Develop. Men. Child Neurol. 1976, 18, 189-197
Epilepsy: a Neurological Complication of Thalidomide Embryopathy J. B. P. Stephenson
Introduction When the teratogenic effect of thalidomide was first discovered in the early 1960s (Lenz 1962), observers were struck by the gross malformations of structures derived from mesoderm (McBride I96 I , Pfeiffer and Kosenow 1962, Pleiss 1962, Spiers 1962), the most obvious being the reduction defects of the limbs. As these children grew older it became clear that the spectrum of thalidomide-induced lesions was much wider than at first thought (d’Avignon et a/. 1967, Smithells 1973). The idea gradually developed that ectodermally-derived structures could be involved, and both German (Horstmann 1966) and Swedish (d’Avignon et a/. 1967) workers emphasised thalidomide damage to the central nervous system, which is of course of neuro-ectodermal origin. These authors raised the question of future epilepsy resulting from neurological involvement in their patients, but because epilepsy may not become manifest for several years, it has only recently been possible to assemble evidence of the correctness of their prediction. It is the purpose of this paper to present this evidence, which convincingly links epilepsy and maternal thalidomide ingestion. -
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- -
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Patients and Method Through the co-operation of the medical and legal personnel involved, and with the consent of the respective families, it was possible to inspect the medical files of all surviving children in the United Kingdom who had defects accepted as resulting from maternal thalidomide ingestion and who had a history suggestive of epilepsy. All of them derived from the 1968 legal settlement group (59 children) or the current ‘X list’ of the 1973 settlement (349 children): a total of 408 ‘thalidomide children’, accepted as such by the Distillers Company (Biochemicals) Ltd. In all cases in which there was doubt about the existence of epilepsy or its nature, the parent(s), and also often the child (if not deaf), were interviewed by loud-speaker telephone and a full history was recorded by the author. The diagnosis of epilepsy o r otherwise was made on the history obtained. The incidence and prevalence of epilepsy in the total surviving population of 408 thalidomide children was compared with the figures derived from the 1958 National Child Development Study (West and Ross 1976). The statistical significance was calculated directly with computor assistance, using a one-tailed test.
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Consultant in Paediatric Neurology, Fraser of Allander Assessment Unit, Royal Hospital for Sick Children, Yorkhill, Glasgow G3 8SJ. D
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DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY.
regarded as having temporal lobe epilepsy, and EEG recordings in 1972 supported this diagnosis. Seizure frequency is up to twice daily, the more severe attacks coming once a month. She has had three episodes of status epilepticus of two or three hours duration. She is now mentally handicapped, with what used to be called an ESN intellectual level.
Where telephone interviews could be arranged, the descriptive terminology used by parent or child has been reproduced in the following historical summaries. To aid the discussion, and in the light of the electroencephalographicfindings of Horstmann (1966) referred to in the Discussion, cases are grouped into those with apparently normal ears, those with abnormal ears, and those in whom the diagnosis is complicated by cardiac abnormalities. With the exception of one child aged 16 years, all the children were aged 13 or 14 years in June 1975.
CASE
Case Histories 1
This boy has minor upper-limb defects. His birth was normal. Very full paediatric neurological notes were available and an interview was not arranged. From the age of 3f years he has had refractory seizures of several types, including brief lapses of consciousness, brief jerks, major convulsive seizures and longer episodes of “minor epileptic status”. He has a particularly disorganised electroencephalogram (EEG) which has included a slow spike-wave abnormality. He has had as many as four anti-epileptic drugs simultaneously, but seizures persist. His mental competence has gradually declined, with difficulties in attention. He now has significant mental handicap. His medical attendants regard him as having epilepsy of temporal lobe origin. CASE
3
This girl’s birth appears to have been normal. She is much handicapped by short upper-limbs. The mother only was interviewed. The child first had seizures from the age of two years, for about nine months until she received phenobarbitone. In these episodes she would lose her balance, her eyes would go “glassy” and she would slump forward for a couple of seconds and then start crying. An attack occurred every six to eight weeks. There followed a period of freedom from seizures, without drugs, between three and 11 years of age. Since then the attacks recommenced but have taken a slightly different form. They have become more frequent, recurring as often as twice a week. At the onset of the seizure she says that there are noises in her head, louder and louder, or merely “mum-mum, I feel terrible”. She is then pale and makes a “funny swallowing noise” in the back of her throat “as if she is trying to swallow”. She then loses her balance altogether, may fall and hurt herself, and is either totally unconscious (and, rarely, incontinent) or unresponsive t o questions. When she comes to, her eyes have a “glaring” appearance as if staring into space. Similir attacks occur a t night. Typically, the child wakes and says her tummy feels like butterflies and there are noises in her head. A few minutes later she makes swallowing noises, her eyes stare and she is unable to speak. She then cries, but afterwards has no memory of the attack apart from a headache. Although the frequency of her seizures has been reduced by phenytoin, the day-time attacks are still sufficiently frequent to cause some disruption at school. There is a family history of a type of seizure disorder presenting in the father after an injury at work, but no further details are available.
CHILDREN WITH NORMAL EARS CASE
1976, 18
2
Extensive medical notes on this girl were available and an i n t h i e w was not arranged. Her birth was induced promptly because of fetal distress, but she was well then and in the ensuing months. She has upper-limb malformations. Seizures began a t the age of seven years, and have since been poorly controlled by a variety of anti-epileptic drugs, most recently phenobarbitone 120mg daily. Some of her episodes are triggered by anxiety or other emotional factors. The seizures vary enormously in character: some are very brief, lasting a few seconds with facial twitching or dribbling; others are longer with complete loss of consciousness, movements of the face and convulsive movements of the right leg. She has been
CASE
4
This girl’s birthweight was low (2380g) but she was well in the neonatal period. The upper limbs show moderate malformations. There is strabismus, with unequal pupils. Her face is normal, apart from a mild left facial weakness which becomes obvious when she is unwell and was first noticed during an attack of gastro-enteritis at the
I90
J. B. P. STEPHENSON
with an upward movement of the eyes, and then she would become very limp (too limp to dress) and pass into a deep sleep. This was different from ordinary sleep, and she could not be taken to nursery school that day if the attack happened in the morning. The second type of seizure also occurred a few times each week, from about the age of 2f years until around the age of nine years. While engaged in some activity she would suddenly stop and stare for up to half a minute, during which time her eyes might show some abnormal movement and sometimes the whites of her eyes were prominent (upward deviation). These episodes could occur in the middle of a sentence or in the middle of speaking a word; when the attacks ended she would resume what she was doing or saying without any sign that she had been aware of what had happened. Her medical advisor considered that these fits should not be treated by drugs unless major seizures developed.
