additional line in the o~-globulin fraction in the patient's serum is marked with the arrow. A: photography; B: drawing. J. neurol. Sci. (1968) 6:269-287
284
1. HAUSMANOWA-PETRUSEWICZel al.
obscure; excessive discharge of the enzyme into the blood stream may be connected with injury of the cell membrane, or, perhaps, with changed cell metabolism due to disorganization of cell structures. Obviously, these are merely hypotheses. The levels of serum o¢1, ~2, and r-globulins were raised at the expense of albumins and y-globulins in about one-half of the cases, irrespective of the form of spinal muscular atrophy. Agar gel immunoelectrophoresis was performed by Scheidegger's semimicromethod. When non-specific serum was used, the pattern and intensity of the precipitation arcs did not differ in the sera of patients and controls. But with the specific diagnostic serum the sera of patients with spinal muscular atrophy gave an additional arc in the zone of ~2-globulins which was not obtained for control sera (Fig. 20). A correlation between this phenomenon and the form of the atrophy could not be detected, which suggests that this abnormality in o~2-globulins may be a specific feature of neurogenic muscular atrophy in general.
ELECTROMYOGRAPHY
Electromyography (EMG) does not serve merely to confirm a clinical diagnosis of spinal muscular atrophy but often determines it, or modifies a previous diagnosis. On analyzing our material from this point of view it was possible to distinguish two groups of cases in which electromyography was diagnostically decisive: (1) so-called "floppy baby" syndromes, where in some cases the EMG enabled the spinal origin of the disorder to be established; and (2) a group of patients with the clinical diagnosis of muscular dystrophy who turned out to have spinal muscular atrophy of the KugelbergWelander type. It should be stressed that in these cases the EMG supplies an answer relatively rapidly and more easily than histopathology; moreover, it makes possible the comparison of many muscles, which adds to the reliability of the results. Since it can be repeated in the same muscle at intervals it also enables the dynamic nature of the morbid process to be appraised. On analysis, our EMG data obtained in spinal muscular atrophy are found to correspond essentially to the generally-known features of a neurogenic pattern. Thus there is a reduced interference pattern on maximal effort (single oscillations or a mixed pattern), the motor unit action potentials are of longer duration and higher amplitude than normal, there is increased synchronization and spontaneous activity in the form of fibrillations and fasciculations. There were, however, certain differences between the various forms of spinal muscular atrophy in our material. Thus, in the acute form of Werdnig-Hoffmann we saw single oscillations, but sometimes the amplitude of potentials was not very high. The duration of potentials was distinctly reduced in some cases, and "giant spinal" units of long duration appeared only occasionally. There were many polyphasic potentials, and spontaneous activity was manifest in this group of patients primarily as fibrillation. In the chronic form there was a reduced pattern on maximal effort, often single oscillations of high amplitude were seen, there were almost no small units, and only a small proportion of polyphasic potentials; the vast majority were "giant spinal" potentials. Synchronization was very distinct, and fasciculations were frequent (Figs. 21 A, B). Differences in the parameters of the potentials recorded in the J. neurol. Sci.
(1968) 6:269-287
INFANTILEAND JUVENILESPINAL MUSCULARATROPHY
285
various clinical groups of cases of spinal atrophy may be determined by differences in the dynamic process of the disappearance or disintegration of units and differences in the arrangement of atrophic and preserved units (cf. histological findings). The considerable elongation of motor unit territory developing during the course of the
A
B
Fig. 21. A: reduced maximal effort pattern (single oscillations)from the deltoid; B: very tall potentials of long duration ("giant" type).
286
l. HAUSMANOWA-PETRUSEWICZe t a [ .
atrophy depends on the one hand on the phenomenon of collateral reinnervation, while on the other it is probably due to synchronous firing of anterior horn cells. In some cases of various clinical types there was a myasthenia-like reaction. Disturbed transmission might be explained by abnormal conduction in the new nerve collaterals and their end-plates, formed as a result of regeneration, or directly by changes in the body of anterior horn cells. A characteristic phenomenon seen only in very longstanding spinal atrophy was the finding of volleys of spontaneous discharges of a pseudomyotonic character. These consisted either of small brief potentials or highamplitude long oscillations, and were most pronounced in the ease of muscles which histologically showed "pseudomyopathic" changes in addition to denervation (Fig. 22).
