1260
OUTCOME OF SURGERY IN 40 CHILDREN WITH TEMPORAL-LOBE EPILEPSY SERENA DAVIDSON
TABLE I-AGE AT ONSET COMPARED WITH AGE AT OPERATION OF 40 CHILDREN * UNDER 16 YEARS
MURRAY A. FALCONER
Neurosurgical Unit of Guy’s, Maudsley, and King’s College Hospitals, London SE5 8AZ
Temporal-lobe epilepsy commonly has childhood, particularly lesion involved is mesial temporal (Ammon’s
its origins in Summary
when the horn) sclerosis. Evidence suggests that this lesion is probably a common cause of chronic epilepsy in adults and that often it is probably the result of a severe febrile convulsion in infancy. 40 children, fifteen years of age and younger, who had an anterior temporal lobectomy were followed up for one to twenty-four years. The findings confirm those already established in adults, that the best results of surgery, not only in seizure relief but also in behaviour, are obtained when mesial temporal sclerosis is the lesion found at operation, and also indicate that a severe febrile convulsion in infancy is often the chief provocative factor in the development of epilepsy.
Introduction OUR experience with the surgical treatment of temporal-lobe epilepsy in children supports the view that mesial temporal (Ammon’s horn) sclerosis is a common cause of chronic epilepsy, that it commonly results from a severe febrile convulsion in infancy, and that good therapeutic results can be expected whenever such sclerosis is encountered at operation.1-6 This lesion was produced in adolescent baboons by inducing prolonged serial grand-mal seizures.7 There is evidence that prompt treatment of febrile convulsions followed by the prophylactic use of phenobarbitone in adequate therapeutic doses reduces the frequency of recurrent febrile convulsions and mesial temporal sclerosis in children.s Phenytoin is not as effective a prophylactic as phenobarbitone.9 Mesial temporal sclerosis may be a preventable disease.
Selection of Patients The outcome of surgery
was
examined in the first 40
12. Dubois, E. L. Medicine, 1969, 48, 217. 13. Wang, R. I. H., Schuller, E. Am. Heart J. 1969, 78, 282. 14. Lown, B., Wolf, M. Circulation, 1971, 44, 130. 15. Talbot, R. G., Nimmo, J., Clark, R. A., Neilson, J. M. M., Julian, D. G., Prescott, L. F. Lancet, 1973, ii, 399. 16. Campbell, N. P. S., Kelly, J. G., Shanks, R. G., Chaturvedi, N. C., Strong, J. E., Pantridge, J. F. ibid. p. 404. 17. Kelly, J. G., Nimmo, J., Rae, R., Shanks, R. G., Prescott, L. F. J. Pharm. Pharmac. 1973, 25, 550. 18. Neilson, J. M. M. in Computers in Cardiology; p. 55. I.E.E.E. Computer Society, Chicago, 1974. 19. Mogensen, L. Acta med. scand. 1970, 513, 1. 20. Kotler, M. J., Mower, M. M., Tabatznik, B. Circulation, 1971, 44, suppl. II, 43. 21. Chiang, B. N., Perlman, L. V., Ostrander, L. D., Epstein, F. H. Ann. intern. Med. 1969, 70, 1159. 22. Pell, S., D’Alonzo, C. A. New Engl. J. Med. 1964, 270, 915. 23. Shanoff, H. M., Alick Little, J., Csima, A., Yano, R. Am. J. Cardiol. 24.
1966, 18, 535. Blackburn, H., Willis Parlin, R. Ann. N.Y. Acad. Sci. 1966, 134,
25. 26. 27. 28.
Lyle, A. M. Trans. Soc. Actuaries, 1963, 15, 324. Vellani, C. W. M.D. thesis, University of Wales, 1972. Karlsson, E. Eur. J. clin. Pharmac. 1973, 6, 245. Talbot, R. G. Am. Heart J. (in the press).
965.
* 25 boys; 15 girls.
children of fifteen years and younger who were operated on in this unit and have been followed up for one to twenty-four years (table i). All were selected because they fulfilled the criteria set out in previous studies,2-6.10.U namely, they had frequent disabling epilepsy which was resistant to adequate drug therapy, neuroradiological studies appeared to have ruled out a gross space-occupying lesion, and the electroencephalographic (E.E.G.) studies, including a special study using sphenoidal electrodes under intravenous thiopentone narcosis, had revealed a spikedischarging focus which was prominent in or confined to one temporal lobe. Patients with gross mental retardation (i.Q. below 70) were avoided as they were likely to have widespread brain damage. Although in 35 of these 40 children chronic epilepsy began during the first decade of life, only 6 of them were operated on in that period, and these figures reflect our caution. Our original philosophy was to operate on children aged between ten and twelve years while they were still at school, so that their education could be completed if they were relieved of their seizures.2 However, some children were operated upon earlier, either because a calcified and readily accessible hamartoma was demonstrated by skull X-rays or because at an even younger age their seizures were severe and the child was in an institution and had a hopeless prognosis.
