J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.13.2.134 on 1 May 1950. Downloaded from

J. Neurol. Neurosurg. Psychiat., 1950, 13, 134.

HEREDITARY SPASTIC BY EDWIN R. BICKERSTAFF From the Department ofNeurology, United Birmingham Hospitals The family under consideration in this paper has from Germany. Families are described in the been studied in detail, not only because its members central and southern American journals, others provide many examples of a disease which is very from the UJnited States, and isolated reports came rare in this country, but also because the differing from Russia and Japan. In Great Britain, how- clinical picture appearing in certain members of the ever, the disease appears to be rare, and indeed, family may contribute to the better understanding of despite an intensive search, Bell and Carmichael the hereditary disorders ofthe central nervous system, (1939) were able to find one family only amongst and their possible inter-relationship. The tendency the records of the last 25 years at the National for the members ofthis family to remain in the same Hospital, Queen Square, London, and the Maida part of the same city, even after marriage, has made Vale Hospital, London. (If one holds to strict it possible to examine the majority of the living diagnostic criteria, the disease is less common in members, and clinical details have been obtained other countries than appears, for it would seem, Protected by copyright. concerning several who have died. as Bell and Carmichael (1939) observe, that the It is evident that the disease is widespread through- major justification for the clinical differentiation of out three generations, and possibly four, and that this condition from the spastic is the absence alongside examples of the fully developed syndrome, of any form of -a rule not always observed.) there are numerous early or abortive cases. A A number of families affected by the disease noteworthy occurrence was the appearance in an have however been reported in this country. otherwise neurologically normal member of the Philip (1886) described a family illustrating worst-affected branch of the family of a typical linkage between two hereditary disorders, the retrobulbar neuritis. This case was seen both in father and one son developing typical spastic the acute phase and while progressing to an optic paraplegia, while the other son and a member of an atrophy. A probably similar occurrence was noted earlier generation showed the pseudo-hypertrophic in a cousin, and sufficient abnormality of the discs form of muscular dystrophy. seen in two other members of the family for the Gee (1889) described a father and two sons, all suspicion of a retrobulbar neuritis to have been being affected from infancy, if not from birth, with raised. a severe spasticity unassociated with ataxia, while http://jnnp.bmj.com/ there were other congenital abnormalities in the The English Families father's mother's family. Though the first description of hereditary spastic Tooth (1891), considering four new cases of his paraplegia is usually ascribed to Strumpell (1880) own in conjunction with Gee's, concluded that there seems little doubt that the same, or a closely hereditary spastic paraplegia was probably a clinical related pathological process was responsible for entity, though post-mortem studies were not then the condition described by Seeligmuller (1876) four available. years earlier, the main clinical difference being the Holmes' (1905) family had two (and possibly on September 28, 2021 by guest. presence of widespread general wasting, which may three) members who had a spastic paraplegia of well have been an atrophy of disuse. Since these early onset combined with localized muscle wasting. early reports a large literature has accumulated, He thought at that time that Seeligmiller's cases excellent reviews of which are given by Rhein might present a different condition, the wasting (1916), Paskind and Stone (1933), and Bell and being generalized and possibly a disuse atrophy. Carmichael (1939), and there is little to be gained The eight cases described by Jones (1907) were by further repetition here. Any study of the all members of one sibship of nine, four having the published cases, however, shows the great majority right side mainly affected. He lays stress on the to be in the continental journals, particularly those maintenance of power despite the spasticity. 134 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.13.2.134 on 1 May 1950. Downloaded from

HEREDITARY SPASTIC PARAPLEGIA 135 Ogilvie (1908) presented to the Royal Society of a diagnosis of disseminated sclerosis, but the Medicine the case of a girl showing spastic para- discovery that other members of his family were plegia without ataxia, whose two sisters were reputed to be similarly affected led to the conclusion similarly affected. It is interesting that this patient that this was, in fact, an example of one of the was reputed to have been ataxic four years earlier. heredo-familial disorders of the central nervous In the discussion following, Dr. Guthrie stated that system. With his death from a cerebral hemorrhage he attended a family in which the father and three in 1944 no further contact was made with his of five children showed spasticity without ataxia. relatives until his grandson was brought to the Manson's (1920) cases both showed mild ataxia Neurological Clinic at the General Hospital, and nystagmus in addition to the spasticity and Birmingham, in 1948. The child's mother gave the probably should not be included under this heading. story that her husband, her brother-in-law, and this No further examples have been traced in the infant had all developed the same condition as her English literature until the one family described by father-in-law. It was decided to examine the father Bell and Carmichael (1939). Three of four sisters and the normal son, and the discovery that the latter were affected, the two who were examined showing had a typical retrobulbar neuritis was of such great signs of marked pyramidal disease with posterior interest that a more extensive investigation was column affection but no ataxia, while a third, not embarked upon to include all the siblings of the seen, was said to have disseminated sclerosis. The original patient (11.9), their children and their parents were second cQusins and the onset of grandchildren. This was carried out personally, symptoms in the three cases occurred at ages 19, each patient being written to, the purpose of the 30, and 40 respectively. investigation explained, and an invitation to attend A familial spastic paraplegia was studied by as an out-patient for examination extended. Worster-Drought and others (1940 and 1944), but In the three generations with whom personal showed an contact their cases accompanying presenile has been possible, there have been 76 Protected by copyright. dementia, the syndrome being caused apparently by a individuals, of whom 20 have died. Of the re- hyaline change in the vessels and resultant demye- maining 56, 43 have been examined, while 13 were lination, and so differing considerably from the on active service with high medical categories, pathological changes usually found in hereditary untraced, living out of the country, or unwilling to spastic paraplegia. attend. It is notable that three only came into this last group. The Present Investigation Attention was first drawn to the existence of this Criteria for Diagnosis family when 11.9 (Fig. 1) was referred to Professor In the course of investigation of such a family, P. C. P. Cloake's clinic in 1940, and later admitted the diagnosis of the fully-developed case of the to the Queen Elizabeth Hospital for investigation disease presents little difficulty. The patient's stiff of his paraplegia. At first his condition suggested but not ataxic gait seen first on entering the examina-