Fig. 22. Pseudomyotonic volley of high frequency spontaneous discharges (deltoid).
TREATMENT
Treatment was pharmacological as well as physical. The patients were given vitamins, Nivalin (galanthamine hydrochloride), anabolic steroids, and synthetic derivatives of adenosinephosphoric acid, but there was no perceptible improvement. Physical therapy was applied only in mild cases, with improvement in some, and there was never an adverse effect. It needs to be borne in mind, however, that slight improvement may be due to the natural course of the disease process and to increasing power in innervated muscle fibres; it may not necessarily be the result of treatment.
SUMMARY AND CONCLUSIONS
Our present clinical and laboratory data, as well as analysis of the pedigrees, seem to indicate that the different forms of spinal muscular atrophy are merely variants of the same disease and differ only in the rate and severity of the denervation process. In this context it appears to be an interesting point that with increasing duration of the neurogenic process biochemical and histological changes resembling those of muscular dystrophyappear. J. neurol. Sci. (1968) 6:269-287
INFANTILE AND JUVENILE SPINAL MUSCULARATROPHY
287
REFERENCES (only some leading recent references are given) ARMSTRONG,R. M., M. H. FOGEL$ONANDD. H, SILBERBERG(1966) Familial proximal spinal muscular atrophy, Arch. Neurol, (Chic.), 14: 208-212. BECKI~R,P. E. (Ed.) (1966) Humangenetik, Vol. 5, Part 1 (Krankheiten des Nervensystems), Thieme, Stuttgart. BRANDT, S. (1950) Werdnig-Hoffmann's Infantile Progressive Muscular Atrophy, Munksgaard, Copenhagen. FENICHEL, G. M. AND W. K. ENGEL (1963) Histochemistry of infantile spinal muscle atrophy, Neurology (Minneap.), 13 : 1059-1066. GUTMANN,E. ANDJ. ZELENA(1962) Morphological changes in denervated muscle. In: E. GUT~A~q (Ed.), The DenervatedMuscle, Publ. House Czechosl. Acad. Sci., Prague, pp. 57-102. HETNARSKA, L., J. PROT AND W. SAWICKA(1968), Creatine phosphokinase activity in spinal muscular atrophy, J. neurol. Sci., 6: 261-267. TSUKAGOSHI,H., H. SUGITA,T. FURUKOWA,T. TSUBAKIAND E. ONO (1966) Kugelberg-Welander syndrome with dominant inheritance, Arch. Neurol. (Chic.), 14: 378-381.
J. nearol. Sci. (1968) 6:269--287
Journal of the neurological Sciences
Elsevier Publishing Company, Amsterdam- Printed in The Netherlands
Infantile and Juvenile Spinal Muscular Atrophy* I, H A U S M A N O W A - P E T R U S E W I C Z , W. ASKANAS, B. BADURSKA, B. EMERYK, A. FIDZIAlqSKA, W. GARBALII~ISKA, L. H E T N A R S K A , H. JEDRZEJOWSKA, Z. K A M I E N I E C K A , I. NIEBROJ-DOBOSZ, J. P R O T AND E. SAWICKA Department of Neurology (Head: Prof. L Hatlsmanowa-Petrusewicz), School of Medicine, Warsaw (Poland)
(Received 25 June, 1967)
INTRODUCTION The classical form of infantile spinal muscular atrophy described by Werdnig and Hoffmann is an acute disease, usually fatal in the early years of life. Cases of initially classical type in which the disease ran a protracted course have been described formerly, but the concept of spinal muscular atrophy in early life has been essentially changed by the work of Kugelberg and Welander. They have clearly established the existence of a mild form, apparently resembling muscular dystrophy in its clinical picture. This is immensely important for practical clinical purposes, because it changes the prognosis in some of the cases. On the other hand, it raises a fundamental theoretical question: are the two forms nosologically distinct entities, or two variants of essentially the same disease? Both views have their advocates. MATERIALAND METHODS We tried to arrive at a conclusion by analyzing 105 cases observed in the course of the past 10 years in the Neurological Department of Warsaw School of Medicine**. In Table 1 the material is divided into three groups according to clinical criteria. Group 1 comprises children who have never walked: here it is possible to distinguish (a) the acute form corresponding to the classical description of Werdnig and Hoffmann, and (b) cases less rapidly fatal, with survival till the fourth year of life. Group 2 comprises children in whom the disease appeared later. However deceptive a criterion time of onset may be, the important fact that distinguishes this group from the previous one is that the children had initially walked unaided. The disease ran a * Summary of a symposium held in the Department of Neurology, 14 January, 1967. These studies are part of a research project, supported by N. I. H., Bethesda, Md. (U.S.A.), under agreement No. 227702. ** The Department operates a consulting centre for muscular diseases, and serves patients from all parts of Poland. J. neurol. Sci. (1968) 6:269-287