Pathological Findings All our patients had an en-bloc resection of the affected temporal lobe including the anterior part of the hippocampus and portions of the amygdala and uncus, so that detailed histology was possible. One of us has had considerable experience of temporallobe epilepsy in adults, and throughout these various studies the pathological findings have been remarkably constant."--12 In about half our cases the lesion which we termed mesial temporal sclerosis was found. It consists of classic or Ammon’s horn sclerosis usually together with sclerosis of adjacent structures in the inner part of the temporal lobe, such as the amygdala and the uncus. In a quarter of adult cases small circumscribed malformations of various types, generally of glial origin and seldom more than 1 cm. in diameter, are encountered and these usually involve either the amygdala or the hippocampal gyrus. These lesions are for the moment termed hamartomas. In about a tenth of adult cases there are miscellaneous lesions, such as scars and infarcts, while no neuronal abnormality is found in the remainder, though there In this last group the lesion was may be gliosis. termed non-specific. All these lesions have been found in much the same proportions by Brown," who examined pathological material from epileptics operated on by P. H. Crandall in Los Angeles. The pathological findings in this group of children (table 11) differ in two important respects from those found in adults. There were more children with mesial temporal sclerosis, and there were no scars or infarcts. 24 patients, or .60%, had mesial temporal
1261 TABLE II-PATHOLOGICAL GROUPINGS AND FREQUENCY OF ANTECEDENT FEBRILE CONVULSIONS IN 40 CHILDREN
I M.T.S.
= mesial
temporal sclerosis.
including two with hamartomas also. Of the in which mesial temporal sclerosis occurred alone, 19 had a clear history of one or more severe febrile convulsions in infancy after teething, sore throats, immunisations, measles, &c. All these children had had convulsions lasting at least half an hour, while many had had a series of convulsions. In only 2 of the 22 children was there a definite history of epilepsy occurring in parents or siblings. The increase in the number of cases of mesial temporal sclerosis may be because p2ediatricians have lately been sending more suitable children and have been aware of the importance of a history of febrile convulsions in infancy. sclerosis
22
cases
Whereas the first 20 children were referred between 1951 and 1969,3 the second 20 all came between 1970 and 1974. The other cases include 7 with hamartomas and 3 with tumours. These tumours were all visible in the temporal lobe at operation and were space replacing rather than space occupying. They were all histologically benign with astrocytomatous characteristics. They had not been suspected before craniotomy, and, as they had not deformed the air encephalogram, we treated them all by a formal temporal lobectomy. The largest was 4 cm. in diameter and occupied the temporal lobe without deforming the temporal horn. This child was thriving and seizure-free with no evidence of recurrence of the tumour or epilepsy after five years and without any intellectual or neurological handicap. She has not had radiation therapy. None of these 10 cases had a history of febrile convulsions. One of the remaining children had chronic viral encephalitis ; his illness began with a fever and a convulsion. This leaves 7 children without any specific neuronal abnormality. ’
Outcome
Epilepsy A psychomotor type of seizure was characteristic of this series, but many patients also had grand-mal or absence seizures with masticatory movements. 20 TABLE III-SEIZURE-RELIEF IN 40 CHILDREN BY PATHOLOGICAI FINDINGS
* Includes 1 hamartoma in each subgroup. t Includes 1 M.T.S. in each subgroup. t Includes 2 patients who have died.
of the children had right-sided resections and 20 had left-sided ones. Improvement (table ni) was always assessed after the first postoperative year, since some patients may have an occasional seizure in the first year and then become seizure-free, while others may become seizure-free in the first year and later have occasional recurrences 1° 14 of the 24 children with mesial temporal sclerosis (58 %) became seizure-free in the long term, usually without medication, while 8 out of the 10 (80%) with hamartomas achieved this goal. Only 1 out of the 7 with non-specific lesions (14%) became seizure-free, probably by interruption of the neuronal pathways responsible for the propagation of seizure discharges. Table ill confirms that good results can be anticipated whenever a focal disease process is found in the resected specimen at
operation. Since operation 2 of our 40 patients have died.3S Both had non-specific lesions and neither was relieved of epilepsy or improved as regards behaviour. 1, aged fifteen years at the time of operation, committed suicide four years later, and the other, aged thirteen TABLE IV-CHANGE IN BEHAVIOUR IN
40 CHILDREN AFTER OPERATION
-
.
Includes 2 with hamartomas. 1 with M.T.S. in each subgroup. 2 patients who have died.
t Includes t Includes
and mentally retarded, died pneumonia.
seven
years later from
Behaviour The early results (table iv) resemble those for seizure relief. In compiling table iv we assessed our patients while they were still of an age to be regarded as children. In some respects the classification given to each child was arbitrary. The children in this series were operated upon primarily for epilepsy; a subsequent improvement in behaviour was regarded as a bonus. The first 20 children who were referred to us were all operated on more than six years ago. They were selected by the referring paediatricians and psychiatrists, and we accepted them for surgery because they fulfilled our criteria for operation.3 Before operation all but 1 child were aggressive to some extent and many were accused of bizarre behaviour. Although none was in trouble with the law, the boys were often involved in gangs and the girls in promiscuous behaviour. Many were accused of stealing. Their antisocial behaviour usually involved intolerable provocation of school mates and teachers. Their tempers were usually short and some reacted strongly to teasing. Many had formidable reputations as fighters. Our referring col.leagues saw their future with foreboding,3 and, though none of us could foretell the outcome as regards behaviour, we expected that we could improve their epilepsy. Only 1 of these 20 was not aggressive, but
1262 TABLE
V-ADJUSTMENT
TO ADULT LIFE AND LENGTH OF TIME SINCE
OPERATION IN FIRST SURGERY
GROUP
OF
20
PATIENTS
REFERRED
FOR
————————!—————————!—————————!—————————t—————————!_________
1 patient is in both subgroups. t 1 patient committed suicide 4 years after operation. t1 patient, an imbecile, died of pneumonia 7 years after operation. *
TABLE
VI-ADJUSTMENT
TO ADULT LIFE AND
SINCE OPERATION IN SECOND GROUP OF FOR SURGERY
he
LENGTH OF TIME
20 PATIENTS
REFERRED
falling behind at school and appeared unlikely pass his public school entrance examination. He has since completed his secondary education and is now working in the junior ranks of hospital adminiwas
to
stration.2,3
reviewing the progress of these children we interest our colleagues in the possibilities of began for surgery temporal-lobe epilepsy in children.3 As the rate at which suitable children are being a result, referred to us is rising steadily (tables v and vi). After
to
Whereas the first 20 children were referred for surgery over a period of eighteen years, the next 8 were referred over a period of three years, and the last 12 over two
years.
