Acta Neurol. Scandinav. 53, 103-118, 1976
University Clinic of Neurosurgery, Rigshospitalet, Copenhagen, Denmark.
TEMPORAL LOBE EPILEPSY
Etiological Factors and Surgical Results INGEJENSEN ABSTRACT Seventy-four patients with temporal lobe epilepsy, resistant to medication, who i n 1960-1969 underwent unilateral temporal lobe resection at Rigshospitalet, Copenhagen. In only 12 patients was no etiological factor found. In three-quarters of the patiehts a peri- or postnatal injury was the suspected etiology of the epilepsy; and in one-third, a history of complications i n the actual and/or abnormal outcome of a previous pregnancy was recorded. Only seven patients had experienced febrile convulsions. Patients with certain combinations of etiological factors, including encephalitis, have a poor prognosis regarding relief from seizures. Patients in whom a n abnormal outcome of the mother’s previous pregnancies is recorded have a poor prognosis as regards psychiatric normalization. Apart from this no correlation has been found between the surgical results and the numbers o r types of the various etiological factors.
One of the most important factors in the prevention of a disease is a knowledge of its etiology, and numerous attempts have been made throughout the centuries to elucidate the etiology of epilepsy, as described by Temkin (1945 and 1971) in “The Falling Sickness”, by Lennox & Lennox (1960) in “Epilepsy and Related Disorders”, and by Rodin (1968) in “The Prognosis of Patients with Epilepsy”. Gastaut & Gastauf (1951) were the first to publish a review of etiological factors related to temporal lobe epilepsy. In 100 patients, predominantly adults, with psychomotor epilepsy and with a temporal EEG focus they recorded that there was a recognized possible etiological factor in 69 per cent of the patients. Half of these patients had suffered from sinusitis, otitis, mastoiditis or a cerebral infection; while birth injury was recorded in only three patients, as can be seen in Table 1. The cause of the cerebral infection was stated in 12 patients: ~~
This study was supported by a grant from The Danish Foundation for the Advancement of Medical Science and from The Danish Epilepsy Association.
Table I . Etiological factors in various surveys o f temporal lobe epilepsy.
Children
Birth injury Postnatal injury Infection Febrile convulsion Miscellaneous Unknown
Ounsted et al. N = 100 p.c.
Bras N = 20
10 6 15 32 4 33
20 10
p.c.
-
Children and adults Hassan et al. N = 34 p.c.
1
Aird
Gastaut & Gastaut N = 100 p.c.
Gibbs & Gibbs N = 678 p.c.
et al. N = 193
3 35 31
11 3 6
21 37 12
p.c.
-
38
-
-
-
5
-
-
65
32
31
4 76
6 23
four syphilis, three tuberculosis, three brucellosis, and two malaria. Lennox & Lennox (1960) did not examine the etiological factors of epilepsy themselves, but relied on the material from the Gibbs’ “Atlas of Encephalography” from 1952. A cause of epilepsy was assigned in only 23.7 per cent (161/678) of the patients suffering from psychomotor seizures alone, as can be seen in Table 1. Eleven per cent of these 678 patients had suffered from postnatal trauma, 6 per cent from infections, and 3 per cent from perinatal trauma. In the groups of patients with either pure focal seizures or pure Jacksonian seizures the percentage of assigned causes were 52 and 59 per cent respectively, with almost equal distribution between the three above-mentioned causative conditions. Bray (1962) in a study of 20 epileptic children with a clearly defined electroencephalographic temporal focus found four patients with neonatal asphyxia, all born prematurely, and one patient in whom a serious head injury occurred in early infancy. These patients all had localized EEG changes without propagation beyond the temporal lobe. One patient with a head injury and four of