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136136EDWIN R. BICKERSTAFF tion room; his complaints of stiffness on climbing accompanied by some other feature or features of stairs, "numbness" of the legs, weakness, un- the fully-established condition, e.g., subjective controllable shaking, nocturnal flexion, tripping, symptoms of stiffness, uncontrollable shaking, or wearing out the toes of the shoes; and the occasionally numbness; increase in tone (itself a finding of spastic limbs usually with well-preserved difficult sign to assess), the characteristic foot power whose reflexes are markedly exaggerated, deformity, long-sustained clonus or abnormal one or both plantars extensor, coordination good plantar responses. By these criteria several mem- but vibration sense diminished in the legs, all bers whose reflexes appeared pathologically brisk combine to make an easily recognizable picture. have not been included as early cases, though in To this must be added the deformity of the feet one of the two most extensive families previously found in many cases, which, though akin to pes investigated (Dobrochtow, 1913), the presence of cavus, differed in that whereas the toes were re- exaggerated reflexes only was considered evidence tracted, and the foot shortened antero-posteriorly ofincipient disease, while Appel (1949) more recently with convexity upwards of the dorsum, yet the has adopted similar criteria. expected concavity of the plantar surface was A very careful examination of the fundi was made reduced and apparently filled in by soft tissue, in all cases, for though optic atrophy is rarer in tending to disappear entirely when the patient stood hereditary spastic paraplegia than in the ataxias, the erect so that the imprint of the foot was normal. finding of a retrobulbar neuritis in one member led A difference in the deformity of the foot in cases of to a search for similar findings or sequelm. Pallor spastic paraplegia from the well-known pes cavus of the discs is so variable and indefinite a sign, of the hereditary ataxias was noted by Bell and however, that it was decided to adopt the attitude Carmichael (1939) from their study of the literature, taken by Bell (1933) and never diagnose optic and Tooth (1891) had remarked that in a member atrophy from pallor of the discs alone, unless visual

of his family " the feet present the appearance of failure was present. Similarly blurring of theProtected by copyright. pes cavus but the arching disappears when he stands edges of the discs was not considered definitely on the feet". This is again mentioned by Jones abnormal unless accompanied by visual failure, or (1907), and Appel (1949) refers to a foot deformity known to progress to atrophy. In this way several similar to that seen in Friedreich's ataxia, but less doubtful abnormalities have not been included in marked, and not typical. This appears particularly the genealogical table, but their presence is noted liable to occur in hereditary spastic paraplegia. in the case histories. This investigation was intended also to discover whether early, incomplete, or abortive forms of the Clinical Data disease existed in apparently unaffected members of Though, as has been mentioned above, this family the family, and many problems thus arose. It is has remained within a small area, comparatively necessary to exert self-discipline and avoid too little contact with one another has been maintained, great a diagnostic enthusiasm, for while it is a great and conflicting statements were made by different advantage for purposes of comparison for one persons regarding the health of the same relatives. neurologist to examine all the members of a family, The greatest difficulty was experienced in respect of the then arises to consider Generation I,* for though the father of Generation yet temptation very slight http://jnnp.bmj.com/ deviations from the normal as examples of incipient II was known to have been perfectly well apart from disease. This applies particularly to the assessment bilateral cataract in later life, no other accurate of tendon reflexes. It is a well-known fact that information was obtainable about any of his siblings nervousness is often accompanied by hyper-active or his parents. The mother of Generation II also reflexes, and at a first medical examination it is not led a healthy life. She was an only child, but had infrequent for patients to exhibit considerable several step-brothers and sisters, one of the former nervousness, particularly when they are aware that being reported by one member of the family to have suffered from similar " leg-trouble " but according the examiner is searching for signs of a disease, on September 28, 2021 by guest. the drastic late results of which they have witnessed to another member to have appeared quite fit in in their relatives. Even ankle-clonus can be present later life. under such circumstances, and many motorists will Generation II (14 members) testify that following some alarming experience 11.1 M. Died 1932 of tuberculosis. Leg attempts to rest the feet upon the pedals may result trouble since childhood, frequently stum- in uncontrollable shaking of the limb. bling; left leg mainly affected; walked Exaggerated reflexes alone were not therefore exactly like US.9 in later life. considered evidence of incipient disease. It was * Numbers refer to genealogical table, Fig. 1 ; ages when first seen required that exaggeration be very marked and unless otherwise stated. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.13.2.134 on 1 May 1950. Downloaded from

HEREDITARY SPASTIC PARAPLEGIA 137 11.2 M. Died in infancy, cause unknown. thenar eminences. Abdominal reflexes absent. 11.3 F. Died in infancy, cause unknown. Wasting left thigh 4 in. Bilateral spasticity oflegs; weakness left leg; exaggerated knee 11.4 M. Age 66. Affected since 36. First and ankle jerks, bilateral extensor plantars. episode probably prolapsed lumbar disc; " Only very slight ataxia on left." C.S.F., still occasional . Increasing stiffness, W.R., x-ray examination of spine, all normal shuffling gait, unsteadiness descending hills. findings. B.P. 190/115 mm. Seen again 1944 Arthritis of knees. Gait spastic, no ataxia. when thought to have swelling left disc ; arm Cranial , arms, trunk normal. Slight reflexes now exaggerated. Found uncon- general wasting lower limbs, marked spas- scious December, 1944; died of cerebral ticity, exaggerated knee and ankle jerks, hmmorrhage. Necropsy details not available. left plantar abnormal. Vibration sense diminished at ankles. 11.10 M. Dead. Little information. Not known to be affected. 11.5 F. Age 64. Lame 24 years. Increasing stiffness, contracture of hamstrings. Pain 11.11 F. Age 51. No complaints except aching and swelling right knee. Jumping and (G 273039) right knee. Mild euphoria. Very slight involuntary flexion left leg. 1944 treated choroidal degeneration in fundi. Arms and by extension, later attempted arthrodesis trunk normal. Hypertonia left leg, bilateral right knee but developed infected joint. contracture gastrocnemii, foot deformity left. Obese. Cranial nerves normal. Arm re- Exaggerated knee and ankle jerks, bilateral flexes much exaggerated. Right knee not extensor plantars. Vibration diminished right examined fully owing to chronic infective ankle, absent left. process. Left also swollen and arthritic. 11.12 M. Killed 1914-1918 war. Said to be Bilateral increase of tone. Left knee and normal. ankle jerks and right ankle jerk exaggerated. 11.13 F. Age 46. Dragging right leg two years, Right plantar equivocal, left extensor. increasing, now affecting left. Loses control