age of 10 months. At that time she was drowsy but had no seizures. Both mother and child were interviewed. From age 18 months to three years the child had rather long episodes of altered consciousness. From age nine years she has had brief attacks of motor arrest (and, rarely, falling), speech arrest and a sensation in her head she described ‘‘as if going side to side in my head very fast”. Her face becomes expressionless. If writing, the writing hand would poise in mid-air, and there could be a slight “judder” of her whole body. The duration of attacks has usually been less than one minute. The maximum frequency was 30 a day, including nocturnal episodes, until suppressed by increased doses of phenobarbitone. Infrequent episodes still occur, despite phenytoin as well as phenobarbitone. The child (who is of high intelligence) says the attacks may be brought on by “lots of bright lights” catching her in the eye. CHILDREN WITH ABNORMAL EARS CASE
CASE
5
This girl’s birth was uneventful. She has normal upper limbs but has bilateral ear abnormalitiesvirtual absence of the ear and no hearing on the left, and a very small deaf ear on the right. There is mild left facial weakness. There are also conjunctival dermoids extending onto the cornea. Her mother was interviewed. At about the age of 18 months the child began t o have trance-like states lasting up to 10 minutes, frequenily followed by a long, deep sleep from which she could not be roused. These attacks began with sudden “staring” and unresponsiveness. The maximum frequency was two in a week. “Blank” attacks, without prolonged loss of consciousness, were more frequent than major attacks. There have been no major attacks since the child has been taking phenobarbitone continuously. An EEG in 1971 showed diffuse bursts of paroxysmal activity “of the type seen in idiopathic epilepsy”. The diagnosis of a form of epilepsy has been accepted by all the neurologists consulted in this case. CASE
7
This girl’s birth was normal, apart from low weight (2240g). She has normal upper limbs, but almost complete absence of the right ear. There was right facial palsy and bilateral sixth nerve palsies. The child and her mother were interviewed. “Blanks”, lasting up to 20 seconds, began in babyhood and still occur. At present the child describes these attacks as “stares”: she feels compelled to stare but doesn’t know what she is staring at. People in the class a t school tell her she has been staring and she “does not know they’ve happened”. At the age of nine years she had two definite clonic seizures, apparently generalised, of about 20 minutes duration shortly after getting u p in the morning, followed by prolonged unconsciousness. She has been taking phenobarbitone since “a baby”. There is a family history of some form of epilepsy in her mother’s sister but no further details are available. CHILDREN WITH CARDIAC ABNORMALI TIES
6 CASE
This girl had a normal birth. Her upper limb deformities are minor, involving only the thumbs. She has deafness, with a right cholesteatoma. She has right facial weakness, attributed to aural surgery. Her mother was interviewed. She said the first type of attack occurred a few times weekly from two months to 18 months of age. There was never a precipitating factor. The child‘s attacks began
8
This boy’s birth was normal but he had a complex medical history, amplified by his father during a telephone interview. He has a variety of malformations, including absent upper-limbs, bilateral colobomata of iris and retina, and bilateral narrowing of the external auditory canals, with severe hearing loss on the right. Pyloric stenojis was diagnosed when he was one month
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408, or 12.5 per 1o00) is statistically significant (p < 0.01). Seven of the 408 children had definite epilepsy (as defined by Gudmundsson 1966) between birth and nine years of age. This prevalence of 17.2 per lo00 is a highly significant rate when compared with the 2.42 per lo00 derived by Gudmundsson (p < 0.OOOl). There were six new cases of epilepsy in the first seven years of life among the thalidomide children, which is equivalent to an annual incidence of 2.1 per 1o00, or approximately five times the expected annual incidence of 0.43 per lo00 at this age (West and Ross 1976). This difference also is statistically significant (p < 0.01).
old. Before the operation he became collapsed and “vacant”, with twitching eyes. A further complication was persistent patent ductus arteriosus. In the years before operative closure in 1972 he had some cyanosis and breathlessness on exertion. In 1967 he became extremely ill, with vomiting and diarrhoea, electrolyte depletion and fever; 10 days after admission to hospital he had a generalised convulsion. In 1968 an EEG showed abnormal slow activity in the right posterior region. His ‘spells’ began a t about two or three years of age, at first as often as once a week. After surgical closure of the patent ductus arterious the attacks recurred every five to six weeks for a period. They appeared to follow exercise, excitement or frustration. He could sense the approach of an attack and would sit or lie down. He appeared to be merely resting, but could not answer questions and was unable to control salivation. There was some blueness about the mouth, followed by pallor as he recovered. He would be ‘dull’ for half an hour, then become normal. These episodes have become rare in the last two years. He still takes phenobarbitone. CASE
1976, 18
Discussion The attributability of thalidomide is not in question in these children. All of them are accepted by Distillers Company (Biochemicals) Limited as having deformities resulting from maternal thalidomide ingestion. Establishing a diagnosis of epilepsy was difficult with the method used in this study, but in clinical practice the neurological history is the main tool in the making of such a diagnosis. Two of the children with cardiac malformations (Cases 8 and 9) have been regarded as suffering from epilepsy, but it is difficult to be certain of this on the available history. Other children, not presented here, have a history of aural vertigo, autonomic attacks, migraine and anxiety, and these paroxysmal phenomena were also seen in some of the children described in this report. The EEG of one such child with attacks of lethargy was reported as “epileptiform” with “multifocal spike discharges”. However, the telephone interview did not suggest any form of epilepsy, nor did the original EEG appear to be outside normal limits when I examined it. In another case, witnesses on the telephone gave a good description of a convulsive seizure, but
9
This boy was born with short, abnormal upper limbs and an ostium secundum atrial septa1 defect, later reported to allow “30 per cent mixing”. The child and his father, and also the family solicitor, were interviewed concerning attacks which the child has suffered since the age of 12 years, at irregular intervals of every two months or so. Onset is always with a complaint of “pain in my side” (on the right) and pallor. He is put to bed and wrapped in clothes. He loses consciousness for 15 minutes and, though pale, feels roasting to the touch. When he is recovering his eyes are “glassy”, and he has no recollection of the attack. He had one attack while on his bicycle and has now been stopped from riding it. At interview, the boy could not remember the episodes described, but said he has a pain in his side when he walks fast or runs.
Results (see Table) Five of the total of 408 children have ‘active’ epilepsy in the same sense as in the National Development Study (West and Ross 1976). Those authors found a prevalence rate at comparable ages of 2 - 7 per IOOO. The increased prevalence in the thalidomide-injured children (five in 192
J. B. P. STEPHENSON
Case no.
Sex
1
TABLE Types of epilepsy in nine thalidomide children Ageat June 1975
--
I
Drugs
1
Age at onset (yrs.)
Latest seizure
1
3+
1
1975
Multiple
7
’
1975
Multiple
1975
Phenytoin
1975
Phenobarbitone phenytoin
I
Seizures
I
Children with normal ears
1
I M
2
F
3
F
4
F
16
1
i --
4
,
:: i
14
6
‘
F
1
1+
13
1) 2/12
14
Infancy
’
_--_ ?I971 ?I971
Phenobarbitone None
’ 1
I
,_______-__
Trances, sleep, stupor.
1975
Tonic, limpness, ‘blank‘ spells, eye-movements. Phenobarb‘Blank‘ spells; two clonic seizitone 1 ures at nine years.
2-3
1975
Phenobarbitone
12
1975
1
I
I
+
~
Various, including minor statui ‘temporal lobe epilepsy’. Various, including major status, ‘temporal lobe epilepsy’. ‘Blank‘ spells, falls, unconsciousness, ‘swallowing’ noises. Altered consciousness, motor arrest.
1
?Epilepsies in children with heart defects ~
~~
14
M I
9
I
14
’
,
blood analysis in this adolescent suggested alcoholic poisoning to be the true diagnosis. The publication in any detail of the case histories of these thalidomide children risks recognition of the individual concerned, but it seemed necessary in the rather small group with suspected epilepsy to allow others to form their own clinical opinion of the diagnosis. Having decided which thalidomide children should be regarded as having a form of epilepsy, it was necessary to determine the annual incidence and the prevalence at the time of this survey, and to compare the results with comparable data relating to the population as a whole. The findings in this study have been compared with the figures of West and Ross (1976) on the 11-year follow-up of the children included in the 1958 National Child Development Study. That is the most
1
Disturbed consciousness, ‘dribbling’. Abdominal ,pain, unconsciousness, amnesia.
careful study of its kind in the United Kingdom, and its subjects are approximately of the same age as the thalidomide children. Of the other studies on the frequency of epilepsy with which West and Ross compare their findings (Logan and Cushion 1958, College of General Practitioners 1960, Kurland 1960, Pond er al. 1960, Brewis er ul. 1966, Gudmundsson 1966, Rutter et ui. 1970), the most comprehensive and critical is the survey of the total population of Iceland by Gudmundsson. In this rigorous study, the prevalence in the 0 to 9 year age-group (over 40,000 children) was 2.42 per 1000. Using similar criteria, the prevalence at that age in our thalidomide children was 17.2 per 1000 (p < 0.0001). Of greater neurological significance than the actual increased prevalence of epilepsy is the occurrence of comparatively unusual 193
DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY.
