Develop. Med. Child Neurol. 1966, 8, 761-767

Gavin Gordon

The Mechanism of Thalidomide Deformities Correlated with the Pathogenic Effects of

Prolonged Dosage in Adults

THE deformity of phocomelia (Latin phoca, a seal) has been known since Babylonian times and was described by Ballantyne' in 1904, though he made no suggestions regarding its causation and did not mention associated deformities.

Such phocomelia bears a striking likeness to the limb deformities seen in neonates whose mothers were given thalidomide as a sedative in the first trimester of pregnancy. The question naturally arises whether the deformities have a common cause--i.e., were the deformities of Babylonian times due to environmental factors, or were they genetically determined? The thalidomide deformities are certainly environmental in origin, and the causative environmental factor should provide the key to the mechanism of causation.

Information on cases of deformity due to thalidomide in England and Wales has been carefully documented by the Ministry of Healthell Much information is available regarding individual cases, along with the results of animal experiments,2, *, 9. Is-

l5, 17, 19, ?') and our present knowledge of the action of this and other drugs on t h e e m b r y o h a s been d i s c u s s e d a t length,16, IH, 23, However, no firm deci-

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Powe House, Keswick, Cumberland.

sion has yet been made regarding the mode of action of thalidomide. Of the tentative suggestions,ls. 23 the possible effect of altered DNA molecules is highly unlikely, since in the 4th week the limbs are repre- sented by buds of undifferentiated meso- derm and at the beginning of the 6th week they are still incompletely differentiated.' Any action at this stage to produce such a limb deformity would have to be on the individuation field directly through the amnion for part of the time,8 as an effective blood circulation does not begin to be established until late in the 4th week when the heart begins to beat.7 A specific effect on some cells of a limb is unlikely; the whole limb would be affected and there would probably also be a general effect on the foetus.

Furthermore, a specific effect on indi- viduation fields in a series of cases due to a general toxic action would not explain the ve ry v a r i e d a n d c o m p l e x r a n g e o f deformities of other organs which fre- q u e n t l y a c c o m p a n y l i m b reduc t ion deformities. l1

What makes thalidomide act so specific- ally? In animal experiments the admini- stration of almost any noxious substance

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will result in foetal deform it^.^^ An important point in this connection is that almost invariably these malformed foetuses are also stunted in general growth, indicating a generalised effect in addition to the specific effect. A spanner in the works is unlikely to lead to the elucidation of the problems of teratology, a conclusion also reached by Woollam.23

Very little work has been done on the action of thalidomide on the central nervous system in animals, but there is experimental evidence of the transference of thalidomide from mother to embryo in rabbiha The skeletal muscle of rabbits was also found to contain thalidomide that had been given 4 hours before death,3 and the observations of Mackenzie and McGrathl0 indicate that thalidomide is a cumulative drug in rats, 10 per cent of the dose given being retained after 48 hours, the concen- tration of drug reaching its peak in the blood 15 minutes and in the brain 30-60 minutes after administration.

Further workz2 shows that it is thalido- mide as such which gets into the embryo, and, once in, it breaks down spontaneously to polar compounds which are not easily eliminated-in other words, thalidomide or its breakdown products act as the teratogenic agent.

Studies of the effects of thalidomide in man indicate that its action can be spread over much of the organogenetic period, resulting in a range of deformities extend- ing from the eyes to the limbs. Most of the children are unmarked mentally, and anencephaly has not been seen. In my belief. the action of thalidomide is essen- tially similar in the embryo and the adult.

Much of the speculation on the action of thalidomidel6. l*, 239 24 arises from the belief that the drug takes effect between the 28th and 42nd days of pregnancy, but the unreliable results of questioning pregnant women,", la taken in conjunction with the possible errors in estimating the time of

conception, make such a precise period decidedly suspect, and, if embryological developmental data are taken into account, the likelihood of this being the significant period becomes highly doubtful. A mistake of some weeks is possible, and, if thalido- mide is regarded as a cumulative drug, then e m b r y o l o g i c a l d a t a b e c o m e m o r e important than the actual time of ingestion when seeking a rational explanation.

At 4-6 weeks the limbs are mere buds with an undifferentiated muscle m;iss, and. unless a n effect on undifferent ia ted blastema is suggested, we must look elsewhere for an explanation.

Deformities are generally recognised as due to inco-ordination of two growth processes at a time of maximal develop- ment in the organogenetic period. From then on the fully developed deformity is produced by stages as the foetus grows. There is no reason to deviate from this view in the case of thalidomide deformities.

Thalidomide exerts a sedative, narcotic or anaesthetising effect on nervous tissue and hence produces a diminution of nervous impulses. Its action at any time will vary according to its concentration in the CNS at that time.