Vibration sense absent ankles. Bilateral walking downhill. Right leg jumps and flexes Protected by copyright. foot deformity. at night. Chronic bronchitis. Discs pink and 11.6 M. Died aged 54 (1944) of pneumonia. indistinct but probably normal. Arms normal Son's description of increasing lameness in except much exaggeration of reflexes. Gross later life, with many falls, one severe, suggests spasticity legs, contracture gastrocnemii involvement to some degree. worse on right. Weakness hip movements 11.7 F. Age 60. Fifteen years tendency to and dorsiflexors of ankle. Knee jerks grossly fall, difficulty climbing stairs, unsteadiness exaggerated and clonic. Ankle jerks difficult downhill, in knees. Obese. Arthritis to elicit owing to contractures. Bilateral of shoulders and knees. Cranial nerves extensor plantars. Bilateral defect vibration normal. Very exaggerated arm reflexes. sense; defect of joint sense right. Grossly Absent abdominal reflexes. Increased tone spastic gait. Crepitus at knees. Marked left leg. Weakness dorsiflexion foot. Knee euphoria in face of considerable disability. jerks much exaggerated. Bilateral extensor 11.14 M. Died at birth. Exact position in family plantars. Gait spastic; no ataxia. uncertain. 11.8 M. Age 59. Worked in India most of life. Lameness since 50. Complained only Generation III (36 members) of dragging legs. Gait grossly spastic with (111.1-8. Offspring of 11.1) http://jnnp.bmj.com/ adductor contractures. Marked euphoria in 111.1 F. Age 44. Legs give way at knee. Others face of grave disability. Cranial nerves, say she walks as if about to fall. Cranial arms, trunk normal. Hip movements and nerves and arms normal except great increase right leg grossly spastic. Contracture ad- in reflexes. Abdominals absent. Bilateral ductors and gastrocnemii. Power good. hypertonia in legs with weakness dorsiflexion Reflexes much exaggerated. Right plantar right foot. Marked exaggeration knee jerks equivocal, left extensor. Vibration sense with patella clonus; exaggerated ankle jerks. absent ankles, diminished at knees. Right plantar extensor; left equivocal. on September 28, 2021 by guest. 11.9 M. (The first member seen at this No ataxia. (C 7150) neurological unit.) Age 48 (1940). History of tuberculosis 1920-23. Left hip gave way 111.2 M. Died at one month, cause unknown. July, 1940. Increasing weakness left leg 111.3 M. Age 41. No complaints except clicking since; trembles when weight-bearing, drags, (C 80288) and swelling left knee and bronchitis. Obese. catches on pavements and trips him up. Bronchitic signs in chest. Cranial nerves and Nocturnal frequency of micturition. Gait arms normal except much exaggeration of spastic. " Only slight ataxia." Cranial nerves reflexes. Abdominals present. Slight hyper- and arms normal except for wasting of the tonia left leg. Weakness left knee. Gross E J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.13.2.134 on 1 May 1950. Downloaded from

138 EDWIN R. BICKERSTAFF exaggeration knee and ankle jerks. Both 111.15 F. Age 40. No definite abnormality. plantars abnormal. " Possibly very slight 111.16 M. Age 39. Legs felt heavy on rising in ataxia." morning for years. Occasional paresthesie. III.4 M. Always unstable. Severed connexions Cranial nerves normal. Left arm reflexes with family and committed suicide at date brisker than right. Abdominals normal. unknown. Not known to have been affected. Mild bilateral foot deformity. Left knee and ankle jerks definitely brisker than right. 111.5 F. Died at birth. Left plantar extensor. Vibration diminished 111.6 F. Died at age 28 of tuberculosis. Not left. known to have been affected. I1.17 M. Not examined but said by brothers to 111.7 F. Died aged 28 of pneumonia (? tubercu- be unaffected. losis). Not known to have been affected. 111.18 M. Died of jaundice, aetiology unknown, 111.8 M. Died aged one month. Cause unknown. aged 2j. 111.9 F. Age 35. Only daughter of 11.4. Ankles 111.19 M. Died of croup, age unknown. swelling 10 years, more recently letting her 111.20 M. Age 30. Feet shake uncontrollably on down. Knees and ankles stiffened. Paraes- weight-bearing. Some visual failure but no thesix at night with . Obese. Bilateral sudden loss. Fundi, right normal; left disc cedema of ankles. Heart and kidneys normal. very sharply outlined with pale segment at Cranial nerves normal. Marked exaggeration 7 o'clock, significance doubtful. No field arm reflexes. Abdominals present. Increased change. Arms, marked exaggeration reflexes. tone right leg with mild foot deformity. Abdominals, right weak; left almost Marked exaggeration knee and ankle jerks unobtainable. Deep reflexes exaggerated. with bilateral extensor plantars. Knee and ankle jerks much exaggerated with patella and ankle clonus. Plantars flexor. (111.10-12. Offspring of 11.5) 111.21 F. Died shortly after birth of congenitalProtected by copyright. 111.10 M. Age 33. Widespread rheumatism. heart disease. Rejected from Army for reputed heart 111.22 F. Age 23. Left leg heavy and letting her disease. Slight stiffness in legs when cold. down for two years. Some vague paresthesim. Heavily built. No abnormality in any system Obesity, particularly of hips and thighs. apart from very brisk reflexes. (Not con- Cranial nerves, arms and legs normal except sidered affected.) for very brisk reflexes. (A very doubtful case 111.11 M. Age 26. No definite complaints. Cranial -symptoms similar to the early stages of (C 80957) nerves, arms, and abdomen normal. Knee the disease but no definite objective evidence.) jerks brisk; ankle jerks exaggerated. Right plantar flexor; left probably extensor; (111.23-26. Offspring of 11.8) Oppenheim extensor. Vibration markedly diminished both ankles; slightly at knees. 111.23 F. Alive, healthy, living in India. Not Foot deformity more of true pes cavus type affected. than in other cases. 111.24 M. Healthy, living too far away to be examined. Not affected. 111.12 M. Killed 1939-45 war. " An unusually I11.25 M. Age 25. No complaints and no abnor- fine physical specimen." (G 273041) mal signs except very brisk arm reflexes and 111.13 M. Age 35. Son of 11.6. No complaints. gross exaggeration knee jerks. (Not con- http://jnnp.bmj.com/ Cranial nerves, arms and trunk normal. sidered sufficient evidence of affection.) Slight hypertonia of legs. Marked exaggera- 111.26 M. Age 23. No complaints. Cranial nerves tion knee and ankle jerks with ankle clonus. normal. Slight weakness left arm. Reflexes Plantars flexor. Bilateral foot deformity. brisker left than right and slightly exag- gerated. Abdominals normal. Tone slightly (111.14-22. Offspring of increased left leg with slight weakness. Knee 11.7) and ankle jerks markedly exaggerated, much 111.14 M. Age 41. Occasional unpredictable