I
~D
°,
16 (1 fatal)
31
3. Pseudodystrophic benign spinal atrophy
18 (llfatal) 40 (6fatal)
Number o f cases
2. Spinal atrophy of late childhood (intermediate)
(b) chronic
I. Spinal atrophy of early childhood (a) acute
Clinical type
TABLE 1
4-17 years
2-5 years
O-12months (never walked) 0 12months (never walked)
Onset o f illness
proximal atrophy only in lower extremities, pseudohypertrophy of calf and gluteal muscles (65 ~), fasciculations (50 ~), knee-jerk areflexia, other reflexes present, benign course not leading to immobilisation
delayed motor development, proximal atrophy, arefiexia, fasciculations, considerable skeletal deformation (immobilisation from about age of 10)
flaccidity, proximal paresis, muscle atrophy masked by fat, areflexia, no fasciculation flaccidity, proximal paresis, muscle atrophy, areflexia, fasciculations, skeletal deformation
Clinical picture
C H A R A C T E R I S T I C S OF T H E C L I N I C A L T Y P E S OF S P I N A L M U S C U L A R A T R O P H Y OF E A R L Y O N S E T
average 16.7
average 13.9
death usually in 1st year average 7.05
Age o f patient at time o f examination (years)
N
-t
0
:Z
to O
INFANTILE AND JUVENILE SPINAL MUSCULAR ATROPHY
271
more protracted course than in group lb, but was nevertheless severe and it was not therefore classified as Kugelberg and Welander's type but as an intermediate form. Finally, we included in group 3 typical cases of the benign pseudodystrophic form of spinal muscular atrophy.
[]
o÷
9
D+
0
Do
[]
[]
8
7
DO
00o
.~ 6
4
o+
3 D÷
[]
2
o
o÷
[]
0 []
D+D+Fq + D+
0
I [3+0+0 + 0 group I
Fig. 1. Occurrence of different clinical types in individual families. Key: tZ: male; o : female; -t- : deceased.
In spite of the considerable differences in clinical picture and course, our material suggests two manifestations of one disease. The fact is that we have seen different clinical pictures in different members of the same family (Fig. 1), and this intrafamilial variability lends support to the theory of a single disease, which becomes manifest in various forms under the influence of some obscure factor (?genetic ?environmental). Occasionally it is suggested in the literature that the two forms are differently transmitted (ARMSTRONG et al. 1966; BECKER 1966; TSUKAGOSHI et aL 1966). T~LE2 DISTRIBUTION BY SIBSHIP OF 7 6 I N D I ~ D U A L S W I T H S P ~ A L ATROPHY
Size of sibship S
Number of sibships Ns
Number of children S × Ns
Number affected R
2 3 4 5 6 7 8 9 12 Totals
16 12 7 7 2 3 1 1 1 50
32 36 28 35 12 21 8 9 12 193
18 17 12 11 5 4 1 3 5 76
J. neurol. Sci. (1968) 6:269-287
272
i. HAUSMANOWA-PETRUSEWICZet al. GENETIC INFORMATION
We have made a thorough analysis of the pedigrees of 90 of our patients, who belong to 64 families. In 14 families the patient was the only child, and this group was not further considered. In the remaining 50 families (Table 2) there were 76 patients (36 girls, and 40 boys), and 117 healthy sibs. The material was analysed by the method of propositi, the sibship, the a priori methods, and the method of Lejeune, whereby the genetic ratios of 18 ~o, 26~o, 25 ~ , and 2 7 ~ , were respectively obtained. This ratio shows that spinal muscular atrophy in our material is transmitted as a recessive autosomal trait with full penetrance. Consanguinity of the parents was established in 2 families. We have not found any case of spinal muscular atrophy among the cousins of our patients. The incidence rate seems to be higher than Brandt's estimate (one per million per year). For instance, we recorded 4 children born in 1958 in the District of Warsaw (population 3.5 million), but our material accounts for only a relatively small proportion of infants with the typical acute form of spinal muscular atrophy, most of whom are admitted to hospital paediatric departments. Karyotype studies of patients with spinal muscular atrophy (by the Moorhead method - - culture of peripheral blood lymphocytes) have yielded normal findings.