Regarding thalidomide as a cumulative narcotising drug, and correlating this with the accepted embryological data,' the probable action of thalidomide can be explained as follows:

(1) T h e e m b r y o l i m b s beg in t o develop at the end of the 4th week, the arm buds being 2 days in advance of the leg buds.

(2) The presence of nerves is not necessary for the full development of the limb.

(3) In the 7th week, muscle, nerves and blood-vessels are apparent through- out the limbs. (4) Muscle action becomes possible in

the 6th week. (5) Late in the 4th week the heart

begins to beat and an effective circula- tion is established.

(6) Unregulated movements can be detected in the foetus at 6 weeks.

(7) Myogenic or neurogenic contrac- tion can occur in the absence of the reflex arc.7

(8) M u s c l e s p i n d l e s b e c o m e differentiated in the 9th week.

(9) In the 11th week nerve fibres reach the myoblasts.

(10) Proprioceptive fibres develop in the spinal cord towards the cuneate and gracile nuclei early in the 2nd month. They are the first nerves to form in the cord.

(11) The subarachnoid space is not fully developed in the 3rd month.

(12) CSF is not secreted until the 4th month.

(13) Innervation, as indicated by co-ordinated movement, proceeds in a cephalo-caudal direction; the spine extends before the limbs.5,

(14) Fibres from the skin accompany the proprioceptive nerve fibres to the cuneate and gracile n ~ c l e i i . ~ ~ In studying the deformities induced by

thalidomide it is necessary to keep in mind that the information available refers to survivors, many of whom represent the maximal deformity possible short of pre- natal death. Many are borderline and die shortly after birth.18 How is the line drawn?

To me, the limb deformities suggest resorption rather than primary deformity -resorption proceeding in a proximodistal direction and involving the upper limbs before the lower and the cranial area and the trunk before the limbs9

So far, attention has been concentrated on the limb deformities, ignoring the multiplicity of associated deformities. Basically the facts also apply to associated deformities if the foetus is regarded as consisting of segments,’ but for the

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moment the limb deformities will be dealt with to establish the broad picture.

Mechanism of Thalidomide Deformities The mechanism of causation is probably

as follows. Thalidomide being a cumu- lative drug, it is highly unlikely that a single dose would give rise to deformity, though in the present state of our know- ledge some effect on a highly susceptible woman cannot be excluded.

In most cases thalidomide will accumu- late in the CNS of both mother and embryo. The mother with an established and mature nervous system suffers no damage in the limited time of medication. The embryo, however, is at risk owing to the presence of thalidomide or its break- down products in the CNS. These damp down the activities of the embryo from the 6th week onwards, acting directly on the muscle in the ‘myogenic’ stage and later preventing the functional junction between nerve and muscle at the time when the intrinsic spinal reflexes come into action in the limb, at about the 11th week.

Since this is the organogenetic phase of development, with optimal periods of development, the various events must be closely co-ordinated, and if thalidomide prevents the initial nerve impulses from the cord getting through to the muscles, the optimal period will lapse without effective control being established. No further development will be possible and the affected part of the limb will be resorbed. Since the innervation of a limb proceeds pi oximodistally, the typical deformity will result.

Since the embryo arm moves before the leg, the maximal incidence and severity of deformity will occur in the upper limb and will affect the proximal part of the limb first.

Nerves are not necessary for the full development of the limb, so that the drug will act on an already formed limb, and its

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toxic eKects will ordinarily subside as pregnancy continues and the drug is withdrawn. With late medication the maximal deformity could occur in the distal part of the limb.

The failure of junction and consequent resorption will occur only during initial innervation. Once innervation is estab- lished the action of thalidomide will be the same as in the adult.

I n cases where the foetus survives with thalidomide deformities, the absence of part of the body image, as represented by proprioception, would not be significant f o r life. The action of the drug being on the nerve impulses and only indirectly on the nervous tissue, anencephaly will not occur.

Malformations Since innervation occurs in a cephalo-

caudal direction, and the spine is capable of extension before the limbs, the limbs will be the last structures to be innervated. This timing makes it possible to explain the observation of Leck and Miller,9 that thalidomide is not usual!y a cause of malformations other than of the limbs occurring alone. Since the drug is only slowly eliminated, its action would cause non-limb malformation continuing on to limb malformation, but, when the drug acts later, limb malformation alone would be possible.

This fact is important when we now come to consider the non-limb deformities. I f t h e y a r e r e g a r d e d a s s e g m e n t a l deformities initiated before the I im b deformities, representing the limits of viability with a largely unrecorded back- ground of foetal death due to interference with vital nerve impulses, then a logical picture develops.