1976, 18
guinea-pig that maternal thalidomide could profoundly alter the electrical activity of the fetal brain, the effect varying with the developmental stage. Those authors noted that the most drastic suppression of fetal cerebral activity occurred at the stage of rapid brain-stem maturation, and postulated that thalidomide could disturb the functions of brain-stem structures in man. McCreadie (1973) has advanced the hypothesis, supported experimentally (McCreadie and McLeod 1974), that fetal neuropathy-cranial, somatic and autonomic-might be responsible for the classical thalidomide malformations which at first sight appear to be of mesenchymal origin. Several lines of evidence confirm neurological involvement in thalidomide embryopathy in man. Pathological and anatomical studies (Miehlke and Partsch 1963, Miehlke 1964) demonstrated that in facial palsy the abnormality was within the brain-stem. Pathological studies of the brains of two affected infants who died in the neonatal period showed gross anatomical malformations (Horstmann 1966). In one of these there was cerebellar aplasia. Pneumoencephalography was abnormal in all six children studied by d’Avignon et al. (1967). Similar results were reported by Bamberger (1965) and Horstmann (1966), but their findings varied and included asymmetries, atrophies and alterations of the shape of ventricular outline. Clinical neurology has further supported direct brain involvement. The cranial-nerve palsies well described by d’Avignon and Barr (1 964) and Horstmann (1966) are difficult to explain, except on the basis of structural brain-stem abnormalities, and neuro-opthalmological studies of United Kingdom children with gaze palsies confirm this (Green et al., unpublished data). From yet another viewpoint, McFie and Robertson (1973), after detailed psychological testing of British
varieties in these thalidomide children. The types of epilepsy in those with normal ears include simple and complex partial (‘temporal lobe’) symptomatology. These epilepsies of apparent focal origin fit with the concept that thalidomide leads to a structural abnormality in the fetal cerebral cortex. It is notable that two of these children have severe refractory epilepsy, suggesting more widespread brain abnormality. The prevalence of severe epilepsy of this sort (5 per lo00 in the thalidomide children) greatly exceeds that expected in the general population(about 0 . 5 per 1000; Rutter et al. 1970, Summer et al. 1974). The thalidomide children with abnormally-formed ears differed in that they had unlocalised or generalised seizures, including simple loss of consciousness. That these were not common genetic epilepsies is supported by the EEG findings of Horstmann (1966), described later in this discussion. An origin in an abnormal brain-stem, malformed by maternal thalidomide, seems to be a more probable explanation. The specific question of epilepsy in thalidomide children must be looked at in the general context of the action of thalidomide on the nervous system. Although early workers assumed that maternal thalidomide affected only mesoderm, it was soon pointed out that certain defects such as ocular colobomata were unquestionably of neuro-ectodermal origin (Cullen 1964). It is not surprising that thalidomide should interfere with the development of the fetal nervous system, in the light of its well-known influence on the nervous system of the adult. Not only was thalidomide widely used as a sedative, but it could also induce a striking sensory neuropathy (Florence 1960) and was widely used in Europe as a provoking agent in the electroencephalographic diagnosis of epilepsy (Lenz 1974). Bergstrom et al. (1964) first showed clearly in the 194
J. B. P. STEPHENSON
children, suggested that thalidomide “may have an adverse effect on the development of the nervous system”. The published EEG findings in thalidomide-damaged children are of the greatest importance. Horstmann (1966) reported 17 such children between the ages of I year 9 months and 6 years 3 months. The EEG was abnormal in nine of these, all but one of whom had perceptible abnormalities of the ears, and the published extracts of the EEG recordings are convincing. The findings were not uniform, but included focal and generalised paroxysmal disturbances, including spikes and irregular spike-wave patterns. In one child the EEG records deteriorated with age, being normal at three years but “convulsive” at four years. Bamberger (1965) mentioned EEG abnormalities in five out of six children, with epileptic foci (“sogar epileptische Herde”) in one. d’Avignon er af. (1967) found “pathological” EEGS in seven children. Their study population was 67 Swedish children, but it was not stated whether EEG recordings were made in all cases. The reported EEG changes were “dysrhythmias, frequently localised, and many epileptogenic changes”. Six of the seven children had abnormal findings on pneumoencephalograph y. At the time of these publications, seizures had not been noticed in any of the children examined, but Horstmann (1966) warned of latent epilepsy or an increased propensity to convulsions (“Es kann in allen Fallen daher lediglich von einer Hirnfunktionsstorung im Sinne einer latent erhonten Kriimpfbereitschaft gesprochen werden”). The predictions from these EEG investigations have been confirmed by the present study, which has demonstrated an abnormally high incidence and prevalence of epilepsy in the United Kingdom population of thalidomide children. The evidence suggests that these epilepsies may
have arisen from cortical or brain-stem abnormalities. In two cases the epilepsy has been exceptionally severe. The proposition that maternal thalidomide ingestion can alter the structure, function and electrical activity of the brain of the affected offspring is supported by clinical, psychological, radiological, pathological and neurophysiological studies. There is little reasonable doubt that epilepsies in our children are attributable to thalidomide, but whether the increased incidence of epilepsy will continue into adolescence and adult life is highly speculative. If it does, then on the basis of the lifetime annual incidence of 0.26 per 1000 (Gudmundsson 1966) being multiplied five-fold to 1 - 3 per 1000, one may predict 21 cases of epilepsy to become manifest in the next 50 years in addition to the expected five. Despite this prediction, whole-scale neurological investigation of the thalidomide population would likely do more harm than good. ADDENDUM
Since this paper was submitted, further historical information has become available on Case 9, the boy with congenital heart-defect and normal ears. The attacks are described as beginning with a complaint of a pain in his left side, succeeded by unconsciousness, during which his right fist is clenched. CIonic movements of the limbs follow for about five minutes before he gradually becomes alert again. Such episodes have recurred every three months, the last being in June 1975. He has not had medication but his Consultant Paediatrician thinks that these attacks are definitely epileptic. The type of epilepsy seems to be partial or focal, with secondary generalisation, and thus resembles that found in the other affected thalidomide children with normal ears. The addition of this case further increases the significance of the high prevalence of ‘active’ epilepsy in the teenage thalidomide population (p = 0.001). 195
DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY.
Acknowledgemenrs: This investigation was suggested at a meeting of the panel of assessors for the thalidomide children. I am most grateful to Mr. Charles White, of Kimber Bull & Co. and now of Kusel White & Co., for arranging the telephone interviews and for acquiring the medical
1976, 18
reports, and also to the many doctors who provided the reports, often with helpful discussion. Dr. Euan Ross kindly provided a copy of West and Ross (1976) when not then generally available. Mr. K. R. Clarke gave expert assistance in the statistical analysis.