LABORATORY STUDIES
The great variability of the clinical picture should be reflected in laboratory results. Histology In the first place we analyzed the histological picture. Our analysis involved 59
Fig. 2. The acute form of Werdnig-Hoffmann disease. Uniform atrophy of whole bundles of fibres in the quadriceps femoris muscle. Haematoxylin-eosin, × 100. J. neurol. Sci. (1968) 6:26%287
INFANTILE AND JUVENILE SPINAL MUSCULAR ATROPHY
273
muscle specimens t a k e n f r o m 56 patients representing the whole range o f clinical pictures. The differences between the i n d i v i d u a l cases were m a n i f e s t e d in the degree o f the a t r o p h i c process a n d the changes in the n o n - a t r o p h i c muscle fibres. I n the acute f o r m o f W e r d n i g - H o f f m a n n , a t r o p h y usually involved m o s t o f the
Fig. 3. Werdnig-Hoffmann disease running a slower course. Beside the atrophic bundl~e of fibres, a well-preserved one is seen. Deltoid. Haematoxylin-eosin, × 400.
Fig. 4. Kugelberg-Welander type. A small group of atrophied fibres is seen (to the left) within a bundle of normal muscle fibres. Deltoid. Haematoxylin-eosin, x 100. J. neurol. Sci. (1968) 6:269-287
274
I. HAUSMANOWA-PETRUSEWICZel al.
fibre bundles (Fig. 2) whereas in the chronic cases (groups lb and 2), well preserved bundles were often seen beside the atrophic ones (Fig. 3); in Kugelberg and Welander's form of spinal muscular atrophy, not infrequently only a part of the fibres in a bundle were atrophic (Fig. 4).
Fig. 5. Kugelberg-Welander type. Hypertrophic fibres (diameter 110/z) with centrally-placed sarcolemmal nuclei, showing hyaline necrosis and a tendency to disintegrate, beside atrophic fibres represented by chains of sarcolemmal nuclei only. Biceps brachii. Haematoxylin-eosin, x 200.
@
@
Fig.6. Pattern of the muscle fibre atrophy. 1, groups of "fascicular" atrophy of muscle fibres; I1, a single non-atrophic muscle fibre is seen within a group of atrophic ones; IIl, a group of several atrophic fibres lie within a normal bundle; IV, thinly-scattered non-atrophic fibres are seen among atrophic ones; V, uneven atrophy of muscle fibres; hypertrophic fibres are present. J. neurol. Sci. (1968) 6:269-287
INFANTILE AND JUVENILE SPINAL MUSCULAR ATROPHY
275
In the chronic cases (group 3) we observed gradual proliferation of the endomysial connective tissue, blurring of the fascicular pattern of atrophy and also structural changes in the non-atrophic muscle fibres. Furthermore, there were hypertrophied fibres (Fig. 5). Changes of this type were seen to be most pronounced in the pseudodystrophic form of the disease. Incidentally, various authors have described structural changes in the non-atrophic fibres in spinal muscular atrophy as well as in other forms of chronic neurogenic atrophy of muscle. Variations in the arrangement of atrophic muscle fibres is shown in the diagram in Fig 6. Patterns I, II and III were met with in all the clinical forms of the disease, but pattern IV was exclusively found in Werdnig-Hoffmann's acute form, and pattern V was seen chiefly in the pseudodystrophic form of Kugelberg and Welander. It appears that pattern III may be explained by muscle fibre atrophy withinsubunits. An explanation for the irregular distribution of atrophic fibres, i.e. the mixed pattern of narrower and broader fibres, might be thought to lie in reinnervation of denervated muscle fibres, or a variable reaction to muscle fibre denervation within a single motor unit, or both. The reasons for the degenerative changes in the non-atrophic muscle fibres and their hypertrophy are, in our view even less clear. We feel unable to propose any convincing explanation, having the choice of three speculative hypotheses: (1) that functional overloading of the muscle fibres which are spared leads to their functional hypertrophy with secondary degeneration; (2) that hypertrophy is due to a change in the mode of innervation of muscle fibres; and (3) that, as appears from some experimental work, such degenerative changes and hypertrophy may represent an early stage of denervation (GUTMANN AND ZELENA 1962). In some cases of spinal muscular atrophy the muscle spindles show the following changes: a thickening of the capsule, proliferation of connective tissue within spindles
Fig. 7. Transverse section through the sarcolemmal bag region of a musclespindle in the deltoid. Thickening of capsule, oedema of intracapsular space. Haematoxylin-eosin, × 200. I. neurol. Sci.