We do not know what proportion of epileptic children our patients form. The first 20 were largely investigated before their admission to the neurosurgical unit and many still are. However, as our unit has all the facilities, especially radiological and E.E.G., for investigating these children, some candidates are now sent to us directly. A few of these have gross lesions, such as unsuspected but demonstrable tumours or gross atrophies requiring hemispherectomy, and are As our experinot therefore included in our tables. ence grows we suspect that we will find more and more children suitable for surgery.
Adaptation
change, which particularly affected the attitudes and expectations of adolescents. Some features of adolescence are common to all epileptic children. The natural urge to rebel, to pose as adults, and to seek their own identity conflicts with the need for protection and security at home. Many of these children had already outlawed themselves at school, and had stretched their parents’ patience and understanding to the limit. When the possibility of operation was discussed with their parents or guardians the most common reaction was unreserved welcome of anything that promised hope of improving their child. After operation the patients were usually accepted at home and school. Those came from institutions and who had already been rejected by their friends and relatives at home and by their local schools faced a more difficult situation, but with suitable care and a disciplined but understanding envirorunent they too were often able to adapt, to control their tempers, and to prepare for work and independence. The first 20 children (table v) were operated on more than six years ago and are already adults. 1 of the first 4, after a searching investigation by the U.S.A. authorities, where epilepsy is a bar to immigration, was admitted to that country and when last heard of was seizure-free and working for a doctorate in an American university 3 5 of the 20 may be regarded as having made a good adjustment, but 10 (including 2 who died) have not, with the remaining 5 in between. However, at the time of their acceptance for surgery the future looked bleak for all of them, with no published work to predict the likely outcome. The second 20 patients operated upon are still adolescents or children and have yet to show their full potential. They seem to have been better selected, as only 3 are unemployable and 7 are working. In the past, E.E.G. evidence about the site of the lesion has often conflicted with radiological findings. It has been our custom to refuse or defer operation in such patients, but experience 14,5 suggests that we may have to modify our criteria in individual cases. Time has yet to teach us the true worth of our diagnostic criteria, but we have not as yet found the need to investigate children with multiple indwelling electrodes inserted into various sites in the brain for six to eight weeks as have Walter and Crandall 16,17 in their adult patients. Walter has expressed a reluctance to do this in children.Is Reluctance to operate upon children for epilepsy may account for the lack of a comparable series in the literature.5
in Adult Life
Late outcome in these children and their adjustment to adult life are shown in tables v and vi. These changes and adjustments are very difficult to measure or to relate to the degree of handicap for each child. Patients came from many different parts of the country and from varied backgrounds. Their fathers ranged
from professional to unskilled workers. Some were unknown to them, and a few children could not recall either parent. Famliy size varied from 9 to 1 children and there were some step-siblings and 4 sets of twins among their brothers and sisters. The twenty-five years of the study covered a period of great social
Conclusions This study shows that surgery had a part to play in the treatment of some children with intractable epilepsy, but a longer and more intensive study is required. The outcome in our patients indicates that the best results of surgery for temporal-lobe epilepsy in children are obtained when mesial temporal sclerosis is found in the resected specimen. Furthermore, 19 out of the 24 (79 %) cases with this lesion had a history of one or more severe febrile convulsions in infancy, whereas only 1 child with other abnormalities did. This child had fever and a convulsion
1263
during chronic viral encephalitis. These results sug gest a very significant association between mesial temporal (Ammon’s horn) sclerosis and antecedent febrile convulsions.1 many colleagues in various hospitals who years have helped us in this study, in particular Dr M. V. Driver of the E.E.G. Department, Maudsley Hospital; Dr J. A. N. Corsellis for help with the pathology; and Prof. C. E. Stroud for assistance with the children. S. D. is grateful for financial support from Guy’s Hospital Medical
We thank
our
throughout the
SchooL
Requests for reprints should be addressed to M. A. F., Neurosurgical Unit, Maudsley Hospital, De Crespigny Park, London SE5 8AZ. REFERENCES 1. 2. 3. 4. 5. 6.
7. 8. 9. 10. 11. 12. 13.
14. 15. 16.