SUMMARY
The possibility of epilepsy resulting from maternal thalidomide ingestion was investigated by obtaining a telephoned neurological history from all suspect families in the United Kingdom in which the specific diagnosis was uncertain. The annual incidence in the first seven years of life was found to be five times the figure for the general population, and the prevalence of active epilepsy is significantly increased in the teenage thalidomide population. That this increased incidence and prevalence of epilepsy is not a chance observation is supported by published clinical and experimental evidence of central nervous system abnormalities in thalidomide embryopathy, in addition to the known neurological effects of the drug in the adult. RCSUMC Epilepsie: complications neurologiques d’embryopathie par thalidomide La possibilitt d’tpilepsie provenant d’une ingestion maternelle de thalidomide a t t i ttudite A partir de l’histoire neurologique obtenue par ttltphone de toutes les familles suspectes du Royaume Uni, 18 oh le diagnostic ttait incertain. La frtquence annuelle dans les sept premibes annCes de vie ttait cinq fois plus forte qu’attendue et la prtvalence d’une tpilepsie active est maintenant significativement accrue chez les adolescents. Que cette incidence accrue et cette permanence de l’tpilepsie ne soient pas likes au hasard est favorist par les publications cliniques et les dtmonstrations exptrimentales, qu’il est possible d’observer des anomalies du systeme nerveux central dans l’embryopathie de thalidomide en addition des effets neurologiques bien connus de la mkdication sur les adultes. ZUSAM MENFASSUNG
Epilepsie: Eine neurologische Komplika fion der Thalidomid Embryopathie Es wurde die Moglichkeit gepruft, ob eine Thalidomid Medikation bei der Mutter als Ursache fur die Entstehung einer Epilepsie infrage kommt, indem man telefonisch eine neurologische Anamnese von allen betroffenen Familien in GroBbrirtanien erhoben hat, bei denen die Diagnose ungeklart war. Die jahrliche Anzahl in den ersten sieben Lebensjahren war funfmal hoher als man erwartet hatte und das vorkommen einer noch aktiven Epilepsie hat sich jetzt bei Teenagern signifikant erhoht. Dieses vermehrte Vorkommen der Epilepsie ist kein Zufallsbefund, dafur sprechen publizierte Daten klinischer und experimenteller Art uber Veranderungen im Zentralnervensystem bei Thalidomid Embryopathie, sowie die wohlbekannten neurologischen Effekte des Medikamentes beim Erwachsenen. RESUMEN
Epilepsia: Una complicacidn neuroldgica de la embriopatia talidomidica Se investigd la posibilidad de epilepsia como resultado de la ingesti6n de talidomida por la madre, mediante la obtencidn por teltfono de la historia neuroldgica de todas las
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J. B. P. STEPHENSON
familias sospechosas en el Reino Unido, en las que el diagnbstico era incierto. La incidencia anual en 10s siete primeros aiios fue cinco veces mayor que las cifras esperadas, y la prevalencia de epilepsia activa es significativamente mayor ahora en 10s adolescentes. Que este aumento en la incidencia y la prevalencia de la epilepsia no es una observacion casual viene avalado por la publicacion de evidencia clinica y experimental de anormalidades del sistema nervioso central en la embriopatia talidomidica, ademas de 10s efectos neurologicos bien conocidos de estos firmacos en 10s adultos. REFERENCES d’Avignon, M., Barr, B. (1964) ‘Ear abnormalities and cranial nerve palsies in thalidomide children.’ Archives of Otolarvngology, 80, 136. - Hellgren, K., Juhlin, I.-M.. Alterback, B. (1967) ‘Diagnostic and habilitation problems of thalidomidetraumatized children with multiple handicaps.’ Developmental Medicine and Child Neurology, 9, 707. Bamberger, P. (1 965) Dy.~melie-Arbeitstagting.2. Monogruphie iiber die Rehabilitation der Dysmelie-Kinder. Bonn: Bundesministerium fur Gesundheitswesen, p. 122. Bergstrom, R. M., Bergstrom, L., Putkonen, P., Sainio, K. (1964) ‘The effects of thalidomide on the electrical activity of the brain in the intra-uterine guinea-pig fetus.’ Medicinu Experimentalis (Busel), 11, 119. Brewis M., Poskanzer, D. C., Rolland, C., Miller, H. (1966) ‘Neurological disease in a n English city.’ A r i d Neurologica Scandinavica, 42, suppl. 24. Cullen J. F. (1964) ‘Ocular defects in thalidomide babies.’ British Journal of Ophfhalmology, 48, 151. Florence, A. L. (1960) ‘Is thalidomide to blame? British Medical Journal, 2, 1954. Gudmundsson, G. (1966) ‘Epilepsy in Iceland.’ Acta Neurologica Scandinavica, 43, Suppl. 25. Horstmann, W. (1966) ‘Hinweise auf zentralnervose Schaden im Rahmen der Thalidomid-Embryopathie.’ Zeitschrift fur Kinderheilkunde, 96, 291. Kurland, L. T. (1960) ’The incidence and prevalence of convulsive disorders in a small urban community.’ Epilepsia, 1, 143. Lenz, W. (1962) ‘Thalidomide and congenital abnormalities.’ Lancer, i , 45. - (1974) Personal communication. Logan, W. P. D., Cushion, A. A. (1958) Morbidity Sfati.stics.fromGenernl Practice. Vol. I (General) C . R . O . Studies on Medical and Population Subjects. London : H.M.S.O. McBride, W. G. (1961) ‘Thalidomide and congenital abnormalities.’ Lancet, ii, 1358. McCreadie, J. (1973) ‘Thalidomide and congenital Charcot’s joints.’ Luncet, ii, 1058. - McLeod, J. G. (1974) ‘Thalidomide and embryonic neuropathy.’ Lancet, i, I I I I. McFie, J., Robertson, J. (1973) ‘Psychological test results of children with thalidomide deformities.’ Developniental Medicine and Child Neurologj-, 15, 71 9. Miehlke, A. (1964) ‘Symposium: facial nerve rehabilitation. Normal and anomalous anatomy of the facial nerve and an embryological study of the thalidomide catastrophe in Germany.’ Transactions of the American Academy of Ophthalmology and Otolaryngology, 68, 1030. - Partsch, C. J. (1963) ‘Ohrmissbildung, Facialis-und Abducenslahmung als Syndrom der ThalidomidSchadigung.’ Arrhiv fur Ohren-. Nasen- und Kehlkopfheilkimde, 181, 155. Pfeiffer, R. A., Kosenow. W. (1962) ‘Thalidomide and congenital abnormalities.’ Lancet, i , 45. Pliess, G. (1962) ‘Thalidomide and congenital abnormalities.’ Lancet, i, 1128. Pond, D. A., Bidwell, B. H., Stein, L. (1960) ‘A study of epilepsy in fourteen general practices. I. Demographic and medical data.’ Psychiatria, Neurologio, Neurochfrurgia,63. 21 7. College of General Practitioners Research Committee ( 1960) ‘A survey of the epilepsies in general practice.’ British Medical Journal, 2, 416. Rutter. M., Graham, P., Yule, W. (1970) A Neurop.s,vrhfntricStrtdv in Childhood. Clinics in Developmental Medicine Nos. 35/36. L.ondon : S.I.M.P./Heinemann Medical Books. Smithells, R. W. (1973) ‘Defects and disabilities of thalidomide children.’ British Medical Journal, 1, 269. Spiers, A. L. (1962) ‘Thalidomide and congenital abnormalities.’ Lancer, i, 303. Sumner, D. D., Verma, K. B. C., Peasland, A. (1974) ‘The epileptic: his call on community resources.’ In Harris, P., Maudsley, C. (Eds.) Epileps).. Proceedings of the Huns Berger Centenary Symposium. Edinburgh: Churchill Livingstone, p. 309. West, P., Ross, E. (1976) Studies in Convulsive Disorder. The Prevalence and Incidence of Epilepsy in Childhood (not yet published).