(1968) 6:269-287
276
I. HAUSMANOWA-PETRUSEWICZe t al.
(Fig. 7), and, rarely, degenerative changes in the intrafusal muscle fibres. These changes are non-specific (they have been observed in various cases of myopathy) and are not very pronounced. The changes we found in intramuscular m o t o r nerve fibres and in the end-plates in the acute form of Werdnig-Hoffmann disease resembled those described by other authors. Changes in the intramuscular terminal nerve bundles were seen in all cases under consideration (Fig. 8). In cases with diffuse muscle atrophy in the biopsy specimens, there was loss of terminal motor innervation. In others, collateral reinnervation was occasionally found. In the Kugelberg-Welander form, numerous collateral, terminal, and subterminal sprouts were seen in areas of non-atrophic muscle fibres
Fig. 8. Marked loss of nerve fibres from an intramuscular nerve bundle comprising exclusively large sensory fibres. Biopsy specimen from the deltoid muscle. Intravital methylene blue staining, x 600. (Fig. 9). Branching was more profuse than in the acute form of the disease, and besides collateral reinnervation of some muscle fibres, there appeared also to be hyperneurotization of a few others. Hence, it is possible that the benign and the acute form of spinal muscular atrophy differ somewhat in the abnormalities of terminal motor innervation which are observed. The problem of the innervation of the non-atrophic muscle fibres seems to deserve further study, notably in connexion with research on the hypertrophy of some muscle fibres and certain electromyographic changes. U l t r a s t r u c t u r a l s t u d i e s . Electron microscopy showed changes to be more pronounced in the acute form of Werdnig-Hoffmann disease. The continuity of the myofibrils was preserved, but they were narrowed, and the interfibrillar spaces were enlarged. Their number was distinctly reduced in some muscle fibres, which resulted in a pattern of "teased" myofibrils (Fig. 10). In other muscle fibres the myofibrils followed an irregular J. neurol. Sci. (1968) 6:26%287
INFANTILE AND JUVENILESPINAL MUSCULARATROPHY
277
and chaotic course, with filaments of a density resembling that of the Z-band running the whole length of the sarcomere or through part of it (Fig. 11). The mitochondria showed changes involving chiefly swelling of the matrix and disintegration of the mitochondrial cristae (Fig. 10). Occasionally there were osmiophilic inclusions (Fig. 11).
A
B
[
"'
Fig. 9. A: collateral branching. Biopsy specimen from the deltoid. Intravital methylene blue staining, × 600; B: drawing from Fig. 9A.
The sarcoplasmic reticulum showed dilatation of its canals with vacuolization (Fig. 12). In the more chronic forms of spinal muscular atrophy the changes were similar; the myofibrils were narrowed with clearing and obliteration of Z-bands, the mitochondria were swollen and disintegrating and the canals of the sarcoplasmic reticulum were dilated with the formation of giant vacuoles (Fig. 13) containing osmiophilic substances. Only in 1 case of the Kugelberg-Welander type, of 20 year duration and late onset, J. neuroL Sci.
(1968) 6:269-287
278
I. HAUSMANOWA-PETRUSEWICZ et al.
Fig. 10. Acute Werdnig-Hoffmann type. Biceps brachii. Longitudinal section. The continuity of myofibrils is preserved. The reduced number of myofilaments creates the impression of "teased" myofibrils (Mf). Z-band is pale. Disintegration of mitochondrial (Mi) cristae with paling of the matrix, X 45,000.