more so on left. Left plantar abnormal. on September 28, 2021 by guest. (C 85160) attacks of numbness in legs. Cranial nerves Oppenheim extensor. normal except middle-ear deafness left. Arms, marked exaggeration reflexes. Left (111.27-29. Offspring of 11.9) upper abdominal reflex very weak. Charac- teristic foot deformity with early contracture 111.27 M. Age 33. Occasional dragging legs since tendo-achilles. Hypertonia, left more than (G 265267) 27. Numbness of feet during 5 years in right, with gross exaggeration knee jerks and Army. Discharged owing to bronchitis. Seen patella clonus; exaggeration ankle jerks first November, 1948. Cranial nerves, arms and ankle clonus. Both plantars apparently and trunk normal. Legs, bilateral increased flexor. Gait, mildly spastic. tone and weakness dorsiflexion feet. Knee J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.13.2.134 on 1 May 1950. Downloaded from

HEREDITARY SPASTIC PARAPLEGIA 139 and ankle jerks markedly exaggerated. (IV.2 and 3. Offspring of 111.3) Bilateral extensor plantars. Bilateral charac- IV.2 M. On active service. Said by father to be teristic foot deformity. No ataxia. Seen normal. again July, 1949. un- changed but left disc margin blurred and IV.3 F. Age 18. Said to walk like her father. vessels humped. (This appearance, though of Right ankle gives way. Gross obesity since doubtful significance, was not present on childhood. Frequency of micturition and previous examination.) Admitted Dudley polyuria. Chronic bronchitis. Obesity of Road Hospital, Birmingham, April, 1948, pituitary type. No abnormality in central and extensively investigated, the only abnor- nervous system apart from weakness dorsi- mality being a histamine-fast achlorhydria. flexion right ankle. (History suspicious, but signs insufficient to include among early 111.28 M. Died 1937, aged 23, of " ". cases.) Obscure multiple contractures ofhamstrings, adductors of thighs, and gastrocnemii since IV.4 and IV.5 Son and daughter of 111.4. Both early infancy. Treated orthopedically with grossly obese and well-known in their varying success, all contractures repeatedly district as "freaks". Not seen, but no recurring during growth. No full neuro- suggestion of disease. logical examination available, but marked IV.6 F. Age 12a. Daughter of 111.6. No abnor- spasticity noted and diagnosed as " spastic mality in central nervous system. Signs in of obscure origin '. heart suggest patent inter-ventricular septum. 111.29 M. Age 28. Quite fit; no abnormal signs. (IV.7 and 8. Offspring of 111.10) (111.30-32. Offspring of 11.10) IV.7 M. Age 6t. Tendency to waddle since 3, 111.30 F. Age 36. No complaints. The only the only abnormality on examination being pes planus. abnormality on was so Protected by copyright. gross an exaggeration of all tendon reflexes IV.8 F. Age 3. Walked early and said to be as to render her highly suspicious of being a " double-jointed ". Examination revealed no subject of early disease. abnormality except for occasional extensor 111.31 M. Age 29. No complaints; no abnormal element to left plantar-probably voluntary. signs. (IV.9 and 10. Offspring of 111.14) 111.32 M. Not examined but considered by brother to be normal. IV.9 F. Age 17. No abnormality in central nervous system. Loud and harsh systolic 111.33 M. Age 31. Son of 11.11. No subjective murmur over the whole precordium- complaints. Cranial nerves, arms, abdomen defect. normal. Slight hypertonia, legs. Marked possible septal exaggeration knee and ankle jerks with IV.10 M. Age 8. Normal. sustained ankle clonus. Right plantar IV.11 F. Age 14. Daughter of I1I.15. Lobar abnormal. Characteristic foot deformity pneumonia with meningism at age 4. bilateral. Complete recovery. Some stiffness following 111.34 M. Son of 11.12. Not traced. exertion recently. Cranial nerves and arms

normal except for exaggerated supinator http://jnnp.bmj.com/ jerks. Left abdominal reflexes very weak. (111.35-36. Offspring of11.13) Left foot smaller than right. Both knee and 111.35 M. Age 23. Illness diagnosed as polio- ankle jerks exaggerated. Left plantar ab- (G 272482) myelitis aged 2. Slight limp left leg since, normal. Oppenheim extensor. but served in Royal Marines during 1939-45 IV.12 and IV.13 M. and F. Children of 111.16. war. Cranial nerves and arms normal except Both quite normal. for very brisk reflexes. Trunk normal. Slight wasting both thighs with weakness quadri- IV.14 M. Son of 111.17. Not seen. Said by

ceps. Right knee jerk weak, others normal. uncles to be normal. on September 28, 2021 by guest. Bilateral ordinary pes cavus. (These signs IV.15 and IV.16 M. and F. Children of 111.23 presumed to be sequelx of poliomyelitis.) and 111.24 respectively. Lived too far away 111.36 F. Age 21. No complaints. Normal to be examined, but said to be normal. (G 273040) examination except very brisk knee and ankle reflexes with ankle clonus. (Not sufficient (IV.17 and 18. Offspring of 111.27) evidence to consider affected.) IV.17 M. Age 9. Well to March, 1948, when lost (G 265268) sight of left eye suddenly. Seen at Birming- Generation IV (26 members) ham Eye Hospital. Had papillcedema left Ml. F. Daughter of 111.1. Age 21. Normal. disc, and no perception of light. Right eye J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.13.2.134 on 1 May 1950. Downloaded from