five patients in whom genetic factors were suspected all had EEGs with propagation to other parts of the brain. In nine patients, the etiology was unknown, but in one of these a cystic astrocytoma was later removed. Ounsfed e f al. (1966), in their survey of 100 children with temporal lobe epilepsy, recorded that the nature of the etiological organic insult was known in 35 patients; that in a further 32 patients the epilepsy had its onset in status without any recognized organic insult; while in the remaining 33 patients neither an insult nor an initiating status was recorded. The organic insult group comprised 10 birth injuries, six head injuries, 15 cerebra1 infections, and four miscellaneous. Hassan et al. (1966) published a review of 135 patients with temporal
lobe epilepsy. In 101 patients with an onset of epilepsy after the age of 18 years, definite etiological factors were recognized in only 13 patients: 10 head injuries, one fever, and two with a genetic predisposition. In the remaining 34 patients, the onset of epilepsy was at 11 years or younger. Thirteen of these patients had a history of febrile convulsions, in ten patients an intranatal or a postnatal trauma was recorded, and in three there was a hereditary factor. In only eight patients could no definite etiological factor be demonstrated. Vorobiev (1968) in his survey of 200 patients with temporal lobe epilepsy found severe birth complications in the form of protracted labour with asphyxia as the etiological factor in half of the patients; in a further 25 per cent of the patients, other birth complications or postnatal head injury were considered to be the cause of the epilepsy. A specially severe type of epilepsy with early onset was observed in patients with natal asphyxia, who were also premature and/or whose mothers had suffered from toxaemia of pregnancy. He further found that 60 per cent of the patients were first-born, compared with 37 per cent of patients with other types of epilepsy. Dalby (1969), in his survey of 346 patients with different types of epilepsy, but all with spike-wave rhythms in the EEG, recorded a known etiological diagnosis in only 49 patients (i.e. 14 per cent). Aird et al. (1969), in a survey of 193 patients with temporal lobe epilepsy, also examined the etiological factors. One hundred and fourteen patients had a trauma in their history, including 42 birth abnormalities. In 24 patients, the epilepsy was caused by infection; in 11, other causes were suspected; and in 44 patients, or almost one-quarter, no etiology was known or suspected.
Surveys of Temporal Lobe Resections Earle et al. (1953) from Montreal, in their survey of 157 patients with seizures originating i n temporal lobe, observed that i n approximately 63 per cent of the cases the pathological findings suggested that compression o r anoxia during birth or infancy was the cause of epilepsy. The etiological factors suggested by the clinical history showed a different scatter: 16 per cent had a history of difficult birth and consistent pathological findings. Thirty-one per cent had a history of a postnatal head injury, but only 29 of these 49 patients had adequate pathological findings. Seventeen per cent had a relevant infection in their history, but only eleven of these 26 patients had pathological findings consistent with the history. In 11 per cent, a neoplasm was suspected and found, and i n 22 per cent no related history was recorded; in these 35 patients, the pathological findings were similar to the birth injury group, as was the case with the patients with pathological findings not consistent with their clinical history. A further two patients had a history of severe anoxia during general anaesthesia, and in the last two the epilepsy was related to injection of pertussis toxoid.