Fig. 11. Acute Werdnig-Hoffmann type. Biceps brachii. Longitudinal section. Chaotic, irregular destruction of myofibrils (Mf). Filaments resembling Z-band in density extend throughout the whole or a part of the length of a sarcomere, x 48,000. Z neurokSci. (1968) 6:269-287
INFANTILE AND JUVENILE SPINAL MUSCULAR ATROPHY
279
Fig. 12. Acute Werdnig-Hoffmarm type. Biceps brachii. Longitudinal section. The myofibrils (Mf) are showing the characteristic cross-striations (Z,M-band). The canals of the sarcoplasmic reticulum (SR) are excessively dilated. Mitochondria (Mi) with clear matrix and numerous short cristae. Nucleus (Nu) is unchanged on periphery of muscle cell, x 48,000.
Fig. 13. Chronic Werdnig-Hoffmarm type. Biceps brachii. Longitudinal section. Paling and disappearance of Z-band. The canals of the sarcoplasmic reticulum (St), are excessively dilated and filled with an osmiophilic substance, × 45,000. J. neuroLSci. (1968) 6:269-287
280
I. HAUSMANOWA-PETRUSEWICZel al.
there were also, besides the changes characteristic of neurogenic atrophy, others which resembled the changes seen by us in muscular dystrophy. They consisted in discontinuities of myofibrils due to focal destruction of myofilaments in different parts of sarcomeres with preservation of the Z-band and with large areas devoid of myofibrils (Fig. 14). The canals of the sarcoplasmic reticulum showed little dilatation, and there were no changes in the mitochondria.
Fig. 14. Kugelberg-Welander type. Deltoid. Longitudinal section. Marked widening of the interfibrillary spaces. Continuity of myofibrils patchily interrupted (Mf). Irregular destruction of myofilaments. Z-band well preserved. Mitochondria (Mi) and their cristae are normal, × 36,000.
This electron microscopic pattern deserves special attention because it shows changes characteristic of neurogenic lesions (loss of the Z-band, reduction of the myofibril diameter, and widening of interfibriUar spaces) together with some changes met with in muscular dystrophy. Histochemistry. Histochemical investigation of muscle specimens* demonstrated changes commonly observed in neurogenic lesions: viz. (1) the difference between type I and II muscle fibres was blurred; (2) enlarged groups of fibres of a single type (Fig. 15), and (3) target fibres were present. FENICnI~L AND ENGEL (1963) reported that in Werdnig-Hoffmann disease, atrophy * The activity of the following enzymes was tested in the sections: succinic dehydrogenase after Pearse's method, lactic dehydrogenase after Novikoff's method, cytochrome oxidase after Burstone's method, in a few cases dehydrogenases, glycerophosphate and glucose-6-phosphate after Barka's method, phosphorylase a and b after Takeuchi and Kuriaki's and Cuh-Wegman's methods, myofibrillar ATP-ase after Padykula's method, acetylcholinesterase after Koelle-Gerebtzoff'smethod. J. neurol. Sci. (1968) 6:269-287
INFANTILE AND JUVENILE SPINAL MUSCULAR ATROPHY
281
and hypertrophy concern only fibres of type I. Our material fails to confirm this view; usually we saw atrophy of fibres of both types (I and II), whereas occasionally blurring of the difference between them made it impossible to establish which type was atrophic or hypertrophic. In a few cases only, there are strikingly selective lesions of the fibres
Fig. 15. Kugelberg-Welander type. Enlarged groups of uniform fibre type. Biceps brachii. Succinic dehydrogenase, x 120.
Fig. 16. Werdnig-Hoffmarm type. Atrophy of type II muscle fibres. Biceps brachii. Myofibrillar ATP-ase, x 100.
of a single type, either I or II (Figs. 16 and 17), as if fibres of the other type had resisted the morbid process longer. This finding deserves further study; it might be indicative of differences in response to the disease between fibres of particular types, or of selective lesions of the anterior horn cells innervating only a single metabolic type of fibre. Much J, neurol. ScL
(1968) 6:269-287
282
I. HAUSMANOWA-PETRUSEWICZet al.
Fig. 17. Kugelberg-Welandertype. Atrophy of type II muscle fibres. Deltoid. Myofibrillar ATP-ase, x 200.
Fig. 18. Werdnig-Hoffmann's form. Group of motor end-plates, some of them having a simplified structure. Biceps brachii. AChe, × 120.
as in other cases of neurogenic atrophy, we saw in spinal muscular atrophy some normal motor end-plates and also large numbers of small ones, some of them having a simplified structure (Fig. 18), and others with acetylcholinesterase activity in foci which were broken up into granules.
