Spastic paraplegia-paraparesis

Journal of the Neurological Sciences, 1980, 46: 1-12

1

© Elsevier/North-Holland Biomedical Press

SPASTIC PARAPLEGIA-PARAPARESIS A Reappraisal

JULIAN Y. UNGAR-SARGON, ROBERT E. LOVELACE and JOHN C.M. BRUST

Departments of Neurology, College of Physicians and Surgeons, Columbia University, Columbia Presbyterian and Harlem Hospital Medical Centers, Clinical Neurophysiology Laboratories of the Neurological Institute, and the H. Houston Merritt Center for Muscular Dystrophy and Related Diseases, New York, N Y (U.S.A.) (Received 9 April, 1979) (Revised, received 18 October, 1979) (Accepted 22 November, 1979)

SUMMARY

During a 16-year period 672 patients were admitted to the Columbia Presbyterian Medical Center with spastic paraplegia-paraparesis (SPP) as a prominent finding. Group L 520 patients (77.3~) had either a familial disorder, sensory findings, other neurological signs, or a diagnosis obvious on admission by history, examination or plain spine roentgenograms. Group II. In 108 patients (16.2~) diagnosis was reached after more extensive investigation. In 78 of these a cause other than multiple sclerosis was found including spinal cord tumor, arteriovenous malformation and cervical spondylotic myelopathy. Thirteen patients had probable multiple sclerosis on the basis of additional signs emerging, and 17 were considered to have possible multiple sclerosis on the basis of elevated CSF gamma-globulin. Group IlL In 44 patients (6.5~) no cause for SPP could be found. Diagnostic considerations for this group included amyotrophic lateral sclerosis, multiple sclerosis, unappreciated structural lesions, hereditary disease, and "primary lateral sclerosis".

Presented in part at the 11th International Congress of Neurology (Amsterdam) 1977. Abstract 717. This work was supported by the Center grants, NS-11766 from the National Institute of Communicative Disease and Stroke, and from the Muscular Dystrophy Association. Dr. Ungar-Sargon was a clinical fellow of the Muscular Dystrophy Association and is currently faculty, Department of Neurology, Temple University, Philadelphia, PA. Correspondence: Dr. Robert E. Lovelace, Box 157, 710 West 168th Street, Neurological Institute of New York, New York, NY 10032, U.S.A.

1N T R O D U C T I O N

The cause of progressive spastic paraplegia or paraparesis (SPP) is often diagnosed on the basis of history, examination and plain spine roentgenograms. There remain, however, patients in whom no diagnosis is reached, even after more extensive investigations including myelography or spinal angiography. Recent reports of SPP of unknown origin are few (Stark 1945; Wechsler 1946; Marshall 1955; Hubbe 1973), and whether the syndrome o f - p r i m a r y lateral sclerosis" (PLS) represents a disease entity remains controversial. A reappraisal of SPP, therefore, seems indicated. The present report is a retrospective review of consecutive admissions of SPP to a large metropolitan teaching hospital. Special attention is given to those in whom exhaustive studies failed to reveal an aetiology. METHODS

The patients were ascertained by searching the Presbyterian Hospital's computer diagnostic index file under international code classification for spastic paraplegia, paraplegia-spastic and spastic paraparesis between the years 1960 and 1976. During the same period similar search for multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and spinocerebellar degeneration (SPCD), respectively, was undertaken in order to determine whether any patients with the above diagnoses presenting with SPP, had failed to be cross registered. Of the 577 patients with MS, 136 patients with ALS and 6 patients with SPCD, there was no instance of failure to cross register. The registry did not record whether the deficit was static or progressive; whether or not other neurological signs such as sensory loss were present; whether a diagnosis was apparent on the basis of history, neurological examination or plain spine roentgenograms; or whether a diagnosis was finally reached after more extensive studies. The 672 cases so registered under SPP were, therefore, reviewed from their charts with special attention to the above criteria. RESULTS