Falconer, M. A. Lancet, 1974, ii, 767. Falconer, M. A. J. Neurosurg. 1970, 33, 233. Falconer, M. A. Med. J. Aust. 1972, i, 1117. Falconer, M. A. Br. med. J. 1972, ii, 631. Falconer, M. A. Irish J. med. Sci. 1972, 141, 147. Falconer, M. A., Davidson, S. in Epilepsy: Proceedings of the Hans Berger Centenary Symposium (edited by P. Harris and C. Mawdsley); p. 209. Edinburgh, 1974. Meldrum, B. S., Horton, R. W., Brierley, J. B. Brain, 1974, 97, 407. Lennox-Buchthal, M. Febrile Convulsions: A Reappraisal. Amsterdam, 1973. Melchior, J. C., Buchthal, F., Lennox-Buchthal, M. Epilepsia, 1971, 12, 55. Falconer, M. A., Serafetinides, E. A., Corsellis, J. A. N. Archs Neurol. Chicago, 1964, 10, 233. Falconer, M. A., Taylor, D. S. ibid. 1966, 19, 353. Corsellis, J. A. N. in Modern Trends in Neurology: 5 (edited by D. Williams); p. 254. London, 1970. Brown, W. J. in Epilepsy: Its Phenomena in Man (edited by M. A. B. Brazier); p. 339. New York, 1973. Engel, J., Driver, M. V., Falconer, M. A. Brain, 1975, 98, 129. Newcombe, R., Shah, S., Hoare, R. D., Falconer, M. A. J. Neurol. Neurosurg. Psychiat. (in the press). Crandall, P. H., Walter, R. D., Rand, R. W. J. Neurosurg. 1963, 20,
improvement of glucose tolerance after 2 months dietary treatment, and 59% of the group achieved adequate diabetic control by this time. It is consome
of
cluded that treatment with diet alone should be the first-line management for patients with newly diagnosed maturity-onset diabetes mellitus.
Introduction A HIGH proportion of maturity-onset diabetic patients can be controlled by diet alone, and doubts about the safety of long-term therapy with some oral antidiabetic drugs 1,2 have re-emphasised the importance of dietary treatment for non-insulin-requiring diabetics. Despite advances in the understanding of the pathophysiology of diabetes, it has not proved possible to predict which patients will require oral antidiabetic drugs in addition to dietary therapy. There have been few studies on the influence of diet alone on oral glucose tolerance and insulin secretion in diabetics. While some improvement of glucose tolerance has usually been found, changes in oral test (O.G.T.T.) plasma-insulin levels Rudnick and Taylor3 found O.G.T.T. plasma-insulin levels to have increased in 6 diabetic
glucose-tolerance have varied.
subjects after 2 months’ dietary treatment. Turtle,’ however, recorded lower o.G.T.T. plasma-levels after dietary treatment. We have investigated various factors influencing the change of glucose tolerance and O.G.T.T. plasmainsulin levels in newly diagnosed maturity-onset diabetic patients treated with diet alone for 2 months.
827.
17. Crandall, P. H. in Epilepsy: Its Phenomena in Man (edited by M. A. B. 18.
Walter, R.
Brazier); p. 288.
New
York, 1973.
D. ibid. p. 99.
INFLUENCE OF TREATMENT WITH DIET ALONE ON ORAL GLUCOSE-TOLERANCE TEST AND PLASMA SUGAR AND INSULIN LEVELS IN PATIENTS WITH MATURITYONSET DIABETES MELLITUS
J. W. H. DOAR C. E. WILDE
M. E. THOMPSON P. F. J. SEWELL
Departments of Medicine and Clinical Chemistry, Doncaster Royal Infirmary Oral
glucose-tolerance test (O.G.T.T.) plasma sugar and insulin levels were measured in 118 newly diagnosed maturity-onset diabetic patients before and after treatment with diet alone for periods of 2 and 6 months. The results of glucose-tolerance tests carried out during treatment could be predicted from the initial test and the weight reduction between the tests. This prediction was not improved by the addition of further variables, including age, obesity, and plasma-insulin levels during the first test. The change in O.G.T.T. plasma-insulin between the first and second tests was predicted by the result of the initial test, the improvement of glucose tolerance between the two tests, and the degree of weight reduction. 95 % of the group achieved Summary
Patients and Methods 118 patients (aged 33-73, mean 56 years) referred to the diabetic clinic with newly diagnosed non-ketotic diabetes mellitus were studied before and after treatment with diet alone for 2 months. Patients with ketonuria and/or a random blood-sugar at the first visit greater than 350 mg. per 100 ml. were excluded. o.G.T.T.s using a load of 1 g. per kg. body-weight of glucose were carried out as previously described.5 Plasma-sugar levels were measured by an automated ferricyanide methodand plasma-insulin assays were done in duplicate by a modified radioimmunoassay technique.7 Paired tests from each patient were always analysed in the same run. Patients were advised to consume a diet containing at least 200 g. carbohydrate for 3 days before the first O.G.T.T. They were then instructed in a diabetic diet designed to reduce the intake of sugar and reduce body-weight when necessary. 2 months later, a second O.G.T.T. was done, and on this occasion the patients adhered to their diet before the test. A third glucose-tolerance test was carried out in 55 patients after a further 4 months’ treatment with diet alone. Each patient’s degree of obesity was obtained by expressing the weight as a percentage of the ideal bodyweight obtained from tables. O.G.T.T. plasma sugar and insulin curves were assessed in terms of the area between the curve and the abscissa Each area was calculated in arbitrary units, assuming straight lines between successive points. In this centre, o.G.T.T.-sugar areas above 1200 units are considered to indicate diabetes mellitus. Standard statistical methods were used including the pairedt test and optimal multiple regression. In regression calculations, logarithmic conversions were carried out before analyses when appropriate. All calculations were performed by a NOVA 1220 computer.