197
Epilepsy: a Neurological Complication of Thalidomide Embryopathy J. B. P. Stephenson
Introduction When the teratogenic effect of thalidomide was first discovered in the early 1960s (Lenz 1962), observers were struck by the gross malformations of structures derived from mesoderm (McBride I96 I , Pfeiffer and Kosenow 1962, Pleiss 1962, Spiers 1962), the most obvious being the reduction defects of the limbs. As these children grew older it became clear that the spectrum of thalidomide-induced lesions was much wider than at first thought (d’Avignon et a/. 1967, Smithells 1973). The idea gradually developed that ectodermally-derived structures could be involved, and both German (Horstmann 1966) and Swedish (d’Avignon et a/. 1967) workers emphasised thalidomide damage to the central nervous system, which is of course of neuro-ectodermal origin. These authors raised the question of future epilepsy resulting from neurological involvement in their patients, but because epilepsy may not become manifest for several years, it has only recently been possible to assemble evidence of the correctness of their prediction. It is the purpose of this paper to present this evidence, which convincingly links epilepsy and maternal thalidomide ingestion. -
~-
- -
~~
Patients and Method Through the co-operation of the medical and legal personnel involved, and with the consent of the respective families, it was possible to inspect the medical files of all surviving children in the United Kingdom who had defects accepted as resulting from maternal thalidomide ingestion and who had a history suggestive of epilepsy. All of them derived from the 1968 legal settlement group (59 children) or the current ‘X list’ of the 1973 settlement (349 children): a total of 408 ‘thalidomide children’, accepted as such by the Distillers Company (Biochemicals) Ltd. In all cases in which there was doubt about the existence of epilepsy or its nature, the parent(s), and also often the child (if not deaf), were interviewed by loud-speaker telephone and a full history was recorded by the author. The diagnosis of epilepsy o r otherwise was made on the history obtained. The incidence and prevalence of epilepsy in the total surviving population of 408 thalidomide children was compared with the figures derived from the 1958 National Child Development Study (West and Ross 1976). The statistical significance was calculated directly with computor assistance, using a one-tailed test.
~
~
Consultant in Paediatric Neurology, Fraser of Allander Assessment Unit, Royal Hospital for Sick Children, Yorkhill, Glasgow G3 8SJ. D
189
DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY.
regarded as having temporal lobe epilepsy, and EEG recordings in 1972 supported this diagnosis. Seizure frequency is up to twice daily, the more severe attacks coming once a month. She has had three episodes of status epilepticus of two or three hours duration. She is now mentally handicapped, with what used to be called an ESN intellectual level.
Where telephone interviews could be arranged, the descriptive terminology used by parent or child has been reproduced in the following historical summaries. To aid the discussion, and in the light of the electroencephalographicfindings of Horstmann (1966) referred to in the Discussion, cases are grouped into those with apparently normal ears, those with abnormal ears, and those in whom the diagnosis is complicated by cardiac abnormalities. With the exception of one child aged 16 years, all the children were aged 13 or 14 years in June 1975.
CASE
Case Histories 1
This boy has minor upper-limb defects. His birth was normal. Very full paediatric neurological notes were available and an interview was not arranged. From the age of 3f years he has had refractory seizures of several types, including brief lapses of consciousness, brief jerks, major convulsive seizures and longer episodes of “minor epileptic status”. He has a particularly disorganised electroencephalogram (EEG) which has included a slow spike-wave abnormality. He has had as many as four anti-epileptic drugs simultaneously, but seizures persist. His mental competence has gradually declined, with difficulties in attention. He now has significant mental handicap. His medical attendants regard him as having epilepsy of temporal lobe origin. CASE
3
This girl’s birth appears to have been normal. She is much handicapped by short upper-limbs. The mother only was interviewed. The child first had seizures from the age of two years, for about nine months until she received phenobarbitone. In these episodes she would lose her balance, her eyes would go “glassy” and she would slump forward for a couple of seconds and then start crying. An attack occurred every six to eight weeks. There followed a period of freedom from seizures, without drugs, between three and 11 years of age. Since then the attacks recommenced but have taken a slightly different form. They have become more frequent, recurring as often as twice a week. At the onset of the seizure she says that there are noises in her head, louder and louder, or merely “mum-mum, I feel terrible”. She is then pale and makes a “funny swallowing noise” in the back of her throat “as if she is trying to swallow”. She then loses her balance altogether, may fall and hurt herself, and is either totally unconscious (and, rarely, incontinent) or unresponsive t o questions. When she comes to, her eyes have a “glaring” appearance as if staring into space. Similir attacks occur a t night. Typically, the child wakes and says her tummy feels like butterflies and there are noises in her head. A few minutes later she makes swallowing noises, her eyes stare and she is unable to speak. She then cries, but afterwards has no memory of the attack apart from a headache. Although the frequency of her seizures has been reduced by phenytoin, the day-time attacks are still sufficiently frequent to cause some disruption at school. There is a family history of a type of seizure disorder presenting in the father after an injury at work, but no further details are available.
CHILDREN WITH NORMAL EARS CASE
1976, 18
2
Extensive medical notes on this girl were available and an i n t h i e w was not arranged. Her birth was induced promptly because of fetal distress, but she was well then and in the ensuing months. She has upper-limb malformations. Seizures began a t the age of seven years, and have since been poorly controlled by a variety of anti-epileptic drugs, most recently phenobarbitone 120mg daily. Some of her episodes are triggered by anxiety or other emotional factors. The seizures vary enormously in character: some are very brief, lasting a few seconds with facial twitching or dribbling; others are longer with complete loss of consciousness, movements of the face and convulsive movements of the right leg. She has been
CASE
4
This girl’s birthweight was low (2380g) but she was well in the neonatal period. The upper limbs show moderate malformations. There is strabismus, with unequal pupils. Her face is normal, apart from a mild left facial weakness which becomes obvious when she is unwell and was first noticed during an attack of gastro-enteritis at the
I90
J. B. P. STEPHENSON
with an upward movement of the eyes, and then she would become very limp (too limp to dress) and pass into a deep sleep. This was different from ordinary sleep, and she could not be taken to nursery school that day if the attack happened in the morning. The second type of seizure also occurred a few times each week, from about the age of 2f years until around the age of nine years. While engaged in some activity she would suddenly stop and stare for up to half a minute, during which time her eyes might show some abnormal movement and sometimes the whites of her eyes were prominent (upward deviation). These episodes could occur in the middle of a sentence or in the middle of speaking a word; when the attacks ended she would resume what she was doing or saying without any sign that she had been aware of what had happened. Her medical advisor considered that these fits should not be treated by drugs unless major seizures developed.