We were able to classify the 672 patients into 3 groups (Table 1). Group I consisted of patients who had either a familial disorder, sensory loss, other neurological signs, or an obvious diagnosis on admission based upon history, examination or plain spine roentgenograms. Group II consisted of patients in whom a diagnosis was not readily apparent on initial evaluation but in whom it was reached after further investigations, including cerebrospinal fluid (CSF) analysis, myelography, spinal angiography or surgery. No patients in Group I1 had sensory loss or other neurological signs on admission; all had progressive courses. Group III consisted of patients with pure progressive SPP in whom no diagnosis was reached. There were 520 patients in Group I (Table 2). Those with hereditary SPP

TABLE I CLASSIFICATION OF PATIENTS Group

Criteria

Numbers

1

Family history, additional neurological signs or etiology apparent on initial evaluation

520

77.3

108

16.2

44

6.5

il III

Etiology found after specialized studies Unknown etiology for SPP "primary lateral sclerosis" Total

672

100

TABLE 2 DIAGNOSES IN GROUP I Diagnosis

No. of patients

Familial spastic paraparesis Multiple cerebrovascular episodes Spinal cord tumor Transverse myelopathy Multiple sclerosis Spinal trauma Miscellaneous congenital "atonic diplegia" a kyphoscoliosis cervical spondylosis arachnoiditis Arnold-Chiari malformation myelomeningocele post meningitis cord stroke amyotrophic lateral sclerosis Pott's disease

16 55 71 68 14 181 115 25 14 26 9 5 10 6 4 7 9 Total

520

3.0 10.6 13.65 13.0 2.69 34.8 22.26

100

a These patients were hypotonic at some time early in their illnesses, but at time of discharge were spastic.

(16 p a t i e n t s f r o m 9 f a m i l i e s ) d i d n o t h a v e s e n s o r y o r o t h e r a b n o r m a l i t i e s . M o s t p a t i e n t s w i t h c e r e b r o v a s c u l a r d i s e a s e h a d p s e u d o b u l b a r f e a t u r e s . S e n s o r y loss w a s p r e s e n t in all w h o h a d r e a d i l y d i a g n o s e d t u m o r s , w h e t h e r i n v o l v i n g the spinal c o r d o r b r a i n ( T a b l e 3). H a l f t h e c o r d t u m o r s

were metastatic

( T a b l e 4). P a t i e n t s

4 TABLE 3 TUMORS CAUSING SPP Histology

Number

Spinal cord

meningioma intraspinal lipoma ependymoma paraganglioma neurofibroma angioblastic meningioma intramedullary tumor metastatic

5 4 4 2 2 2 6 35 Total

60

Brain

neuroblastoma parasagittal meningioma corpus callosal tumor right parietal meningioma brain stem glioma undiagnosed brain tumor

1 1 1 2 4 2

Total

11

TABLE 4 PRIMARY ORGAN CAUSING METASTATIC DISEASE TO THE SPINAL CORD Lung Breast Bladder Prostate Phaeochromocytoma Reticular cell sarcoma Liver Penis Melanoma Myeloma Osteogenic sarcoma Lymphosarcoma Total

lI 6 1 2 3 3 1 1 1 1 1 1 35

d i a g n o s e d s i m p l y as " t r a n s v e r s e m y e l o p a t h y "

h a d p r o m i n e n t s e n s o r y loss; m a n y

w e r e s u s p e c t e d to h a v e M S . F o u r t e e n a d d i t i o n a l p a t i e n t s w e r e c o n s i d e r e d to h a v e d e f i n i t e M S o n the basis o f h i s t o r y a n d e x a m i n a t i o n . M o s t p a t i e n t s w i t h spinal t r a u m a h a d b e e n flaccid for v a r i a b l e i n t e r v a l s a f t e r t h e injury. M a n y h a d , in a d d i t i o n , s e n s o r y loss. P a t i e n t s classified as " c e r v i c a l s p o n d y l o s i s " h a d in a d d i t i o n

TABLE 5 GROUP II DIAGNOSES D!agnosis

No. of patients

Spinal cord tumor Cervical spondylosis Skeletal deformities kyphoscoliosis 4 tuberculosis and Pott's disease 4 Paget's, odontoid malunion 2 Narrow canal syndrome, cast atrophy 6 Arteriovenous malformation Arnyotrophic lateral sclerosis Subarachnoid hemorrhage Arachnoiditis Syphilis Hallervorden-Spatz disease Multiple sclerosisprobable Multiple sclerosis possible Total