BIOCHEMICALSTUDIES The biochemical methods were those commonly used in muscle disease. Even if the physiological creatinuria of children is taken into account, we found the level of urinary creatine in spinal muscular atrophy to be raised in the form of WerdnigHoffmann more so than in that of Kugelberger and Welander. Increased serum aldolase and pyruvic transaminase activity was a finding in 66 ~o of the cases in the clinical groups 1 and 2 taken together, and in 56 ~ of those of the KugelbergWelander type, but the "scatter" of activity values was much larger in the latter condition. Oxalacetic transaminase activity in the serum behaved somewhat differently, rising to the highest relative levels in the more acute cases. Serum creatine kinase aetivJ. neurol. Sci. (1968) 6:269-287
283
INFANTILE AND JUVENILE SPINAL MUSCULAR ATROPHY
ity (Fig. 19) was elevated in many cases of the Kugelberg-Welander type (in 70 of the cases). It was highest in 5 patients with clinically distinct pseudodystrophic features and with a histological pattern which in certain respects resembled that of progressive muscular dystrophy (HETNARSKA e t al. 1968). The cause of this finding is
40
30"
20.
10-
.-.'. ~-~*, . 2r Acute form of WerdnigHoffmann disease
.....
o-~--
.....
2T
//2-
Spinalatrophy of lore childhood 'intermediate rarer
KugelbergWe[ander form
Fig. 19. Mean values of creatine phosphokinase in serum in various types of spinal muscular atrophy.
A W/./,• R
]!
Fig. 20. Immunoelectrophoresis performed with rabbit anti-Werdnig-Hoffmarm serum (AWHS~). The additional line in the o~-globulin fraction in the patient's serum is marked with the arrow. A: photography; B: drawing. J. neurol. Sci. (1968) 6:269-287
284
1. HAUSMANOWA-PETRUSEWICZel al.
obscure; excessive discharge of the enzyme into the blood stream may be connected with injury of the cell membrane, or, perhaps, with changed cell metabolism due to disorganization of cell structures. Obviously, these are merely hypotheses. The levels of serum o¢1, ~2, and r-globulins were raised at the expense of albumins and y-globulins in about one-half of the cases, irrespective of the form of spinal muscular atrophy. Agar gel immunoelectrophoresis was performed by Scheidegger's semimicromethod. When non-specific serum was used, the pattern and intensity of the precipitation arcs did not differ in the sera of patients and controls. But with the specific diagnostic serum the sera of patients with spinal muscular atrophy gave an additional arc in the zone of ~2-globulins which was not obtained for control sera (Fig. 20). A correlation between this phenomenon and the form of the atrophy could not be detected, which suggests that this abnormality in o~2-globulins may be a specific feature of neurogenic muscular atrophy in general.
ELECTROMYOGRAPHY
Electromyography (EMG) does not serve merely to confirm a clinical diagnosis of spinal muscular atrophy but often determines it, or modifies a previous diagnosis. On analyzing our material from this point of view it was possible to distinguish two groups of cases in which electromyography was diagnostically decisive: (1) so-called "floppy baby" syndromes, where in some cases the EMG enabled the spinal origin of the disorder to be established; and (2) a group of patients with the clinical diagnosis of muscular dystrophy who turned out to have spinal muscular atrophy of the KugelbergWelander type. It should be stressed that in these cases the EMG supplies an answer relatively rapidly and more easily than histopathology; moreover, it makes possible the comparison of many muscles, which adds to the reliability of the results. Since it can be repeated in the same muscle at intervals it also enables the dynamic nature of the morbid process to be appraised. On analysis, our EMG data obtained in spinal muscular atrophy are found to correspond essentially to the generally-known features of a neurogenic pattern. Thus there is a reduced interference pattern on maximal effort (single oscillations or a mixed pattern), the motor unit action potentials are of longer duration and higher amplitude than normal, there is increased synchronization and spontaneous activity in the form of fibrillations and fasciculations. There were, however, certain differences between the various forms of spinal muscular atrophy in our material. Thus, in the acute form of Werdnig-Hoffmann we saw single oscillations, but sometimes the amplitude of potentials was not very high. The duration of potentials was distinctly reduced in some cases, and "giant spinal" units of long duration appeared only occasionally. There were many polyphasic potentials, and spontaneous activity was manifest in this group of patients primarily as fibrillation. In the chronic form there was a reduced pattern on maximal effort, often single oscillations of high amplitude were seen, there were almost no small units, and only a small proportion of polyphasic potentials; the vast majority were "giant spinal" potentials. Synchronization was very distinct, and fasciculations were frequent (Figs. 21 A, B). Differences in the parameters of the potentials recorded in the J. neurol. Sci.