106 Penfield & Paine (1955) found i n a group of 67 patients with seizures due t o birth injury that the patients with lesions i n their temporal lobe had a later age of onset of epilepsy than those with lesions elsewhere i n the brain. Th. Rasmussen (1969), i n the survey of 583 epileptic patients treated with temporal lobectomy a t t h e Montreal Neurological Institute up to 1966, found that the presumed cause was birth trauma in 36 per cent, postnatal brain trauma i n 16 per cent, postinflammatory scarring i n 16 per cent, miscellaneous i n 5 per cent, and unknown in 26 per cent of the patients. Bengzon et al. (1968) selected from the 650 patients who had been treated with a temporal lobectomy a t the Montreal Neurological Institute since 1928 a group with therapeutic success and compared these patients with a group with slight or no improvement. They concluded that a presumed etiology of seizures was a prognostic factor of no statistical significance. Falconer e f al. (1964) recorded a postnatal head injury in 19 per cent of their patients, and found that the incidence was lowest i n the pathological group characterized by mesial sclerosis. Further they found that the number of miscellaneous factors such as meningitis, mastoid disease, febrile illness without convulsions, and encephalitis was small. A history of prolonged febrile convulsions usually amounting to status epilepsicus was obtained in 23 patients i n the first series and i n 17 patients in the second series (overlapping of about 50 patients). They found that 40 per cent of the patients in the group characterized by mesial sclerosis (i.e. 47 patients) in the first series of 100 patients had suffered from febrile convulsions. Falconer (1971), who used the large materials from the Guy’s-Maudsley Hospital as the basis for his review of genetic and etiological factors, concluded: The birth was likely to have been injurious to the baby whenever there was a history of prolonged labour, instrumental birth o r precipitate birth. He could not tell from the case records which babies had been horn asphyxiated, but considered that this information would be parallelled by the history of a difficult birth. He found no significance i n the incidence of difficult birth among the various pathological groups. Paillas (1958) i n his surgical series of 50 temporal lobe resected patients correlated the pathogenesis to the operative result, and found that there were significant differences between the various etiological factors. A comparatively large number of patients (i.e. 38 per cent) had convulsions of infancy as the assigned cause. Nineteen per cent had a birth injury, 1 4 per cent an infection, 2 per cent a hamartoma, and i n 27 per cent the etiology was unknown. Talairach e f al. (1974), in their survey of 146 patients with drug-resistant epilepsy, treated operatively (but only i n 68 cases with a temporal lobectomy), have recorded the ctiological factors for the total material. In 56 per cent of the cases the cause was recorded, but without correlation to the effect of the operation: i n 38 cases there was a neonatal complication; in 16 an infection; in 12 a postnatal injury; and lastly in 16 miscellaneous causes, comprising 10 astrocytomas, one glioma, three aneurysms, and two phacomatosis. H u l l a y (1955), i n his survey of 25 patients, records t h a t 10 of these gave a history of a postnatal head injury, but only four of these exhibited gross lesions consistent with the trauma. Stephieri e f al. (1969) correlated the effect of temporal lobectomy to etiology i n their survey of 54 patients with drug-resistant epilepsy of non-tumourous origin. They concluded that in patients with evident birth injury in the history there were
Table 2. Etiological factors in various surveys of patients treated with unilateral temporal lobe resection. Montreal Gny’s-M. Marseille Paris Warsaw Phoenix N = 583 N = 100 N = 37 N = 146 N = 54 N = 88 p.c. p.c. p.c. p.c. P.C. p.c.
Place Birth injury Postnatal injury Infection Febrile convulsion Miscellaneous2 ) Unknown 1)
36 16 16 -
5 26
Including miscellaneous.
28 19 201) 23 17 2)
19 -
14 38 3 27
26 8 11
15 22
25 24
-
24 2 37
}16 17 18
11 44
Sidney N r 30 p.c.
30 17 3 23 23 3
Including possible genetics.
up to 87.5 per cent with good results; while when there were causes other than birth injury there were only 33 per cent with good results. John R . Green (1967), in his survey of 88 patients without space-occupying lesions treated with temporal lobectomy i n 1948-1965, records the following scatter of etiologies : 22 difficult births including anoxia; 14 febrile convulsions during infancy (but including encephalitis and meningitis) ; 16 obscure causes; and 15 neoplasms, of whom 1 0 later died from recurrences. Ifauis (1963), in his survey of 30 temporal lobe resected patients, found nine with perinatal brain damage, seven with postnatal serial convulsions, one infection, five postnatal cranio-cerebral trauma, two glioma, four hamartoma, one postnatal anoxic episode, and one not ascertained. PRESENT INVESTIGATION The Danish material consists of 74 patients with temporal lobe epilepsy, resistant to medication, who during the period 1960-1969 underwent unilateral temporal lobe resection at Rigshospitalet, Copenhagen. Neither before nor during the operation was any tumour o r gross vascular malformation recognized i n any of the patients. A thorough follow-up investigation was undertaken 1970-1971, described in detail by the author (1975) and by the author and K . Vaernet (1975). Even though this investigation was retrospective, the patients’ birth histories and the details of the mothers’ pregnancies are well elucidated for all 74 patients. This information is dealt with in an independent article and only the main items will be summarized here. Information regarding the remaining etiological factors has been obtained from the patients, their parents, and from the 1,174 hospital records.