15 15 16

13.8 13.8 14.8

21 3/ 21

19.4 10.5

13 17 108

12.0 15.7 100

to radiographic evidence, lower motor neurone findings in the upper extremities as well as sensory loss or pain. Nine patients with arachnoiditis had previous spinal operations, myelography, or intrathecal injection. Seven patients with ALS had atrophy of hand muscles and fasciculations in addition to SPP. All 108 patients in Group II had SPP as the sole finding on admission examination and further investigations resulted in a diagnosis (Table 5). Spinal cord tumors were diagnosed at surgery and included meningioma, lymphosarcoma, Hodgkin's disease, neurofibroma, osteogenic sarcoma, epidermoid carcinoma, leukemia, lipoma, astrocytoma, oligodendroglioma, ileal sarcoma, and lung carcinoma. Patients with cervical spondylosis had evidence of cord compression on myelography. Diagnosis was made by tomography and myelography in the patients with Pott's disease. Arteriovenous malformation of the spinal cord was diagnosed by tortuous vessels on myelography or by spinal angiography. Patients with amyotrophic lateral sclerosis had no evidence of motor neurone disease clinically, but electromyography revealed widespread denervation, fasciculations and giant motor units. Subarachnoid hemorrhage led to angiographic diagnosis of an anterior communicating aneurysm in one patient; in another no cause for bleeding was found. The characteristic pattern of arachnoiditis on myelography was found in another patient who had no history of previous infection, spinal anesthesia, myelography or surgery. Patients with syphilis had positive cerebrospinal fluid VDRLs; two had positive and 2 negative fluoroscent treponemal antibodies in the

serum. T h e p a t i e n t with H a l l e r v o r d e n - S p a t z disease d e v e l o p e d SPP at the age o f 4 with little p r o g r e s s i o n o f s y m p t o m s for 4 years before she was f o u n d to be m e n t a l l y dull at age 14. A t age 16 she was seen a g a i n for m a j o r m o t o r seizures, d y s a r t h r i a a n d dementia. She died 7 m o n t h s later, a n d a u t o p s y ( p e r f o r m e d by Dr. R. Defendini, 1973) r e v e a l e d the typical p a t h o l o g i c a l features a n d a n o r m a l spinal cord. Thirteen p a t i e n t s f r o m G r o u p II were c o n s i d e r e d to have " p r o b a b l e M S " on the basis o f s u b s e q u e n t a d d i t i o n a l n e u r o l o g i c a l findings such as optic a t r o p h y a n d cerebellar signs. A further 17 p a t i e n t s with pure SPP a n d no o t h e r n e r v o u s system i n v o l v e m e n t were d e e m e d to have " p o s s i b l e M S " on the basis o f a high C S F g a m m a globulin fraction (over 13~o total protein). In no case d i d the C S F p r o t e i n exceed 100 mg/dl. G r o u p I I I c o m p r i s e d 44 p a t i e n t s in w h o m exhaustive studies failed to reveal a diagnosis. T o assess the l i k e l i h o o d o f these patients having M S , they were c o m p a r e d in detail to those p a t i e n t s in G r o u p II with p r o b a b l e a n d possible MS. S y m p t o m s first a p p e a r e d at a later m e a n age a m o n g patients o f G r o u p III t h a n a m o n g the M S p a t i e n t s in G r o u p II (Table 6). In half the G r o u p III p a t i e n t s s y m p t o m s b e g a n after age 50 with a greater range o f age onset, from 17 to 72 years. N o M S p a t i e n t in G r o u p II h a d onset o f s y m p t o m s below age 20 or over age 70. 69~o o f the p r o b a b l e a n d 76~o o f the possible M S patients in G r o u p II were female ( n u m b e r s too small for statistics), but the sexes were a l m o s t equally divided in G r o u p III (Table 7). T h e r e was no difference in the severity o f spasticity between G r o u p II M S p a t i e n t s a n d G r o u p I I l patients. T w e n t y - e i g h t percent o f

TABLE 6 AGE ONSET IN PROBABLE AND POSSIBLE MS PATIENTS OF GROUP 1I AND GROUP III Difference in mean age of onset between probable MS and Group 111 patients is significant at the 95% level (Student's t-test = 2; P = 0.05). Age onset (yr)

under 20 20~30 3(L40 40-50 50-60 60-70 over 70

Probable MS patients Group II

Possible MS patients Group II

SPP unknown aetiology Group 1II patients

No.