140 EDWIN R. BICKERSTAFF and field normal. All relevant investigations (IV.25 and 26. Offspring of 111.35) negative. Gradual recovery of sight and IV.25 M. Age 4. Normal. regression of papilloedema, with appearance IV.26 M. Age 5 months. No abnormality on of pallor of disc. Seen personally Nov., limited examination. 1948. No abnormal signs except pallor left disc. Va., left 6/24, right 6/9. Seen again of Clinical Data July, 1949, left disc now showing definite Analysis optic atrophy and right possibly paler than This family illustrates how widespread the normal. Va., left 6/24, right 6/9. Fields: not disease may be throughout its various members. very reliable subject but only slight indrawing Of the 76 individuals who make up the three of all isopters, a little more marked in left generations, 27 were affected either in major or lower nasal field. Colour vision impaired minor degree, the fully-developed syndrome being centrally but no true scotoma detected. present in 18, and possibly in one other who had IV.18 M. Age 2j. Late walking. Drags feet and died, while incipient disease was present in 7, and (G 264128) trips easily. Never straightens right knee. possibly in two others. Ocular defects alone were Wears out toes of shoes. Said to be normal found in two. mentally. Examination very unsatisfactory Nine of the fourteen members of Generation II when first seen (Oct., 1948), but reviewed were affected, eight known to have shown the July, 1949 (age 3), when condition had progressed to bilateral foot-drop, and fully-developed syndrome. In Generation III (36 uncontrollable shaking of limbs when riding members), eight of the thirteen affected were con- tricycle. Cranial nerves normal. Slight sidered to show the complete picture though hypertonia arms. Commencing contracture generally in a milder form or stage than their gastrocnemii producing limitation dorsi- forebears. Of the 26 members of the fourth flexion feet. Hamstring contracture also generation, one was severely affected; one (and developing. Tone increased, left more than possibly one other) had the abortive or early form, Protected by copyright. right. Gross exaggeration of reflexes, left and two had signs referable to the eyes only. more than right, with bilateral ankle clonus. The severity of the disease appeared to have Left plantar extensor. diminished in successive generations. This may be due to a natural tendency for the disease to die out, (IV.19-21. Offspring of 111.30) or to be referable only to the earlier age at which IV.19 M. Died in infancy. Cause unknown. the patients were seen, the disease being progressive. Nevertheless one of the most severely affected IV.20 M. Age 9. Normal. patients was IV.18, 3 years old when examined, IV.21 M. Age 7. Sudden inability to see black- while 111.28 was severely affected from the first board on day before examination. No definite month of life. abnormality in central nervous system apart The character of the disease remained constant from fundi. Could not read largest type. in Generations II and 111, but the appearance of Bilateral myopia. Both discs pale. Both disc retrobulbar neuritis with papillerdema in the margins very blurred and vessels humped as fourth generation may indicate an alteration in they enter disc. Re-examined in total darkness the maximal, or perhaps http://jnnp.bmj.com/ with same impression. Reviewed five months the first, site of affection. It later. Refractive error corrected with some will be valuable to follow these children through improvement in acuity. R. 6/12 L. 6/36. their early adult life to detect the early stages of any Right disc now clearly seen. Left disc still neurological disease which may later develop. very blurred and vessels humped at edges. The age at which the disease was discovered was Too young to co-operate in examination of earlier in each successive generation. It is not fields. justifiable, however, to draw from this any con- clusions regarding the age of onset, for in Genera- (IV.22-24. Offspring of 111.31) tions IlI and IV knowledge that their family bore on September 28, 2021 by guest. an affliction prompted earlier recognition of IV.22 F. Age 10. No abnormalities. symptoms. Yet even so, the knowledge that the IV.23 F. Age 21. No definite abnormality on disease progresses, and its discovery in minor form examination except for plantar reflexes which in symptomless subjects, does suggest that in most gave consistently extensor responses. (This of the established cases the onset of symptoms came was so definite that considered possibly considerably later than the first objective evidence incipient disease.) of the disease, had the latter been sought. IV.24 F. Age 10 months. Reflexes all very brisk, In Generation II the average age of onset of otherwise normal. symptoms was 45, with limits 36 and 56. In J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.13.2.134 on 1 May 1950. Downloaded from

HEREDITARY SPASTIC PARAPLEGIA 141

Generation III so few gave any clear history of blackboard at school was the complaint of the two onset of symptoms that little reliability could be children with ocular disturbances. In the younger attached to any attempt to find a mean age. Three the presence of a myopia made this of doubtful members however recognized symptoms at ages significance, but the elder developed a large central between 25 and 30 and the average age at which the scotoma which gradually cleared. affected members of this generation were discovered was 34, with limits 23 and 44. (This is omitting Abnormal Signs.-These have already been men- 111.28 who was affected from infancy.) The two tioned under the heading " criteria for diagnosis " children of Generation IV who were affected with and will not be repeated in detail here. Spasticity, the same syndrome as their relatives were aged grossly exaggerated reflexes, abnormal plantar 14 and 3 respectively, while the two boys with responses, and, in eight cases, the characteristic foot ocular changes were 9 and 6 respectively. deformity mentioned above, were the main abnor- Eighteen males and eight females were affected, malities, while vibration sense was defective in the there being 48 male and 28 female members in the legs in seven cases and contractures were present in three generations, which figures show only a slightly five. Weakness was found in seven cases only, and greater tendency for the male sex to be affected. in some of the most severely spastic limbs remark- It is apparent that the disease can be transmitted ably good power was maintained. The abdominal through either sex, and in one instance only was it reflexes were weak or absent in six cases, while the found in the offspring of a clinically normal parent. arms were affected in 13. In 13 of the cases who This may apply also to another branch of the family were personally examined, there was a -predominance in which the father, now dead, was not examined, of affection to one side or the other. It is inter- but was reputed to be normal. The finding of so esting to note that this was the left side in 1 1 ofthese many who had objective evidence of disease unsus- 13 cases, and in two of these the picture was that of