age of 10 months. At that time she was drowsy but had no seizures. Both mother and child were interviewed. From age 18 months to three years the child had rather long episodes of altered consciousness. From age nine years she has had brief attacks of motor arrest (and, rarely, falling), speech arrest and a sensation in her head she described ‘‘as if going side to side in my head very fast”. Her face becomes expressionless. If writing, the writing hand would poise in mid-air, and there could be a slight “judder” of her whole body. The duration of attacks has usually been less than one minute. The maximum frequency was 30 a day, including nocturnal episodes, until suppressed by increased doses of phenobarbitone. Infrequent episodes still occur, despite phenytoin as well as phenobarbitone. The child (who is of high intelligence) says the attacks may be brought on by “lots of bright lights” catching her in the eye. CHILDREN WITH ABNORMAL EARS CASE
CASE
5
This girl’s birth was uneventful. She has normal upper limbs but has bilateral ear abnormalitiesvirtual absence of the ear and no hearing on the left, and a very small deaf ear on the right. There is mild left facial weakness. There are also conjunctival dermoids extending onto the cornea. Her mother was interviewed. At about the age of 18 months the child began t o have trance-like states lasting up to 10 minutes, frequenily followed by a long, deep sleep from which she could not be roused. These attacks began with sudden “staring” and unresponsiveness. The maximum frequency was two in a week. “Blank” attacks, without prolonged loss of consciousness, were more frequent than major attacks. There have been no major attacks since the child has been taking phenobarbitone continuously. An EEG in 1971 showed diffuse bursts of paroxysmal activity “of the type seen in idiopathic epilepsy”. The diagnosis of a form of epilepsy has been accepted by all the neurologists consulted in this case. CASE
7
This girl’s birth was normal, apart from low weight (2240g). She has normal upper limbs, but almost complete absence of the right ear. There was right facial palsy and bilateral sixth nerve palsies. The child and her mother were interviewed. “Blanks”, lasting up to 20 seconds, began in babyhood and still occur. At present the child describes these attacks as “stares”: she feels compelled to stare but doesn’t know what she is staring at. People in the class a t school tell her she has been staring and she “does not know they’ve happened”. At the age of nine years she had two definite clonic seizures, apparently generalised, of about 20 minutes duration shortly after getting u p in the morning, followed by prolonged unconsciousness. She has been taking phenobarbitone since “a baby”. There is a family history of some form of epilepsy in her mother’s sister but no further details are available. CHILDREN WITH CARDIAC ABNORMALI TIES
6 CASE
This girl had a normal birth. Her upper limb deformities are minor, involving only the thumbs. She has deafness, with a right cholesteatoma. She has right facial weakness, attributed to aural surgery. Her mother was interviewed. She said the first type of attack occurred a few times weekly from two months to 18 months of age. There was never a precipitating factor. The child‘s attacks began
8
This boy’s birth was normal but he had a complex medical history, amplified by his father during a telephone interview. He has a variety of malformations, including absent upper-limbs, bilateral colobomata of iris and retina, and bilateral narrowing of the external auditory canals, with severe hearing loss on the right. Pyloric stenojis was diagnosed when he was one month
191
DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY.
408, or 12.5 per 1o00) is statistically significant (p < 0.01). Seven of the 408 children had definite epilepsy (as defined by Gudmundsson 1966) between birth and nine years of age. This prevalence of 17.2 per lo00 is a highly significant rate when compared with the 2.42 per lo00 derived by Gudmundsson (p < 0.OOOl). There were six new cases of epilepsy in the first seven years of life among the thalidomide children, which is equivalent to an annual incidence of 2.1 per 1o00, or approximately five times the expected annual incidence of 0.43 per lo00 at this age (West and Ross 1976). This difference also is statistically significant (p < 0.01).
old. Before the operation he became collapsed and “vacant”, with twitching eyes. A further complication was persistent patent ductus arteriosus. In the years before operative closure in 1972 he had some cyanosis and breathlessness on exertion. In 1967 he became extremely ill, with vomiting and diarrhoea, electrolyte depletion and fever; 10 days after admission to hospital he had a generalised convulsion. In 1968 an EEG showed abnormal slow activity in the right posterior region. His ‘spells’ began a t about two or three years of age, at first as often as once a week. After surgical closure of the patent ductus arterious the attacks recurred every five to six weeks for a period. They appeared to follow exercise, excitement or frustration. He could sense the approach of an attack and would sit or lie down. He appeared to be merely resting, but could not answer questions and was unable to control salivation. There was some blueness about the mouth, followed by pallor as he recovered. He would be ‘dull’ for half an hour, then become normal. These episodes have become rare in the last two years. He still takes phenobarbitone. CASE
1976, 18
Discussion The attributability of thalidomide is not in question in these children. All of them are accepted by Distillers Company (Biochemicals) Limited as having deformities resulting from maternal thalidomide ingestion. Establishing a diagnosis of epilepsy was difficult with the method used in this study, but in clinical practice the neurological history is the main tool in the making of such a diagnosis. Two of the children with cardiac malformations (Cases 8 and 9) have been regarded as suffering from epilepsy, but it is difficult to be certain of this on the available history. Other children, not presented here, have a history of aural vertigo, autonomic attacks, migraine and anxiety, and these paroxysmal phenomena were also seen in some of the children described in this report. The EEG of one such child with attacks of lethargy was reported as “epileptiform” with “multifocal spike discharges”. However, the telephone interview did not suggest any form of epilepsy, nor did the original EEG appear to be outside normal limits when I examined it. In another case, witnesses on the telephone gave a good description of a convulsive seizure, but
9
This boy was born with short, abnormal upper limbs and an ostium secundum atrial septa1 defect, later reported to allow “30 per cent mixing”. The child and his father, and also the family solicitor, were interviewed concerning attacks which the child has suffered since the age of 12 years, at irregular intervals of every two months or so. Onset is always with a complaint of “pain in my side” (on the right) and pallor. He is put to bed and wrapped in clothes. He loses consciousness for 15 minutes and, though pale, feels roasting to the touch. When he is recovering his eyes are “glassy”, and he has no recollection of the attack. He had one attack while on his bicycle and has now been stopped from riding it. At interview, the boy could not remember the episodes described, but said he has a pain in his side when he walks fast or runs.
Results (see Table) Five of the total of 408 children have ‘active’ epilepsy in the same sense as in the National Development Study (West and Ross 1976). Those authors found a prevalence rate at comparable ages of 2 - 7 per IOOO. The increased prevalence in the thalidomide-injured children (five in 192
J. B. P. STEPHENSON
Case no.
Sex
1
TABLE Types of epilepsy in nine thalidomide children Ageat June 1975
--
I
Drugs
1
Age at onset (yrs.)
Latest seizure
1
3+
1
1975
Multiple
7
’
1975
Multiple
1975
Phenytoin
1975
Phenobarbitone phenytoin
I
Seizures
I
Children with normal ears
1
I M
2
F
3
F
4
F
16
1
i --
4
,
:: i
14
6
‘
F
1
1+
13
1) 2/12
14
Infancy
’
_--_ ?I971 ?I971
Phenobarbitone None
’ 1
I
,_______-__
Trances, sleep, stupor.
1975
Tonic, limpness, ‘blank‘ spells, eye-movements. Phenobarb‘Blank‘ spells; two clonic seizitone 1 ures at nine years.
2-3
1975
Phenobarbitone
12
1975
1
I
I
+
~
Various, including minor statui ‘temporal lobe epilepsy’. Various, including major status, ‘temporal lobe epilepsy’. ‘Blank‘ spells, falls, unconsciousness, ‘swallowing’ noises. Altered consciousness, motor arrest.
1
?Epilepsies in children with heart defects ~
~~
14
M I
9
I
14
’
,
blood analysis in this adolescent suggested alcoholic poisoning to be the true diagnosis. The publication in any detail of the case histories of these thalidomide children risks recognition of the individual concerned, but it seemed necessary in the rather small group with suspected epilepsy to allow others to form their own clinical opinion of the diagnosis. Having decided which thalidomide children should be regarded as having a form of epilepsy, it was necessary to determine the annual incidence and the prevalence at the time of this survey, and to compare the results with comparable data relating to the population as a whole. The findings in this study have been compared with the figures of West and Ross (1976) on the 11-year follow-up of the children included in the 1958 National Child Development Study. That is the most
1
Disturbed consciousness, ‘dribbling’. Abdominal ,pain, unconsciousness, amnesia.
careful study of its kind in the United Kingdom, and its subjects are approximately of the same age as the thalidomide children. Of the other studies on the frequency of epilepsy with which West and Ross compare their findings (Logan and Cushion 1958, College of General Practitioners 1960, Kurland 1960, Pond er al. 1960, Brewis er ul. 1966, Gudmundsson 1966, Rutter et ui. 1970), the most comprehensive and critical is the survey of the total population of Iceland by Gudmundsson. In this rigorous study, the prevalence in the 0 to 9 year age-group (over 40,000 children) was 2.42 per 1000. Using similar criteria, the prevalence at that age in our thalidomide children was 17.2 per 1000 (p < 0.0001). Of greater neurological significance than the actual increased prevalence of epilepsy is the occurrence of comparatively unusual 193
DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY.