No.

No.

,

3 5 4 5 15 4 3

7.6 12.8 10.3 12.8 38.6 10.3 7.6

0 6 3 1 1 2 0 Total

13

o/,,, 0 46.6 23 7.5 7.5 15.4 0 100

0 1 3 9 0 4 0 17

a In 5 patients age onset was unclear from the record.

'!;, 0 5.8 17.6 52.9 0 23.7 0 100

39 ~t

t00

TABLE 7 SEX R A T I O IN P R O B A B L E A N D POSSIBLE MS P A T I E N T S IN G R O U P II A N D IN SPP P A T I E N T S IN G R O U P III

Approximate binomial distribution: no significant differences in sex incidence. Probable MS patients

Sex

Male Female Total

Possible MS patients

SPP patients

4 9

4 13

20 24

13

17

44

TABLE 8 CSF G A M M A - G L O B U L I N F R A C T I O N

The means of gamma globulin levels for the Probable and Possible MS patients are significantly higher than the SPP Group 1II (Student's t-test = 5.43; P < 0.001). Test

Probable MS patients

LP & gamma-globulin Performed 12 No. of patients 13 % Protein 0-5 5 10 10-15 15-20 20-30 3(~40 over 40 range mean

0 1 3 3 2 3 0 8-35~ 20~

Possible MS patients

SPP patients

17 17

24 44

0 0 0 6 7 2 2

1 7 14 2 0 0 0

17-35~ 23 ~o

7-15~ 9.7~o

Group II MS patients and 3 0 ~ of group III patients had CSF proteins greater than 50 mg/dl; there was no significant difference between their mean values (T value greater than 0.80). By definition all patients in Group II with possible MS and none in Group III had elevated gamma-globulin fractions (Table 8). In eight of Group II probable MS patients, the gamma-globulin exceeded 13~ of total protein. Although no cord compression was seen on myelography in any Group II MS patient or Group III patient, 38~o of the Group III patients had minor spondylotic changes compared to 6 ~ of the possible MS (Group II) patients and none of the probable MS (Group II). Atrophy of the extremities was more common in Group III patients than in Group II MS patients but in each case was attributed to disuse. Electromyography showed no denervation or abnormal nerve conduction velocities in the 22 Group III patients on whom it was performed.