OUTCOME OF SURGERY IN 40 CHILDREN WITH TEMPORAL-LOBE EPILEPSY SERENA DAVIDSON
TABLE I-AGE AT ONSET COMPARED WITH AGE AT OPERATION OF 40 CHILDREN * UNDER 16 YEARS
MURRAY A. FALCONER
Neurosurgical Unit of Guy’s, Maudsley, and King’s College Hospitals, London SE5 8AZ
Temporal-lobe epilepsy commonly has childhood, particularly lesion involved is mesial temporal (Ammon’s
its origins in Summary
when the horn) sclerosis. Evidence suggests that this lesion is probably a common cause of chronic epilepsy in adults and that often it is probably the result of a severe febrile convulsion in infancy. 40 children, fifteen years of age and younger, who had an anterior temporal lobectomy were followed up for one to twenty-four years. The findings confirm those already established in adults, that the best results of surgery, not only in seizure relief but also in behaviour, are obtained when mesial temporal sclerosis is the lesion found at operation, and also indicate that a severe febrile convulsion in infancy is often the chief provocative factor in the development of epilepsy.
Introduction OUR experience with the surgical treatment of temporal-lobe epilepsy in children supports the view that mesial temporal (Ammon’s horn) sclerosis is a common cause of chronic epilepsy, that it commonly results from a severe febrile convulsion in infancy, and that good therapeutic results can be expected whenever such sclerosis is encountered at operation.1-6 This lesion was produced in adolescent baboons by inducing prolonged serial grand-mal seizures.7 There is evidence that prompt treatment of febrile convulsions followed by the prophylactic use of phenobarbitone in adequate therapeutic doses reduces the frequency of recurrent febrile convulsions and mesial temporal sclerosis in children.s Phenytoin is not as effective a prophylactic as phenobarbitone.9 Mesial temporal sclerosis may be a preventable disease.
Selection of Patients The outcome of surgery
was
examined in the first 40
12. Dubois, E. L. Medicine, 1969, 48, 217. 13. Wang, R. I. H., Schuller, E. Am. Heart J. 1969, 78, 282. 14. Lown, B., Wolf, M. Circulation, 1971, 44, 130. 15. Talbot, R. G., Nimmo, J., Clark, R. A., Neilson, J. M. M., Julian, D. G., Prescott, L. F. Lancet, 1973, ii, 399. 16. Campbell, N. P. S., Kelly, J. G., Shanks, R. G., Chaturvedi, N. C., Strong, J. E., Pantridge, J. F. ibid. p. 404. 17. Kelly, J. G., Nimmo, J., Rae, R., Shanks, R. G., Prescott, L. F. J. Pharm. Pharmac. 1973, 25, 550. 18. Neilson, J. M. M. in Computers in Cardiology; p. 55. I.E.E.E. Computer Society, Chicago, 1974. 19. Mogensen, L. Acta med. scand. 1970, 513, 1. 20. Kotler, M. J., Mower, M. M., Tabatznik, B. Circulation, 1971, 44, suppl. II, 43. 21. Chiang, B. N., Perlman, L. V., Ostrander, L. D., Epstein, F. H. Ann. intern. Med. 1969, 70, 1159. 22. Pell, S., D’Alonzo, C. A. New Engl. J. Med. 1964, 270, 915. 23. Shanoff, H. M., Alick Little, J., Csima, A., Yano, R. Am. J. Cardiol. 24.
1966, 18, 535. Blackburn, H., Willis Parlin, R. Ann. N.Y. Acad. Sci. 1966, 134,
25. 26. 27. 28.
Lyle, A. M. Trans. Soc. Actuaries, 1963, 15, 324. Vellani, C. W. M.D. thesis, University of Wales, 1972. Karlsson, E. Eur. J. clin. Pharmac. 1973, 6, 245. Talbot, R. G. Am. Heart J. (in the press).
965.
* 25 boys; 15 girls.
children of fifteen years and younger who were operated on in this unit and have been followed up for one to twenty-four years (table i). All were selected because they fulfilled the criteria set out in previous studies,2-6.10.U namely, they had frequent disabling epilepsy which was resistant to adequate drug therapy, neuroradiological studies appeared to have ruled out a gross space-occupying lesion, and the electroencephalographic (E.E.G.) studies, including a special study using sphenoidal electrodes under intravenous thiopentone narcosis, had revealed a spikedischarging focus which was prominent in or confined to one temporal lobe. Patients with gross mental retardation (i.Q. below 70) were avoided as they were likely to have widespread brain damage. Although in 35 of these 40 children chronic epilepsy began during the first decade of life, only 6 of them were operated on in that period, and these figures reflect our caution. Our original philosophy was to operate on children aged between ten and twelve years while they were still at school, so that their education could be completed if they were relieved of their seizures.2 However, some children were operated upon earlier, either because a calcified and readily accessible hamartoma was demonstrated by skull X-rays or because at an even younger age their seizures were severe and the child was in an institution and had a hopeless prognosis.