pected by themselves or their relatives led one, a left hemiplegia, the right side being almost com- Protected by copyright. however, to view such assertions of normality with pletely normal. Similarly it was noted that in the suspicion. five patients in whom ophthalmoscopic abnor- malities were recorded, the left eye was affected Symptomatology.-The symptomatology of the in each case. Euphoria was a feature of several of disease was in many cases masked by associated the affected individuals and in four cases was quite conditions some of which may well have been an outstanding sign. secondary effects of the basic disorder. Chronic The only cranial abnormalities were arthritis of the knees was, for instance, the main referable to the eyes. The most definite and complaint of four of Generation It, was present to a dramatic sign was found in IV.17, who, seen four marked degree in another member, and pain around days after a sudden loss of vision ofthe left eye, was the knees and crepitus on movement were frequent shown to have a mild papilloedema, with no percep- findings. It is not difficult to understand how tion of light and only a sluggish pupil reaction. repeated minor (and major) traumata which affect Three weeks later he could count fingers, and two the joints of a spastic limb may result in a traumatic months later vision was 6/24, the cedema had osteo-arthritis, such as was so marked in 11.5 that cleared, being replaced by a definite pallor. Sixteen the underlying spasticity was originally completely months after the onset visual acuity was R.6/9, http://jnnp.bmj.com/ unsuspected. Otherwise however the main symp- L.6/24, the right disc was slightly pale and the left toms were stiffness, especially on climbing stairs; showed definite optic atrophy. Perimetry showed a dragging the feet; tripping over the pavement; slight depression of the peripheral fields to 1-3/330, giving way at the ankles; uncontrollable shaking a little more marked in the lower nasal quadrant. when weight is placed on the feet; flexing and jum- A consecutive atrophy with diminished acuity could ping of the legs at night; heaviness of the feet; account for these slight changes, and no scotoma and contractures. The term " unsteadiness " was was colour vision was demonstrated, though on September 28, 2021 by guest. used by three patients, each of whom said this was defective. The boy was a poor subject for scoto- only on going downhill, and as no demonstrable metry, and the fields cannot be considered com- ataxia was present, either in gait or in tests of co- pletely reliable. Case IV.21 was seen the day after ordination, it seems possible that the retardation of he complained of inability to see the blackboard, movement in the spastic limb was responsible for and had a definite myopia with pallor of the discs, this symptom. Five patients complained of numb- but the edges of the discs were very blurred, and ness in the legs, but in no case was any superficial the vessels were humped as they entered. Five sensory loss discovered. Weakness was complained months later vision was improved slightly with of by one patient only. Sudden inability to see the spectacles, and the right disc was clearly seen. The J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.13.2.134 on 1 May 1950. Downloaded from

142 EDWIN R. BICKERSTAFF left was still very blurred and the vessels appeared the disease. In general the impression was gained to be humped. Two other patients showed blurring that those who became affected after adult life with of the discs on the left side, which in one patient the fully-developed syndrome reached a maximum personally examined twice at ten months' interval disability gradually over the ten-year period follow- was not present on the first occasion. In neither ing the onset, after which the condition remained case was there definite visual impairment, and they stationary or progressed only very slowly, and in were not diagnosed as retrobulbar neuritis. It several patients was an annoyance rather than a is interesting however that these two were the very grave disability. In not one case could death father and the grandfather of the definite case of have been attributed to the disease. Onset of the retrobulbar neuritis (IV.17). disease in childhood or during the period of growth was more serious, for the contractures which Associated Abnormalities.-Arthritis of the knees tended to develop needed frequent correction and was severe in five cases, four of these being in usually recurred. Those who had developed to an Generation II. Case 11.5 was so severely affected advanced stage showed a remarkable similarity of that the underlying neurological condition had clinical picture, a similarity that was enhanced by been effectively masked. A milder degree of the striking facial resemblance between many mem- arthritis was present in many of Generation III. bers of the family. It was interesting that 111.29, Obesity of severe enough degree to be disabling coming to the clinic, by coincidence, on the same was present in eight patients. Case 11.1 was said afternoon as 11.8, his uncle, recognized him immedi- to be very obese, but the most gross examples ately from his resemblance in appearance, posture of obesity appeared in those members of the fourth and gait to his own father (11.9), despite the fact generation having II.1 as a common ancestor. Cases that 11.8 had left for India before 111.29 was born, IV.4 and 5 were well-known in their own area as and the latter had no idea that he had ever returned " freaks " because of their enormous size, and to this country. Protected by copyright. IV.3, older, but similar in appearance, had, in addition, increased frequency of micturition and Discussion polyuria. None complained of any menstrual In the last 100 years the heredo-familial diseases disturbances. of the nervous system have been the subject of much Chronic bronchitis was widespread throughout interest and a steadily growing volume of literature. the families descending from 11.1, and occurred not The comparative rarity of widely affected families, infrequently in other members. Tuberculosis was the sparsity of necropsy material, the ignorance as contracted by four individuals, two of whom, and to etiology, and the remarkable variety of the possibly a third, died of the condition. syndromes described, has led to much theorizing Congenital heart disease was known to be the as to their fundamental nature and their possible cause of death of 111.21, and the clinical diagnosis of inter-relationship. Opinions on the latter can be a patent interventricular septum was made in IV.6 grouped in general into three: the two extremes and IV.9. Many babies had died shortly after who consider (a) that each syndrome is a separate birth from causes in most cases unknown: it is genetic entity, a view held now by only very few; possible that some of these may have had con- or (b) that all the syndromes are but different genital abnormalities, but there were no others manifestations of the same process, the features http://jnnp.bmj.com/ discovered in the patients examined, except for being determined by the particular part of the crooking of the little finger. This was observed in nervous system affected. The third class of opinion several instances, but unfortunately no precise note includes those who feel that the majority of the of this was made, and the frequency is uncertain. ataxias are variations of the same process, while A similar deformity is mentioned by Bell and some of the other heredo-familial disorders, incluld- Carmichael (1939). ing hereditary spastic paraplegia, are separate entities. Bell and Carmichael (1939), for instance, Laboratory Investigations.-The whole of this on September 28, 2021 by guest. review was carried out at an out-patient clinic and consider Friedreich's ataxia and the spastic ataxias C.S.F. findings are known in two cases only, namely due to the same gene under the influence of modi- 11.9 and his son, 111.27. These were normal. fiers, but are less certain about hereditary spastic Wassermann tests were done on seven affected paraplegia. Calculations regarding the sex, distri- bution, average total duration of illness, and age at patients and were all negative. death provided evidence in favour of genetic inter- Course.-One patient only (11.9) was observed relationship, but clinically they were unable to find for more than a year, and one has to judge from the records of spastic paraplegia occurring in the same history and relatives' reports as to the progress of stock as the ataxias. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.13.2.134 on 1 May 1950. Downloaded from