1976, 18
guinea-pig that maternal thalidomide could profoundly alter the electrical activity of the fetal brain, the effect varying with the developmental stage. Those authors noted that the most drastic suppression of fetal cerebral activity occurred at the stage of rapid brain-stem maturation, and postulated that thalidomide could disturb the functions of brain-stem structures in man. McCreadie (1973) has advanced the hypothesis, supported experimentally (McCreadie and McLeod 1974), that fetal neuropathy-cranial, somatic and autonomic-might be responsible for the classical thalidomide malformations which at first sight appear to be of mesenchymal origin. Several lines of evidence confirm neurological involvement in thalidomide embryopathy in man. Pathological and anatomical studies (Miehlke and Partsch 1963, Miehlke 1964) demonstrated that in facial palsy the abnormality was within the brain-stem. Pathological studies of the brains of two affected infants who died in the neonatal period showed gross anatomical malformations (Horstmann 1966). In one of these there was cerebellar aplasia. Pneumoencephalography was abnormal in all six children studied by d’Avignon et al. (1967). Similar results were reported by Bamberger (1965) and Horstmann (1966), but their findings varied and included asymmetries, atrophies and alterations of the shape of ventricular outline. Clinical neurology has further supported direct brain involvement. The cranial-nerve palsies well described by d’Avignon and Barr (1 964) and Horstmann (1966) are difficult to explain, except on the basis of structural brain-stem abnormalities, and neuro-opthalmological studies of United Kingdom children with gaze palsies confirm this (Green et al., unpublished data). From yet another viewpoint, McFie and Robertson (1973), after detailed psychological testing of British
varieties in these thalidomide children. The types of epilepsy in those with normal ears include simple and complex partial (‘temporal lobe’) symptomatology. These epilepsies of apparent focal origin fit with the concept that thalidomide leads to a structural abnormality in the fetal cerebral cortex. It is notable that two of these children have severe refractory epilepsy, suggesting more widespread brain abnormality. The prevalence of severe epilepsy of this sort (5 per lo00 in the thalidomide children) greatly exceeds that expected in the general population(about 0 . 5 per 1000; Rutter et al. 1970, Summer et al. 1974). The thalidomide children with abnormally-formed ears differed in that they had unlocalised or generalised seizures, including simple loss of consciousness. That these were not common genetic epilepsies is supported by the EEG findings of Horstmann (1966), described later in this discussion. An origin in an abnormal brain-stem, malformed by maternal thalidomide, seems to be a more probable explanation. The specific question of epilepsy in thalidomide children must be looked at in the general context of the action of thalidomide on the nervous system. Although early workers assumed that maternal thalidomide affected only mesoderm, it was soon pointed out that certain defects such as ocular colobomata were unquestionably of neuro-ectodermal origin (Cullen 1964). It is not surprising that thalidomide should interfere with the development of the fetal nervous system, in the light of its well-known influence on the nervous system of the adult. Not only was thalidomide widely used as a sedative, but it could also induce a striking sensory neuropathy (Florence 1960) and was widely used in Europe as a provoking agent in the electroencephalographic diagnosis of epilepsy (Lenz 1974). Bergstrom et al. (1964) first showed clearly in the 194
J. B. P. STEPHENSON
children, suggested that thalidomide “may have an adverse effect on the development of the nervous system”. The published EEG findings in thalidomide-damaged children are of the greatest importance. Horstmann (1966) reported 17 such children between the ages of I year 9 months and 6 years 3 months. The EEG was abnormal in nine of these, all but one of whom had perceptible abnormalities of the ears, and the published extracts of the EEG recordings are convincing. The findings were not uniform, but included focal and generalised paroxysmal disturbances, including spikes and irregular spike-wave patterns. In one child the EEG records deteriorated with age, being normal at three years but “convulsive” at four years. Bamberger (1965) mentioned EEG abnormalities in five out of six children, with epileptic foci (“sogar epileptische Herde”) in one. d’Avignon er af. (1967) found “pathological” EEGS in seven children. Their study population was 67 Swedish children, but it was not stated whether EEG recordings were made in all cases. The reported EEG changes were “dysrhythmias, frequently localised, and many epileptogenic changes”. Six of the seven children had abnormal findings on pneumoencephalograph y. At the time of these publications, seizures had not been noticed in any of the children examined, but Horstmann (1966) warned of latent epilepsy or an increased propensity to convulsions (“Es kann in allen Fallen daher lediglich von einer Hirnfunktionsstorung im Sinne einer latent erhonten Kriimpfbereitschaft gesprochen werden”). The predictions from these EEG investigations have been confirmed by the present study, which has demonstrated an abnormally high incidence and prevalence of epilepsy in the United Kingdom population of thalidomide children. The evidence suggests that these epilepsies may
have arisen from cortical or brain-stem abnormalities. In two cases the epilepsy has been exceptionally severe. The proposition that maternal thalidomide ingestion can alter the structure, function and electrical activity of the brain of the affected offspring is supported by clinical, psychological, radiological, pathological and neurophysiological studies. There is little reasonable doubt that epilepsies in our children are attributable to thalidomide, but whether the increased incidence of epilepsy will continue into adolescence and adult life is highly speculative. If it does, then on the basis of the lifetime annual incidence of 0.26 per 1000 (Gudmundsson 1966) being multiplied five-fold to 1 - 3 per 1000, one may predict 21 cases of epilepsy to become manifest in the next 50 years in addition to the expected five. Despite this prediction, whole-scale neurological investigation of the thalidomide population would likely do more harm than good. ADDENDUM
Since this paper was submitted, further historical information has become available on Case 9, the boy with congenital heart-defect and normal ears. The attacks are described as beginning with a complaint of a pain in his left side, succeeded by unconsciousness, during which his right fist is clenched. CIonic movements of the limbs follow for about five minutes before he gradually becomes alert again. Such episodes have recurred every three months, the last being in June 1975. He has not had medication but his Consultant Paediatrician thinks that these attacks are definitely epileptic. The type of epilepsy seems to be partial or focal, with secondary generalisation, and thus resembles that found in the other affected thalidomide children with normal ears. The addition of this case further increases the significance of the high prevalence of ‘active’ epilepsy in the teenage thalidomide population (p = 0.001). 195
DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY.
Acknowledgemenrs: This investigation was suggested at a meeting of the panel of assessors for the thalidomide children. I am most grateful to Mr. Charles White, of Kimber Bull & Co. and now of Kusel White & Co., for arranging the telephone interviews and for acquiring the medical
1976, 18
reports, and also to the many doctors who provided the reports, often with helpful discussion. Dr. Euan Ross kindly provided a copy of West and Ross (1976) when not then generally available. Mr. K. R. Clarke gave expert assistance in the statistical analysis.