Pathological Findings All our patients had an en-bloc resection of the affected temporal lobe including the anterior part of the hippocampus and portions of the amygdala and uncus, so that detailed histology was possible. One of us has had considerable experience of temporallobe epilepsy in adults, and throughout these various studies the pathological findings have been remarkably constant."--12 In about half our cases the lesion which we termed mesial temporal sclerosis was found. It consists of classic or Ammon’s horn sclerosis usually together with sclerosis of adjacent structures in the inner part of the temporal lobe, such as the amygdala and the uncus. In a quarter of adult cases small circumscribed malformations of various types, generally of glial origin and seldom more than 1 cm. in diameter, are encountered and these usually involve either the amygdala or the hippocampal gyrus. These lesions are for the moment termed hamartomas. In about a tenth of adult cases there are miscellaneous lesions, such as scars and infarcts, while no neuronal abnormality is found in the remainder, though there In this last group the lesion was may be gliosis. termed non-specific. All these lesions have been found in much the same proportions by Brown," who examined pathological material from epileptics operated on by P. H. Crandall in Los Angeles. The pathological findings in this group of children (table 11) differ in two important respects from those found in adults. There were more children with mesial temporal sclerosis, and there were no scars or infarcts. 24 patients, or .60%, had mesial temporal
1261 TABLE II-PATHOLOGICAL GROUPINGS AND FREQUENCY OF ANTECEDENT FEBRILE CONVULSIONS IN 40 CHILDREN
I M.T.S.
= mesial
temporal sclerosis.
including two with hamartomas also. Of the in which mesial temporal sclerosis occurred alone, 19 had a clear history of one or more severe febrile convulsions in infancy after teething, sore throats, immunisations, measles, &c. All these children had had convulsions lasting at least half an hour, while many had had a series of convulsions. In only 2 of the 22 children was there a definite history of epilepsy occurring in parents or siblings. The increase in the number of cases of mesial temporal sclerosis may be because p2ediatricians have lately been sending more suitable children and have been aware of the importance of a history of febrile convulsions in infancy. sclerosis
22
cases
Whereas the first 20 children were referred between 1951 and 1969,3 the second 20 all came between 1970 and 1974. The other cases include 7 with hamartomas and 3 with tumours. These tumours were all visible in the temporal lobe at operation and were space replacing rather than space occupying. They were all histologically benign with astrocytomatous characteristics. They had not been suspected before craniotomy, and, as they had not deformed the air encephalogram, we treated them all by a formal temporal lobectomy. The largest was 4 cm. in diameter and occupied the temporal lobe without deforming the temporal horn. This child was thriving and seizure-free with no evidence of recurrence of the tumour or epilepsy after five years and without any intellectual or neurological handicap. She has not had radiation therapy. None of these 10 cases had a history of febrile convulsions. One of the remaining children had chronic viral encephalitis ; his illness began with a fever and a convulsion. This leaves 7 children without any specific neuronal abnormality. ’
Outcome
Epilepsy A psychomotor type of seizure was characteristic of this series, but many patients also had grand-mal or absence seizures with masticatory movements. 20 TABLE III-SEIZURE-RELIEF IN 40 CHILDREN BY PATHOLOGICAI FINDINGS
* Includes 1 hamartoma in each subgroup. t Includes 1 M.T.S. in each subgroup. t Includes 2 patients who have died.
of the children had right-sided resections and 20 had left-sided ones. Improvement (table ni) was always assessed after the first postoperative year, since some patients may have an occasional seizure in the first year and then become seizure-free, while others may become seizure-free in the first year and later have occasional recurrences 1° 14 of the 24 children with mesial temporal sclerosis (58 %) became seizure-free in the long term, usually without medication, while 8 out of the 10 (80%) with hamartomas achieved this goal. Only 1 out of the 7 with non-specific lesions (14%) became seizure-free, probably by interruption of the neuronal pathways responsible for the propagation of seizure discharges. Table ill confirms that good results can be anticipated whenever a focal disease process is found in the resected specimen at
operation. Since operation 2 of our 40 patients have died.3S Both had non-specific lesions and neither was relieved of epilepsy or improved as regards behaviour. 1, aged fifteen years at the time of operation, committed suicide four years later, and the other, aged thirteen TABLE IV-CHANGE IN BEHAVIOUR IN
40 CHILDREN AFTER OPERATION
-
.
Includes 2 with hamartomas. 1 with M.T.S. in each subgroup. 2 patients who have died.
t Includes t Includes
and mentally retarded, died pneumonia.
seven
years later from
Behaviour The early results (table iv) resemble those for seizure relief. In compiling table iv we assessed our patients while they were still of an age to be regarded as children. In some respects the classification given to each child was arbitrary. The children in this series were operated upon primarily for epilepsy; a subsequent improvement in behaviour was regarded as a bonus. The first 20 children who were referred to us were all operated on more than six years ago. They were selected by the referring paediatricians and psychiatrists, and we accepted them for surgery because they fulfilled our criteria for operation.3 Before operation all but 1 child were aggressive to some extent and many were accused of bizarre behaviour. Although none was in trouble with the law, the boys were often involved in gangs and the girls in promiscuous behaviour. Many were accused of stealing. Their antisocial behaviour usually involved intolerable provocation of school mates and teachers. Their tempers were usually short and some reacted strongly to teasing. Many had formidable reputations as fighters. Our referring col.leagues saw their future with foreboding,3 and, though none of us could foretell the outcome as regards behaviour, we expected that we could improve their epilepsy. Only 1 of these 20 was not aggressive, but
1262 TABLE
V-ADJUSTMENT
TO ADULT LIFE AND LENGTH OF TIME SINCE
OPERATION IN FIRST SURGERY
GROUP
OF
20
PATIENTS
REFERRED
FOR
————————!—————————!—————————!—————————t—————————!_________
1 patient is in both subgroups. t 1 patient committed suicide 4 years after operation. t1 patient, an imbecile, died of pneumonia 7 years after operation. *
TABLE
VI-ADJUSTMENT
TO ADULT LIFE AND
SINCE OPERATION IN SECOND GROUP OF FOR SURGERY
he
LENGTH OF TIME
20 PATIENTS
REFERRED
falling behind at school and appeared unlikely pass his public school entrance examination. He has since completed his secondary education and is now working in the junior ranks of hospital adminiwas
to
stration.2,3
reviewing the progress of these children we interest our colleagues in the possibilities of began for surgery temporal-lobe epilepsy in children.3 As the rate at which suitable children are being a result, referred to us is rising steadily (tables v and vi). After
to
Whereas the first 20 children were referred for surgery over a period of eighteen years, the next 8 were referred over a period of three years, and the last 12 over two
years.