DISCUSSION

Whether SPP of unknown origin represents a disease entity, primary lateral sclerosis (PLS), has long been a subject of debate (Gowers 1886; Spiller 1904; Oppenheim 1923 ; Swank and Putnam 1933 ; Wilson 1940). Autopsies by Charcot (1865), Morgan and Dreschfield (1881), and Minkowski (1884) demonstrated marked sclerosis of the pyramidal tracts from the lumbar to cervical cord with sparing of anterior horn cells. Spiller (1903), on the other hand, performed autopsies on 8 patients who clinically were considered to have '~primary degeneration of the pyramidal tracts"; in only two cases were the anterior horns spared, the other 6 representing amyotrophic lateral sclerosis. Marshall (1955), reviewing Greenfield's and Blackwood's 35 necropsy cases of SPP, concluded that in all cases a diagnosis other than PLS was possible, including tumor (11), prolapsed disc (2), syringomyelia (3), other diagnoses (7), and 12 in whom an explanation for the paraplegia was found at autopsy (multiple sclerosis: 6). On the other hand, Fisher (1977), reporting autopsy findings in 2 patients with pure SPP, suggested PLS might be a disease entity. Similar findings were observed in a case of Thompson and Ungar-Sargon (to be published). There have been several clinical studies without pathological data. Stark and Moersch (1946) reported 43 cases, and Wechsler and Brody (1946) 30 cases of nonfamilial PLS. They believed they were observing a disease entity which differed from MS because of its lack of dissemination and its insidiously progressive course without remissions; all cases were followed for at least 5 years without apparent involvement of other systems. Duration often exceeded 20-30 years. For 10 years Marshall (1955) followed 52 patients with SPP beginning in middle age; diagnoses included MS (10), spinal cord tumor (7), disc (3), syrinx (1) and other conditions (6); 25 remained "undiagnosed". Hubbe (1973) analyzed 255 patients with SPP; in only 43 (16.8~o) was no diagnosis apparent on initial evaluation. 10 of these were familial. 5 years later, 15 of the 33 remaining patients were still without a diagnosis, the others having MS (7), spinocerebellar degeneration (1) and spinal cord tumors (2). Among several series of patients with SPP from India (Minchin 1940; Desai 1954; Bhargava 1957; Mehrota 1966; Patel 1971), not only were patients often included who had obvious involvement of other parts of the nervous system, but it was often unclear to what degree nutritional factors such as lathyrism might have played a role. Five of Fisher's unautopsied 6 patients with undiagnosed pure SPP had symptoms of pseudobulbar palsy. Although our study began with 672 patients presenting with SPP as a prominent finding, separation of Groups I and II by additional neurological signs and immediate or delayed diagnosis reduced the number with pure undiagnosed SPP (Group III) to 44 cases. In 70 (63~o) of the 108 cases in Group II with pure SPP a cause other than MS was found, including arteriovenous malformation (AVM) (19.4~o), spinal cord tumor (13.8~o), cervical spondylosis (13.8~o) and other skeletal abnormalities (14.8~o). That cord tumor and AVM can present as pure SPP has been noted by others (Marshall 1955; Hubbe 1973) although the latter is

9 a very infrequent cause (Brion 1952; Aminoff and Logue 1974; Tobin 1976). Cervical spondylosis poses a special problem, for it is so common in older people that without other neurological signs, e.g., pain, sensory loss, or weakness in the arms, it is not always certain that it is the cause of SPP, even when cord compression is seen on myelography. Nurick (1972) found 91 patients with spondylosis and 34 with MS from a total of 135 with cervical cord disease, and he demonstrated the lack of correlation between the severity of spondylosis and paraparesis. Cervical spondylosis moreover may affect the cord by compromising its vascular supply, without compression being myelographically demonstrable. Of the miscellaneous diagnoses, also problematic are the 4 patients with positive CSF VDRLs. Meningovascular syphilis has been considered a cause of acute transverse myelitis and of progressive SPP in patients with positive CSF serology (Merritt et al. 1946). In the absence of pathological data it is not known whether syphilis was indeed the cause of SPP in reported cases or in our own 4 patients. Only 3 of the 108 patients in Group II had ALS. Although they had no clinical signs of motor neurone disease, electromyography revealed widespread denervation with normal motor and sensory nerve conduction velocities. They contrasted with the few patients with ALS in Group I in whom SPP was a prominent finding, but in association with obvious signs of denervation. No other patients with SPP were identified among the 136 cases of ALS registered in the computer index file during the same period under study. Although patients with arachnoiditis are more likely to be flaccid (Brock 1936; Kamman and Baker 1943; Kennedy 1945), Wood and Franklin (1951) described arachnoiditis with SPP and in 34 out of 41 cases reported by Elkington (1936) SPP was found simulating spinal cord tumor. Hallervorden-Spatz disease has been associated with Friedreich's ataxia (Guiraud and Roualt 1959) as well as leukodystrophic forms of infantile neuroaxonal dystrophy (Seitelberger and Gross 1957; Seitelberger 1971). Our patient was atypical in that SPP was the presenting sign. Fourteen patients were readily diagnosed on admission as having MS, i.e. those in Group I. Thirteen in Group II were found on subsequent examination to have lesions elsewhere in the nervous system and were diagnosed as having MS. A further 17 patients in Group II had pure SPP with elevated CSF gammaglobulin and were thought to have "possible MS". The 44 patients in Group III in whom no diagnosis could be reached, represented 6 ~ of the original 672 patients. None of these 44 patients had evidence of motor neurone disease. Fasciculations were absent, and atrophy, when present, was mild and consistent with disuse. There was no denervation in the 22 patients tested by electromyography. Swank and Putnam (1943) had 21 cases labelled primary lateral sclerosis (PLS) in their series of ALS patients. They justified this inclusion by the precedent of Spiller's series of patients with PLS with 6 out of 8 having anterior horn cell involvement at autopsy. We would have labeled these 6 patients of Spiller as ALS. McAlpine described progressive SPP of middle life as a form of "possible"