The earliest innervation will occur in the cranial nerves. Where muscle and body image (proprioception) are involved they will be at risk according to the amount of thalidomide in the muscles and CNS and its

rate of breakdown and absorption. This will vary from person to person both in the rate of breakdown and the uniformity of the process, so that a greatly varied picture can be expected according to dosage, rate of absorption and retention, rate of break- down and uniformity of breakdown. There are many factors and the results will vary from early death of the embryo to minor deformity at birth.

It is not intended to cover all deformities in this paper, but by applying the principles outlined above it is possible to explain the deformities listed by the Ministry of Health.

Remembering that the deformities seen clinically are those consistent with life viewed against a background of early death in other cases, several examples ciin be given. The action of the drug as the eyes develop could result in strabismus, colo- boma or microphthalmia, with involve- ment of one or all of the motor nerves to the eye.

Involvement of the facial nerve would give rise to facial palsy, which is consistent with life, but involvement of the hypo- glossal verve would lead to complete absence of the tongue and early death.

Severe involvement of the vagus nerve would also result in early death, but lesser degrees would result in deformity of the ears, neck, heart, and/or gastro-intestinal tract.

At first sight it seems difficult to explain the absence of the ears. but interference with the innervation of the ear muscles (facial nerve) and the absence of proprio- ceptive impulses would result in resorption.

Similarly with the kidney in cases of renal agenesis all parts of a body segment are connected by nerves to a corresponding segment of the spinal cord, and the kidney is supplied by the loth, I Ith and 12th dorsal segments. When a narcotic afrecls these nerves a1 a vital stage of develop- ment, renal resorption (partial or com-

GAVIN GORDON

plete) will occur rather than renal agenesis. Hare-lip and cleft palate are equally

susceptible of explanation. To consolidate this explanation, the

general principles would have to be applicable to the adult clinical picture, remembering that once the neuromuscular connection is established in the organo- genetic period the narcotic effect will not result in resorption.

Effects of Thalidornide in Adults The clinical picture resulting from

prolonged ingestion of thalidomide in adults has been clearly recorded.4 There are several important points of difference from the embryo:

( I ) In adults the legs are affected before the arms. The opposite occurs in the foetus.

(2) The CSF has a very high protein content. CSF is not secreted in the foetus until the 3rd month and it is the 4th month before the subarachnoid space is formed.

(3) Prolonged administration is neces- sary before symptoms arise, suggesting acc u m u I a t i on.

(4) Signs and symptoms are slow to subside after withdrawal, and sensory changes, particularly in the fingers, may persist.

(5) A c c o r d i n g t o F u l l e r t o n a n d Kramer,4 nerve conduction is unim- paired in the motor nerves but affected in the sensory nerves.

(6) Biopsy has shown changes typical of peripheral neuritis in the affected muscles.

(7) The diminution of sensation is of the glove-and-stocking variety, and the weakness is greatest in the proximal part of the limbs.

In adults the high concentration of protein in the CSF strongly suggests that thalido- mide or its breakdown products are deposited in the CSF following the primary

systemic effect on nerve conduction. Indirectly, this supposition is supported by the observation that barbiturates given in high dosage collect in this situation.21

Presuming-and the time for verification has passed-that thalidomide collects slowly in the CSF over a long period, raising the protein content considerably, then a full explanation of the clinical picture becomes possible.

The spinal nerve roots will become bathed in an increasing concentration of thalidomide or its products, exerting a narcotic effect. This effect will be greatest on the roots with the longest course in the subarachnoid space. Moreover, the most superficial fibres of the nerves will be the most affected, as far as the motor nerve roots are concerned; this would explain the proximal muscle weakness.

Sensory Effects With regard to sensory changes, the

glove-and-stocking type of paraesthesia is more difficult to explain, but here the posterior ganglion will be involved, and, although probably the whole limb shows sensory loss, it will be most noticeable in its effect on fine sensation at the finger-tips with nutritional changes particularly in the longer axons, and continued action will result in permanent sensory impairment- through the ganglion cells.

It has been clearly established3 that motor nerve conduction is unaffected, but sensory nerve conduction is diminished. However, the all-or-none principle would apply here. At the site of immersion of the nerve-root in the CSF conduction would be affected, but the impulses which did get through would show no diminution and the nerve would appear normal on testing. The sensory nerves would show some diminution owing to the effect on the ganglion giving rise to nutritional changes. The extraspinal portion of the peripheral motor nerve would be unaffected, but the

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DEVELOPMENTAL MEDICINE A N D CHILD NEUROLOGY. 1966, 8

number of impulses getting through would 8th cranial nerve, that there is a profound be diminished, giving rise to appearances effect on the CNS. This is what one would in the muscles suggesting peripheral expect, for all the cerebral and spinal neuritis. nerve-roots would be affected to some

Fullerton and Kramer4 maintain, with degree, according to their length and an illustrative case of involvement of the vulnerability.