We do not know what proportion of epileptic children our patients form. The first 20 were largely investigated before their admission to the neurosurgical unit and many still are. However, as our unit has all the facilities, especially radiological and E.E.G., for investigating these children, some candidates are now sent to us directly. A few of these have gross lesions, such as unsuspected but demonstrable tumours or gross atrophies requiring hemispherectomy, and are As our experinot therefore included in our tables. ence grows we suspect that we will find more and more children suitable for surgery.
Adaptation
change, which particularly affected the attitudes and expectations of adolescents. Some features of adolescence are common to all epileptic children. The natural urge to rebel, to pose as adults, and to seek their own identity conflicts with the need for protection and security at home. Many of these children had already outlawed themselves at school, and had stretched their parents’ patience and understanding to the limit. When the possibility of operation was discussed with their parents or guardians the most common reaction was unreserved welcome of anything that promised hope of improving their child. After operation the patients were usually accepted at home and school. Those came from institutions and who had already been rejected by their friends and relatives at home and by their local schools faced a more difficult situation, but with suitable care and a disciplined but understanding envirorunent they too were often able to adapt, to control their tempers, and to prepare for work and independence. The first 20 children (table v) were operated on more than six years ago and are already adults. 1 of the first 4, after a searching investigation by the U.S.A. authorities, where epilepsy is a bar to immigration, was admitted to that country and when last heard of was seizure-free and working for a doctorate in an American university 3 5 of the 20 may be regarded as having made a good adjustment, but 10 (including 2 who died) have not, with the remaining 5 in between. However, at the time of their acceptance for surgery the future looked bleak for all of them, with no published work to predict the likely outcome. The second 20 patients operated upon are still adolescents or children and have yet to show their full potential. They seem to have been better selected, as only 3 are unemployable and 7 are working. In the past, E.E.G. evidence about the site of the lesion has often conflicted with radiological findings. It has been our custom to refuse or defer operation in such patients, but experience 14,5 suggests that we may have to modify our criteria in individual cases. Time has yet to teach us the true worth of our diagnostic criteria, but we have not as yet found the need to investigate children with multiple indwelling electrodes inserted into various sites in the brain for six to eight weeks as have Walter and Crandall 16,17 in their adult patients. Walter has expressed a reluctance to do this in children.Is Reluctance to operate upon children for epilepsy may account for the lack of a comparable series in the literature.5
in Adult Life
Late outcome in these children and their adjustment to adult life are shown in tables v and vi. These changes and adjustments are very difficult to measure or to relate to the degree of handicap for each child. Patients came from many different parts of the country and from varied backgrounds. Their fathers ranged
from professional to unskilled workers. Some were unknown to them, and a few children could not recall either parent. Famliy size varied from 9 to 1 children and there were some step-siblings and 4 sets of twins among their brothers and sisters. The twenty-five years of the study covered a period of great social
Conclusions This study shows that surgery had a part to play in the treatment of some children with intractable epilepsy, but a longer and more intensive study is required. The outcome in our patients indicates that the best results of surgery for temporal-lobe epilepsy in children are obtained when mesial temporal sclerosis is found in the resected specimen. Furthermore, 19 out of the 24 (79 %) cases with this lesion had a history of one or more severe febrile convulsions in infancy, whereas only 1 child with other abnormalities did. This child had fever and a convulsion
1263
during chronic viral encephalitis. These results sug gest a very significant association between mesial temporal (Ammon’s horn) sclerosis and antecedent febrile convulsions.1 many colleagues in various hospitals who years have helped us in this study, in particular Dr M. V. Driver of the E.E.G. Department, Maudsley Hospital; Dr J. A. N. Corsellis for help with the pathology; and Prof. C. E. Stroud for assistance with the children. S. D. is grateful for financial support from Guy’s Hospital Medical
We thank
our
throughout the
SchooL
Requests for reprints should be addressed to M. A. F., Neurosurgical Unit, Maudsley Hospital, De Crespigny Park, London SE5 8AZ. REFERENCES 1. 2. 3. 4. 5. 6.
7. 8. 9. 10. 11. 12. 13.
14. 15. 16.