HEREDITARY SPASTIC PARAPLEGIA 143 Haldane (1941 a and b) and Sj0gren (1943) differ It is interesting to note that 11.9 was at one time as to whether the three have a common genetic basis considered to be an example of amyotrophic lateral or whether the ataxias must be separated into sclerosis. He had wasting of the thigh of one leg, different genotvpes. and of the thenar eminences, and had weakness of From the purely clinical point of view, the the right hand and of both legs, with spastic para- strongest evidence for associating the various plegia. One can go no further, on the evidence of heredo-familial disorders is the existence of two or one isolated example, than to suggest that the more different varieties in the same family, and of process affecting this family and producing typical transicion forms between two different varieties in examples of hereditary spastic paraplegia, may also the same individual. Friedreich's ataxia, and the be the cause of this local muscle wasting. clinically very different spastic ataxias, present little The picture of a cerebral diplegia, occurring at, difficulty in this respect, and Bell and Carmichael or immediately after birth, was produced in one (1939) were able to find 32 families in which both member of the family, and this suggests that families types of disease occurred. Roth (1948) recently afflicted early enough with the manifestations of has described two families in which association is this disease could show the picture of familial suggested between Friedreich's ataxia and Charcot- cerebral diplegia, without having to indict some Marie-Tooth's disease in one, and between these other specific process. two and Marie's ataxia in the other. In his paper The occurrence of retrobulbar neuritis pro- published work is mentioned associating (a) Fried- gressing to atrophy in this family forces one further reich's ataxia, spastic ataxia, and spastic paraplegia; to consider possible connexions between hereditary (b) Friedreich's ataxia and Charcot-Marie-Tooth's spastic paraplegia and Leber's optic atrophy, or disease; (c) Friedreich's ataxia and the myopathies; even disseminated sclerosis. Johnson Taylor (1892), (d) Friedreich's ataxia and a form of optic atrophy Behr (1909), Takashima (1913), Imamura and

clinically similar to that described by Leber; and Ichikawa (1919), and Ferguson and Critchley (1928), Protected by copyright. (e) neurological disorders and other congenital have all reported the heredo-familial occurrence of abnormalities. To this we can add the family of optic atrophy, often bilateral, with dense central or Philip (1886) in which occurred both myopathy and centro-cecal scotomata, following in some cases a spastic paraplegia, and the views expressed by Rhein known swelling of the discs and associated with (1916) that transition forms exist between the pure signs elsewhere in the nervous system, including spastic and those with ataxia or mus- pyramidal signs and ataxia, and Behr considered his cular atrophy, and by Delearde and Minet (1908) cases a transition between Leber's disease and that all forms exist between hereditary spastic para- StrUimpell's on the one hand, and the heredo- plegia, familial amyotrophic lateral sclerosis, familial ataxias on the other (a view which would be disputed cerebral diplegia, and familial disseminated sclerosis. by those who consider Leber's optic atrophy a It has already been mentioned that any record of disease essentially and specifically confined to the overlap in the same stock between the ataxias and optic nerves). Though the optic discs in IV.17 had the pure spastic paraplegia is difficult to find. Ballet developed a definite optic atrophy following the and Rose (1905) and Raymond and Rose (1909) initial papillmedema, yet the good return of vision, considered their cases, however, to show transition and the absence of any gross field defect are points from the spastic ataxias to hereditary spastic very much against this being an example of Leber's http://jnnp.bmj.com/ paraplegia, and Bell and Carmichael (1939) suggest disease. Is it, rather, the early stage of disseminated that a careful search among the siblings of spastic sclerosis ? If this child were to develop pyramidal paraplegics might uncover signs of ataxia in some. signs later in life, the previous history of retro- It was notable in this family that this did not occur. bulbar neuritis would almost inevitably lead to a Cases of minor or minimal disease were discovered, diagnosis of disseminated sclerosis. It might be but the clinical picture in each case was that of the emphasized here that euphoria was a marked sign

fully-developed disease at an earlier stage, or of in several of the severely affected cases. on September 28, 2021 by guest. lesser severity, and in two cases only was a very Though this association of papilloedema and slight and most dubious ataxia recorded. One of hereditary spastic paraplegia is extremely rare, it these was not examined personally, and both were has been noted previously. Bremer (1922) des- severely involved in the fully-developed spastic cribed two families with hereditary spastic paraplegia, process and had some difficulty in executing the in the second of which two members had optic tests for co-ordination. No further direct evidence atrophy and one a swelling of the disc. Kastan can be deduced from this study of association (1945) in a paper concerning a family showing between the hereditary ataxias and hereditary spastic paraplegia, Pelizeus-Merzbacher disease and spastic paraplegia. leucodystrophy in different members. mentioned J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.13.2.134 on 1 May 1950. Downloaded from

144 EDWIN R. BICKERSTAFF one child who was seen to have blurred discs in members who are past the average age of onset. 1939 and optic atrophy in 1940. Whether these are early cases of a progressive Andre-van Leeuwen and van Bogaert (1949) have disease, or abortive cases which will progress no recently discussed the question of the association of further, can only be decided by long-term observa- what they term the " retrobulbar neuritis" type of tion, but their presence demonstrates how important optic atrophy with the hereditary ataxias. Their it is in investigating such a family, to examine such differentiation from other types rests on the presence patients in detail, and not merely to rely on relatives' of central, centrocecal or paracentral scotomata. statements. They ask whether this type " is really as rare in Can the appearance of retrobulbar neuritis and hereditary ataxia as it seems at first sight to be". optic atrophy in the fourth generation be purely It appears from their review that if careful visual coincidental ? It is difficult to believe this, when we field examinations were made in all cases of optic know optic atrophy to be so characteristic a feature atrophy in hereditary disorders of the nervous of many of the hereditary disorders of the nervous system, this type might not infrequently be demon- system. Whether it indicates a change in character strated, and from the family under consideration now, of the disease itself, or merely of the site of maximal it appears probable that many of these, if seen early (or earliest) affection, cannot be determined until enough, might show cedema of the nerve head, its the progress of these children has been watched for presence possibly being controlled by the anatomical many years. It appears however that the same relationship of the lesion to the disc. process, possibly altered by modifying genes or by The fundamental cause of the chromosomal environment, is capable of producing a series of modification which is responsible for the explosive closely related clinical syndromes, varying mainly appearance of the condition in one generation in the site of maximal affection. Some show remains unknown. If we are to ignore the very evidence of familial amyotrophic lateral sclerosis;