10 multiple sclerosis when radiographic studies excluded other causes. We considered patients to have "probable" MS when additional nervous system lesions were evident and "possible" MS when there was elevation of CSF gamma-globulin. "Possible" MS has been considered by some authors (Allison 1954; McAlpine 1972) with progressive SPP alone, whereas McDonald (1974) called this category "progressive possible". Elevated CSF gamma-globulin (IgG) occurs in encephalomyelopathies other than MS (Kabat 1950; Schneck 1969) and in degenerative disorders and CNS neoplasm (Harter et al. 1962; Laterre et al. 1970). In MS it is elevated in only 6 6 - 8 5 ~ of patients using electroimmunodiffusion techniques (Tourtellotte 1975; Laterre 1965; Poser 1965; Schneck and Slaman 1969; Link and Muller 1971). Oligoclonal IgG patterns characterized by abnormality in the ratio of lambda to kappa light chains have been said to be more specific for MS (Link and Muller 1971) and to be present in 9 4 ~ of cases. This technique, unavailable to our patients, might well have identified some from our Group III as having possible MS. Visual evoked response (VER) testing would probably have identified still others. Halliday and MacDonald (1977) studied VER in 27 patients with "steadily progressive" SPP of middle life. Ten were diagnosed clinically as having MS, and 8 of these had abnormal VERs. Four patients with normal VERs were later found to have spinal cord tumors. The remaining 13 patients had undiagnosed pure SPP, and only 5 had abnormal VERs (38~). Asselman found abnormal VERs in 34 patients (70j°/) with clinical evidence for MS and only one abnormal VER in l0 patients with undiagnosed SPP (10~), but autopsy studies on patients with SPP and abnormal VERs have yet to be reported (Asselman 1975; Halliday 1976). It seems likely, therefore, that even had our patients been studied by oligoclonal IgG determinations and VER recording, a number would have remained undiagnosed. This view is supported by differences in age of onset and sex ratio between Group III patients and those MS patients of Group II (Tables 6 and 7). That some of our Group III patients may have had structural lesions (e.g., neoplasm or AVM) missed by myelography or angiography is suggested by the fact that several of Marshall's (1955) and Hubbe's (1973) cases were so diagnosed only after being followed for several years. Dominant inheritance may be missed when history is inaccurate, when onset is late in life, when the disorder results from spontaneous mutation, or when there are variations in penetrance or expressivity. Recessive inheritance may be missed when there are few or no siblings. Most cases of "familial spastic paraplegia" have additional neurological lesions (Schwartz 1952), but some have pure SPP with only corticospinal tract degeneration found on pathological examination (Jakob 1909; Raymond and Rose 1909; Kahlstorf 1937; Farago 1947). Our familial cases had clinically pure SPP, but it is possible that some of our Group llI cases also had hereditary disease. In conclusion, a study of the sparse literature suggests the occurrence of so-called "primary lateral sclerosis" as a disease entity. Until a large number of patients such as those similar to our Group III are followed to autopsy, its frequency will remain uncertain.