SUMMARY The wide variety of deformities in neonates following the use of thalidomide as B

sedative by the mother can only be the result of a toxic factor acting on the initial nerve impulses to muscles in the organogenetic phase of development. This explanation is developed to cover all the deformities seen in ‘thalidomide babies’ and is correlated with the pathogenic picture in adults following prolonged dosage.

I t is suggested that the thalidomide deformities are the result of minor degrees of resorption.

RESUMC Corrcilation en (re le mkcanisme de l’e‘tiologie des difformitls dGes ir la thalidotnide et les efjets

pathogkniques d’une adtninistration prolongke chez les adultes La large varitte des difformitks survenues chez les nouveau-nes aprts I’usage de la

thalidomide par la mere peut seulement &tre le rtsultat d’un facteur toxique agissant sur les impulsions initiales du nerf sur les muscles dans la phase organogtnktique du dCveloppe- ment. Cette explication est appliquee a toutes les difformitts vues chez les btbts-thialomide et rend compte des relations avec le tableau pathogenique chez les adultes suivarit un traitenient prolongt.

11 apparait que ces difformitts sont le rtsultat de la rtsorption A faible degrks.

ZUSAM MENFASSUNG Der Mechanismus der Thalidomid-Deformationen in Zusammenhang gestellt mit den

pathogenen Effekten einer langdauernden Dosierung hei Erwachsenen Es wird daraufhin gedeutet dass die grosse Vielfaltigkeit von Missbildungen bei

Neugeborenen, die auf das Einnehmen von Thalidomid bei der Mutter folgt, nur von einem toxischen Faktor herruhren kann, der auf die ursprunglichen Nerven-Impulse an die Muskeln in der organo-genetischen Entwicklungsphase einwirkt. Diese Erklirung wird erweitert, als Erklarung all der Deformationen, die bei Thalidomid-Neugeborenen auftreten, und in Zusammenhang gestellt mit dem pathogenen Bild bei Erwachsenen nach langdauernden Dosen.

Somit wird es offenbar dass diese Missbildungen das Ergebnis minorer Resorptions- Grade sind.

RESUMEN El mecanismo de maljormaciones dehidas a la talidomida; correlacidn con 10s rfectos

patogknicos de una dosificacidn prolongada en 10s adultos Se sugiere que la gran variedad de malformaciones vistas en recitn nacidos cuyas madres

recibieron talidomida, pueden resultar solamente de la accibn de un factor tbxico sobre las impulsiones nerviosas iniciales a 10s mirsculos en la fase organogenktica del desarrollo.

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Esta explicacion se prosigue hasta incluir todas las malformaciones vistas en recih nacidos cuyas madres recibieron talidomida, y se correlaciona con el cuadro patogenico en adultos despuis de una dosificacion prolongada. De eso se ve que estas malformaciones son causadas por grados menores de resorcion.

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4. Fullerton, P. M., Kramer, M. (1961) ‘Neuropathy after intake of thalidomide (Distaval).’ Brit. med. J.,

5 . Hamilton, W. J., Boyd, J. D., Mossman, H. W. (1945) Human Embryology. Cambridge: Heffer, p. 104. 6. Kajii, T. (1962) ’Thalidomide and congenital deformities.’ Lancer, ii, 151. 7. Keith, Sir Arthur (1948) Human Embryology and Morphology. London: Arnold. 8. Kemper, F. (1962) ‘Thalidoniide and congenital abnormalities.’ Lancet, ii, 836. 9. Leck, T. M., Millar, E. L. M. (1962) ‘Incidence of malformations since the introduction of thalidomide.’

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1 I . Ministry of Health (1964) Deformities Caused by Thalidoniide. London: H.M.S.O. 12. Morgan, B. C. (1962) ‘Thalidomide (Distaval) and foetal abnormalities.’ Brit. med. J., i, 792. 13. Owen, R., Smith, A. (1962) ‘Cor triloculare and thalidoniide.’ Lancet, ii, 836. 14. Petersen, C. E., Wiedeniann, H. R. (1963) ’Thalidoniide and foetal abnormalities.’ Lancet, i, 174. 1 5 . Robertson, W. F. (1962) ‘Thalidoniide and vitamin B deficiency.’ Brit. med. J . , i, 792. 16. Robson, J. M. (1963) ‘Pharmacological considerations.’ Proc. roy. SOC. Med., 56, 600. 17. Saunders, H., Wright, R., Hodgkin, K. (1962) ‘Thalidomide and congenital deformities.’ Brit. med. J.,

18. Smithells, R. W. (1965) ‘The thalidomide legacy.’ Proc. roy. SOC. Med., 58, 491. 19. Tsu-Ju Yang, Tzu-Szu Yang, Hsu-Mu Liang (1963) ‘Thalidoniide and congenital abnormalities.’

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