SUMMARY
The possibility of epilepsy resulting from maternal thalidomide ingestion was investigated by obtaining a telephoned neurological history from all suspect families in the United Kingdom in which the specific diagnosis was uncertain. The annual incidence in the first seven years of life was found to be five times the figure for the general population, and the prevalence of active epilepsy is significantly increased in the teenage thalidomide population. That this increased incidence and prevalence of epilepsy is not a chance observation is supported by published clinical and experimental evidence of central nervous system abnormalities in thalidomide embryopathy, in addition to the known neurological effects of the drug in the adult. RCSUMC Epilepsie: complications neurologiques d’embryopathie par thalidomide La possibilitt d’tpilepsie provenant d’une ingestion maternelle de thalidomide a t t i ttudite A partir de l’histoire neurologique obtenue par ttltphone de toutes les familles suspectes du Royaume Uni, 18 oh le diagnostic ttait incertain. La frtquence annuelle dans les sept premibes annCes de vie ttait cinq fois plus forte qu’attendue et la prtvalence d’une tpilepsie active est maintenant significativement accrue chez les adolescents. Que cette incidence accrue et cette permanence de l’tpilepsie ne soient pas likes au hasard est favorist par les publications cliniques et les dtmonstrations exptrimentales, qu’il est possible d’observer des anomalies du systeme nerveux central dans l’embryopathie de thalidomide en addition des effets neurologiques bien connus de la mkdication sur les adultes. ZUSAM MENFASSUNG
Epilepsie: Eine neurologische Komplika fion der Thalidomid Embryopathie Es wurde die Moglichkeit gepruft, ob eine Thalidomid Medikation bei der Mutter als Ursache fur die Entstehung einer Epilepsie infrage kommt, indem man telefonisch eine neurologische Anamnese von allen betroffenen Familien in GroBbrirtanien erhoben hat, bei denen die Diagnose ungeklart war. Die jahrliche Anzahl in den ersten sieben Lebensjahren war funfmal hoher als man erwartet hatte und das vorkommen einer noch aktiven Epilepsie hat sich jetzt bei Teenagern signifikant erhoht. Dieses vermehrte Vorkommen der Epilepsie ist kein Zufallsbefund, dafur sprechen publizierte Daten klinischer und experimenteller Art uber Veranderungen im Zentralnervensystem bei Thalidomid Embryopathie, sowie die wohlbekannten neurologischen Effekte des Medikamentes beim Erwachsenen. RESUMEN
Epilepsia: Una complicacidn neuroldgica de la embriopatia talidomidica Se investigd la posibilidad de epilepsia como resultado de la ingesti6n de talidomida por la madre, mediante la obtencidn por teltfono de la historia neuroldgica de todas las
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familias sospechosas en el Reino Unido, en las que el diagnbstico era incierto. La incidencia anual en 10s siete primeros aiios fue cinco veces mayor que las cifras esperadas, y la prevalencia de epilepsia activa es significativamente mayor ahora en 10s adolescentes. Que este aumento en la incidencia y la prevalencia de la epilepsia no es una observacion casual viene avalado por la publicacion de evidencia clinica y experimental de anormalidades del sistema nervioso central en la embriopatia talidomidica, ademas de 10s efectos neurologicos bien conocidos de estos firmacos en 10s adultos. REFERENCES d’Avignon, M., Barr, B. (1964) ‘Ear abnormalities and cranial nerve palsies in thalidomide children.’ Archives of Otolarvngology, 80, 136. - Hellgren, K., Juhlin, I.-M.. Alterback, B. (1967) ‘Diagnostic and habilitation problems of thalidomidetraumatized children with multiple handicaps.’ Developmental Medicine and Child Neurology, 9, 707. Bamberger, P. (1 965) Dy.~melie-Arbeitstagting.2. Monogruphie iiber die Rehabilitation der Dysmelie-Kinder. Bonn: Bundesministerium fur Gesundheitswesen, p. 122. Bergstrom, R. M., Bergstrom, L., Putkonen, P., Sainio, K. (1964) ‘The effects of thalidomide on the electrical activity of the brain in the intra-uterine guinea-pig fetus.’ Medicinu Experimentalis (Busel), 11, 119. Brewis M., Poskanzer, D. C., Rolland, C., Miller, H. (1966) ‘Neurological disease in a n English city.’ A r i d Neurologica Scandinavica, 42, suppl. 24. Cullen J. F. (1964) ‘Ocular defects in thalidomide babies.’ British Journal of Ophfhalmology, 48, 151. Florence, A. L. (1960) ‘Is thalidomide to blame? British Medical Journal, 2, 1954. Gudmundsson, G. (1966) ‘Epilepsy in Iceland.’ Acta Neurologica Scandinavica, 43, Suppl. 25. Horstmann, W. (1966) ‘Hinweise auf zentralnervose Schaden im Rahmen der Thalidomid-Embryopathie.’ Zeitschrift fur Kinderheilkunde, 96, 291. Kurland, L. T. (1960) ’The incidence and prevalence of convulsive disorders in a small urban community.’ Epilepsia, 1, 143. Lenz, W. (1962) ‘Thalidomide and congenital abnormalities.’ Lancer, i , 45. - (1974) Personal communication. Logan, W. P. D., Cushion, A. A. (1958) Morbidity Sfati.stics.fromGenernl Practice. Vol. I (General) C . R . O . Studies on Medical and Population Subjects. London : H.M.S.O. McBride, W. G. (1961) ‘Thalidomide and congenital abnormalities.’ Lancet, ii, 1358. McCreadie, J. (1973) ‘Thalidomide and congenital Charcot’s joints.’ Luncet, ii, 1058. - McLeod, J. G. (1974) ‘Thalidomide and embryonic neuropathy.’ Lancet, i, I I I I. McFie, J., Robertson, J. (1973) ‘Psychological test results of children with thalidomide deformities.’ Developniental Medicine and Child Neurologj-, 15, 71 9. Miehlke, A. (1964) ‘Symposium: facial nerve rehabilitation. Normal and anomalous anatomy of the facial nerve and an embryological study of the thalidomide catastrophe in Germany.’ Transactions of the American Academy of Ophthalmology and Otolaryngology, 68, 1030. - Partsch, C. J. (1963) ‘Ohrmissbildung, Facialis-und Abducenslahmung als Syndrom der ThalidomidSchadigung.’ Arrhiv fur Ohren-. Nasen- und Kehlkopfheilkimde, 181, 155. Pfeiffer, R. A., Kosenow. W. (1962) ‘Thalidomide and congenital abnormalities.’ Lancet, i , 45. Pliess, G. (1962) ‘Thalidomide and congenital abnormalities.’ Lancet, i, 1128. Pond, D. A., Bidwell, B. H., Stein, L. (1960) ‘A study of epilepsy in fourteen general practices. I. Demographic and medical data.’ Psychiatria, Neurologio, Neurochfrurgia,63. 21 7. College of General Practitioners Research Committee ( 1960) ‘A survey of the epilepsies in general practice.’ British Medical Journal, 2, 416. Rutter. M., Graham, P., Yule, W. (1970) A Neurop.s,vrhfntricStrtdv in Childhood. Clinics in Developmental Medicine Nos. 35/36. L.ondon : S.I.M.P./Heinemann Medical Books. Smithells, R. W. (1973) ‘Defects and disabilities of thalidomide children.’ British Medical Journal, 1, 269. Spiers, A. L. (1962) ‘Thalidomide and congenital abnormalities.’ Lancer, i, 303. Sumner, D. D., Verma, K. B. C., Peasland, A. (1974) ‘The epileptic: his call on community resources.’ In Harris, P., Maudsley, C. (Eds.) Epileps).. Proceedings of the Huns Berger Centenary Symposium. Edinburgh: Churchill Livingstone, p. 309. West, P., Ross, E. (1976) Studies in Convulsive Disorder. The Prevalence and Incidence of Epilepsy in Childhood (not yet published).
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