11 ACKNOWLEDGEMENTS

We wish to thank Dr. Lewis P. Rowland and our colleagues at the Neurological Institute for allowing us to investigate the records and publish these data concerning patients seen by them. Mrs. Amy Lopat, librarian, Neurological Institute, was very helpful in connection with the references and the typing was performed by Miss Nancy Baker and Miss Jacqueline Sikoryak. Mr. Leonard Zablow advised on the statistical studies. REFERENCES Allison, R. S. and J. H. D. Millar (1954) Prevalence and familial incidence of disseminated sclerosis in North Ireland, Ulster med. J., 23 : 1-92 (Supplement). Aminoff, M.S. and V. Logue (1974) Clinical features of spinal vascular malformation, Brain, 97: 197-210. Asselman, P., D.W. Chadwick and C.D. Marsden (1975) Visual evoked responses in the diagnosis and management of patients suspected of multiple sclerosis, Brain, 98: 261-282. Bhargava, H.S. and J.N. Berry (1961) A study of 50 paraplegia cases with reference to aetiology, J. Ass. Phys. lndia, 9: 211-220. Brion, S., M.G. Netsky and H.M. Zimmerman (1952) Vascular malformation of the spinal cord, Arch. Neurol. Psychiat., 68: 339-361. Brock, S., A. Bell and C. Davison (1936) Nervous complications following spinal anesthesia - - Clinical study of 7 cases, with tissue study in one instance, J. Amer. med. Ass., 106: 441447. Charcot, J.M. (1865) Scl6rose des cords lat6raux de la mo~lle epineuse chez une femme hyst6rique atteinte de contracture peiman des quatre menieres, Bull. Soc. mkd. H6p. (Paris), 2: 24. Defendini, R., W.R. Markesbery, A.R. Mastri and P.E. Duffy (1973) Hallervorden-Spatz disease and infantile neuroaxonal dystrophy, J. neurol. Sci., 20: 7-23. Desai, A. (1955) Paraplegia - - An analysis of 232 cases, Neurology (Minneap.), 4: 23-30. Elkington, J. St.C. (1936) Meningitis serosa circumscripta spinalis (spinal arachnoiditis), Brain, 59: 181-203. Farago, I. (1947) Beitrag zur Vererbung und Pathohistologie der spastischen Spinalparalyse, Mschr. Psychiat. Neurol., 114: 161-178. Fisher, C. M. (1977) Pure spastic paralysis of corticospinal origin, Canad. J. neurol. Sci., 4: 251-258. Gowers, W.R. (1886) Manual of Diseases o f the Nervous System, 1Iol. 1, J. and A. Churchill, London, p. 330. Guiraud, P. and A. Roualt de la Vigne (1959) Hallervorden-Spatz disease, Friedreich's disease and mental disorders - - Progressive nervous cachexia, EncOphale, 48:217-234. Halliday, A. M. and W. I. McDonald (1977) Pathophysiology of demyelinating disease, Brit. med. Bull., 33i (1): 21-27. Halliday, A.M., E. Halliday, A.. Kriss, W.I. McDonald and J. Mushin (1976) The pattern-evoked potential in compression of the anterior visual pathways, Brain, 99 : 357-374. Hubba~ P. and A. Mouritzen Dam (1973) Spastic paraplegia of unknown origin, Acta neurol, scand., 49 : 536542. Jakob, C. (1909) Spastische Spinalparalyse, Riv. Soc. med. Argent., 17: 665. Kabat, E.A., D.A. Freedman, J.P. Murray et al. (1950) A study of crystalline albumin, gamma globulin and total protein in the cerebrospinal fluid of 100 cases of MS. Kahlstorf, A. (1937) Klinischer und histopathologischer Beitrag zur heredit~iren spastischen Spinalparalyse, Z. ges. Neurol. Psychiat., 159: 774-780. Kamman, G. R. and A. B. Baker (1943) Damage to spinal cord and meninges following spinal anesthesia - - Clinicopathological study, Minnesota Med., 26: 786-791. Kennedy, F., H.M. Somberg and B. R. Goldberg (1945) Arachnoiditis and paralysis following spinal anesthesia, J. Amer. reed. Ass., 129: 664-670. Laterre, E.C. (1965) Les Prot~ines du Liquide C~phalo-Rachidien - - A l'Etat Normal et Pathologique, Arscia, Brussels. Laterre, E.C., A. Callewaert and J.F. Heremans (1970) Electrophoretic morphology of gamma

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