(1968) 6:269-287
INFANTILEAND JUVENILESPINAL MUSCULARATROPHY
285
various clinical groups of cases of spinal atrophy may be determined by differences in the dynamic process of the disappearance or disintegration of units and differences in the arrangement of atrophic and preserved units (cf. histological findings). The considerable elongation of motor unit territory developing during the course of the
A
B
Fig. 21. A: reduced maximal effort pattern (single oscillations)from the deltoid; B: very tall potentials of long duration ("giant" type).
286
l. HAUSMANOWA-PETRUSEWICZe t a [ .
atrophy depends on the one hand on the phenomenon of collateral reinnervation, while on the other it is probably due to synchronous firing of anterior horn cells. In some cases of various clinical types there was a myasthenia-like reaction. Disturbed transmission might be explained by abnormal conduction in the new nerve collaterals and their end-plates, formed as a result of regeneration, or directly by changes in the body of anterior horn cells. A characteristic phenomenon seen only in very longstanding spinal atrophy was the finding of volleys of spontaneous discharges of a pseudomyotonic character. These consisted either of small brief potentials or highamplitude long oscillations, and were most pronounced in the ease of muscles which histologically showed "pseudomyopathic" changes in addition to denervation (Fig. 22).
Fig. 22. Pseudomyotonic volley of high frequency spontaneous discharges (deltoid).
TREATMENT
Treatment was pharmacological as well as physical. The patients were given vitamins, Nivalin (galanthamine hydrochloride), anabolic steroids, and synthetic derivatives of adenosinephosphoric acid, but there was no perceptible improvement. Physical therapy was applied only in mild cases, with improvement in some, and there was never an adverse effect. It needs to be borne in mind, however, that slight improvement may be due to the natural course of the disease process and to increasing power in innervated muscle fibres; it may not necessarily be the result of treatment.
SUMMARY AND CONCLUSIONS
Our present clinical and laboratory data, as well as analysis of the pedigrees, seem to indicate that the different forms of spinal muscular atrophy are merely variants of the same disease and differ only in the rate and severity of the denervation process. In this context it appears to be an interesting point that with increasing duration of the neurogenic process biochemical and histological changes resembling those of muscular dystrophyappear. J. neurol. Sci. (1968) 6:269-287
INFANTILE AND JUVENILE SPINAL MUSCULARATROPHY
287
REFERENCES (only some leading recent references are given) ARMSTRONG,R. M., M. H. FOGEL$ONANDD. H, SILBERBERG(1966) Familial proximal spinal muscular atrophy, Arch. Neurol, (Chic.), 14: 208-212. BECKI~R,P. E. (Ed.) (1966) Humangenetik, Vol. 5, Part 1 (Krankheiten des Nervensystems), Thieme, Stuttgart. BRANDT, S. (1950) Werdnig-Hoffmann's Infantile Progressive Muscular Atrophy, Munksgaard, Copenhagen. FENICHEL, G. M. AND W. K. ENGEL (1963) Histochemistry of infantile spinal muscle atrophy, Neurology (Minneap.), 13 : 1059-1066. GUTMANN,E. ANDJ. ZELENA(1962) Morphological changes in denervated muscle. In: E. GUT~A~q (Ed.), The DenervatedMuscle, Publ. House Czechosl. Acad. Sci., Prague, pp. 57-102. HETNARSKA, L., J. PROT AND W. SAWICKA(1968), Creatine phosphokinase activity in spinal muscular atrophy, J. neurol. Sci., 6: 261-267. TSUKAGOSHI,H., H. SUGITA,T. FURUKOWA,T. TSUBAKIAND E. ONO (1966) Kugelberg-Welander syndrome with dominant inheritance, Arch. Neurol. (Chic.), 14: 378-381.
J. nearol. Sci. (1968) 6:269--287