Falconer, M. A. Lancet, 1974, ii, 767. Falconer, M. A. J. Neurosurg. 1970, 33, 233. Falconer, M. A. Med. J. Aust. 1972, i, 1117. Falconer, M. A. Br. med. J. 1972, ii, 631. Falconer, M. A. Irish J. med. Sci. 1972, 141, 147. Falconer, M. A., Davidson, S. in Epilepsy: Proceedings of the Hans Berger Centenary Symposium (edited by P. Harris and C. Mawdsley); p. 209. Edinburgh, 1974. Meldrum, B. S., Horton, R. W., Brierley, J. B. Brain, 1974, 97, 407. Lennox-Buchthal, M. Febrile Convulsions: A Reappraisal. Amsterdam, 1973. Melchior, J. C., Buchthal, F., Lennox-Buchthal, M. Epilepsia, 1971, 12, 55. Falconer, M. A., Serafetinides, E. A., Corsellis, J. A. N. Archs Neurol. Chicago, 1964, 10, 233. Falconer, M. A., Taylor, D. S. ibid. 1966, 19, 353. Corsellis, J. A. N. in Modern Trends in Neurology: 5 (edited by D. Williams); p. 254. London, 1970. Brown, W. J. in Epilepsy: Its Phenomena in Man (edited by M. A. B. Brazier); p. 339. New York, 1973. Engel, J., Driver, M. V., Falconer, M. A. Brain, 1975, 98, 129. Newcombe, R., Shah, S., Hoare, R. D., Falconer, M. A. J. Neurol. Neurosurg. Psychiat. (in the press). Crandall, P. H., Walter, R. D., Rand, R. W. J. Neurosurg. 1963, 20,
improvement of glucose tolerance after 2 months dietary treatment, and 59% of the group achieved adequate diabetic control by this time. It is consome
of
cluded that treatment with diet alone should be the first-line management for patients with newly diagnosed maturity-onset diabetes mellitus.
Introduction A HIGH proportion of maturity-onset diabetic patients can be controlled by diet alone, and doubts about the safety of long-term therapy with some oral antidiabetic drugs 1,2 have re-emphasised the importance of dietary treatment for non-insulin-requiring diabetics. Despite advances in the understanding of the pathophysiology of diabetes, it has not proved possible to predict which patients will require oral antidiabetic drugs in addition to dietary therapy. There have been few studies on the influence of diet alone on oral glucose tolerance and insulin secretion in diabetics. While some improvement of glucose tolerance has usually been found, changes in oral test (O.G.T.T.) plasma-insulin levels Rudnick and Taylor3 found O.G.T.T. plasma-insulin levels to have increased in 6 diabetic
glucose-tolerance have varied.
subjects after 2 months’ dietary treatment. Turtle,’ however, recorded lower o.G.T.T. plasma-levels after dietary treatment. We have investigated various factors influencing the change of glucose tolerance and O.G.T.T. plasmainsulin levels in newly diagnosed maturity-onset diabetic patients treated with diet alone for 2 months.
827.
17. Crandall, P. H. in Epilepsy: Its Phenomena in Man (edited by M. A. B. 18.
Walter, R.
Brazier); p. 288.
New
York, 1973.
D. ibid. p. 99.
INFLUENCE OF TREATMENT WITH DIET ALONE ON ORAL GLUCOSE-TOLERANCE TEST AND PLASMA SUGAR AND INSULIN LEVELS IN PATIENTS WITH MATURITYONSET DIABETES MELLITUS
J. W. H. DOAR C. E. WILDE
M. E. THOMPSON P. F. J. SEWELL
Departments of Medicine and Clinical Chemistry, Doncaster Royal Infirmary Oral
glucose-tolerance test (O.G.T.T.) plasma sugar and insulin levels were measured in 118 newly diagnosed maturity-onset diabetic patients before and after treatment with diet alone for periods of 2 and 6 months. The results of glucose-tolerance tests carried out during treatment could be predicted from the initial test and the weight reduction between the tests. This prediction was not improved by the addition of further variables, including age, obesity, and plasma-insulin levels during the first test. The change in O.G.T.T. plasma-insulin between the first and second tests was predicted by the result of the initial test, the improvement of glucose tolerance between the two tests, and the degree of weight reduction. 95 % of the group achieved Summary
Patients and Methods 118 patients (aged 33-73, mean 56 years) referred to the diabetic clinic with newly diagnosed non-ketotic diabetes mellitus were studied before and after treatment with diet alone for 2 months. Patients with ketonuria and/or a random blood-sugar at the first visit greater than 350 mg. per 100 ml. were excluded. o.G.T.T.s using a load of 1 g. per kg. body-weight of glucose were carried out as previously described.5 Plasma-sugar levels were measured by an automated ferricyanide methodand plasma-insulin assays were done in duplicate by a modified radioimmunoassay technique.7 Paired tests from each patient were always analysed in the same run. Patients were advised to consume a diet containing at least 200 g. carbohydrate for 3 days before the first O.G.T.T. They were then instructed in a diabetic diet designed to reduce the intake of sugar and reduce body-weight when necessary. 2 months later, a second O.G.T.T. was done, and on this occasion the patients adhered to their diet before the test. A third glucose-tolerance test was carried out in 55 patients after a further 4 months’ treatment with diet alone. Each patient’s degree of obesity was obtained by expressing the weight as a percentage of the ideal bodyweight obtained from tables. O.G.T.T. plasma sugar and insulin curves were assessed in terms of the area between the curve and the abscissa Each area was calculated in arbitrary units, assuming straight lines between successive points. In this centre, o.G.T.T.-sugar areas above 1200 units are considered to indicate diabetes mellitus. Standard statistical methods were used including the pairedt test and optimal multiple regression. In regression calculations, logarithmic conversions were carried out before analyses when appropriate. All calculations were performed by a NOVA 1220 computer.