dubious story ofaffection ofa member ofGeneration some of familial diplegia; some appear to be the Protected by copyright. I, we must consider Generation II as being the first earliest stage of disseminated sclerosis; and the to show evidence of what becomes a dominant remainder are typical of the hereditary spastic genetic characteristic. Consanguinity was unknown paraplegia. Extending this hypothesis beyond the in the family. Alcoholism has often been indicted affections of the pyramidal tracts-and the posterior by the earlier writers, and though it is known that columns were affected in several of this present Generation II, as children, were reared under the family-it is not difficult to imagine an infinite worst social conditions, and that their father was variety of ataxias, paraplegias, and amyotrophies, " fond of the bottle " no gross degree of alcohol grouped together on a closely related genetic addiction is suggested. There has been no evidence basis, and in this way to simplify the confusion of syphilitic disease in any member. of syndromes which at present overburdens To the mathematician and geneticist, families the literature. such as this form an interesting study from which careful search may provide a wealth of material, Summary but even here, where it has been possible to examine so many members, figures are bound to be unreliable, A family is described in detail in which hereditary for if so many who are reputed to be normal can be spastic paraplegia is unusually widespread through- http://jnnp.bmj.com/ found to be affected, assurances as to normality of out three generations. deceased relatives are bound to be open to question Careful search among apparently normal members Nor can we know how many of those children who of the family has uncovered several examples of died in infancy would have developed signs of the early or abortive disease. disease in later life. Their observations may, Eighteen individuals have been affected with the however, be of great assistance to the clinician who fully-developed syndrome, while seven have shown is faced with the regarding the signs of incipient disease. patient's anxiety on September 28, 2021 by guest. danger of transmission of the disease, or of the One child had a retrobulbar neuritis with disease developing in unaffected members at a later papilleedema which progressed to optic atrophy, date. Statistics suggest that the age of onset of leaving diminished visual acuity, but practically these conditions is within fairly narrow limits for a normal visual fields. One other child is probably particular sibship, and older members, if unaffected, affected in the same manner and two adults have may consider their outlook more favourable. A been suspected of having swollen optic discs. completely confident answer cannot however be Some members showed a picture similar to given, and this family illustrates the presence of cerebral diplegia, and in one case to amyotrophic definite signs of the disease in apparently unaffected lateral sclerosis. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.13.2.134 on 1 May 1950. Downloaded from

HEREDITARY SPASTIC PARAPLEGIA 145 It is suggested that this family gives further Delearde, A., and Minet, J. (1908). Rev. Medecine, support to the view that the heredo-familial disorders 28, 181. Dobrochotow, M. (1913). Dtsch. Z. Nervenheilk., of the nervous system are inter-related. 49, 1. Ferguson, F. R., and Critchley, MacD. (1928). J. Without the ready co-operation of the members of Neurol. Psychopath., 9, 120. the F. family this work would not have been possible. Gee, S. (1889). St. Bart's Hosp. med. Rep., 25, 81. I wish also to acknowledge the assistance given by Haldane, J. B. S. (1941a). J. Genet., 41, 141. Mr. G. M. Barling, late ofthe Birmingham Eye Hospital; --(1941b). Ibid., 41, 149. Mr. M. James, of the Royal Cripples Hospital, and Holmes, G. (1905). Rev. Neurol. Psychiat., 3, 256. Dr. H. M. D. Shepherd, of Dudley Road Hospital, who Imamura, S., and Ichikawa, K. (1919). Rev. neurol., supplied details of the patients who had passed through 26, 277. their hands. Jones, E. (1907). Rev. Neurol. Psychiat., 5, 98. In particular my gratitude is due to Professor P. C. P. Kastan, M. (1945). J. nerv. ment. Dis., 101, 357. Cloake, who first drew my attention to this family, Manson, J. S. (1920). Brit. med. J., 2, 477. in whose clinic all the patients were seen, and who has Ogilvie. G. (1908). Proc. R. Soc. Med., 1, 91. given encouragement throughout, and to Dr. E. Arnold Paskind, H. A., and Stone, T. T. (1933). Arch. Neurol. Carmichael and Dr. Julia Bell, whose criticism was Psychiat., Chicago, 30, 481. invaluable. Philip, R. W. (1886). Brain, 8, 520. Raymond, F., and Rose, F. (1909). Encephale, 1, 209. Rhein, J. H. W. (1916). J. nerv. ment. Dis., 44, 115 and REFERENCES 224. Andr6-van Leeuwen, M., and Bogaert, L. van (1949). Roth, M. (1948). Brain, 71, 416. Brain, 72, 340. Seeligmiiller, 0. (1876) Dtsch. med. Wschr., 2, 185. Appel, L. (1949). Acta. Neurol. Psychiat. Beig., 49, Sjogren, T. (1943). Acta. Psychiat. Kbh., Supplement 27. 415. Strumpell, A. (1880). Arch. Psychiat. Nervenkr., 10, Ballet, G., and Rose, F. (1905). Nouv. Iconogr. Salpet., 676. 18, 404. Takashima, S. (1913). Klin. Mbl. Augenheilk., 16, 714. Behr, C. (1909). Klin. Mbl. Augenheilk., 47, 138. Taylor, S. Johnson (1892). Trans. ophthal. Soc. U.K., Bell, J. (1933). " Treasury of Human Inheritance." 12, 146. Protected by copyright. Cambridge Univ. Press, 2, Part IV. Tooth, H. H. (1891). St. Bart's Hosp. med. Rep., 27, 7. -, and Carmichael, E. A. (1939). Ibid., 4, Part III. Worster-Drought, C., Greenfield, J. G., and McMenemy, Bremer, F. W. (1922). Arch. Psychiat. Nervenkr., 66, W. K. (1940). Brain, 63, 237. 477. (1944). Ibid., 67, 38. http://jnnp.bmj.com/ on September 28, 2021 by guest.