Perinafaf Compfications As can be seen from Table 3, 37.8 per cent of the patients had a birth injury, with a total of 61 complications recorded i n these 28 patients. In 13 patients this t r a u m a is considered to be the main etiology of the epilepsy; i n a further eight patients it is considered to be a major factor; and i n only seven patients to be of minor importance. A low
1)
No prenatal, natal, o r postnatal etiological factor.
~
5 11 12
Psychiatric status Normal Markedly improved Unchanged/deteriorated
~~
26 (35%)
28 (38%)
Total
9 7 10
13 8 5
17 4 7
n
n
Effect of operation No seizures Marked reduction No change
Postnatal head trauma
Birth trauma
8 3 7
1 1 1
3 (4%)
1
5
18 (24%)
1
1
n
Miscellaneous
10 3
n
infection
4 1 2
7 (9%)
1
6 -
n
convulsions NO
3 2 7
i
12 (16%)
2
8 2
n
etiologyl)
22 (30%) 20 (27%) 32 (53%)
74(100%)
45 (61%) 15 (20%) 14 (19%)
N
Total
TabIe 3. Possible natal and postnatal causes of temporal lobe epilepsy correlated to effect of operation and psychiatric status at follow-up.
co
109 birth weight is not in itself considered a birth complication. Five patients had a birth weight of 2500 g or less, and all of these had accompanying complications. A total of 13 patients were “small for dates”, and eight patients weighed 4000 g or more; both these figures are very high compared with the distribution in the general population. Three patients were twins, compared with an expected one. In eleven patients artificial assistance was necessary; in three of these forceps were applied. Intrauterine and/or neonatal asphyxia was recorded in nine patients. The presence of a birth injury does not p e r se significantly influence the surgical prognosis, even if the patients in the “no change” group apparently have a higher frequency of perinatal complications than the remaining patients. The patients found to be psychiatrically abnormal at follow-up also seem to have an increased complication rate compared with the psychiatrically normal patients.
Postnatal Head Trauma Altogether 43 patients had suffered a head trauma prior to their epilepsy; but in only 26, or roughly one-third of the total group, is it considered severe enough to be of any importance: i.e. the patient must either have been unconscious in immediate connection with the trauma or have displayed some major cerebral symptoms post-traumatically. In 16 of these 26 patients, the trauma was considered to be the main cause of the epilepsy, and the remaining 10 patients were equally distributed in the groups of major and minor etiological importance. As can be seen from Table 3 the presence of a postnatal head trauma does not influence the surgical prognosis o r the psychiatric status at follow-up. In the period from onset of epilepsy to unilateral temporal lobectomy, nine patients had one o r more moderate to severe head traumas; and a further 24 patients had head traumas without unconsciousness or other cerebral symptoms. Patients with no head trauma in the preoperative period had a better prognosis than the patients with such trauma, this difference being significant at the 5 per cent level (0.0250). The prognostic difference between the patients with no or a slight head trauma and the patients with moderate to severe head traumas falls just short of statistical significance. The patients with poor operative results have significantly (0.0006) more head traumas postoperatively than the patients who became free from seizures or who had a reduction in their seizure frequency of at least 75 per cent (i.e. 8/12 compared to 9/60, as the two patients who died in the immediate postoperative period have been disregarded).
110 Cerebral Infections In 18 patients a cerebral infection is recorded; for 11 of these it is considered to be the main cause of their epilepsy; and for a further four patients, of major etiological importance. Six patients had encephalitis of unknown origin. Of the remaining 12 patients: three had encephalitis in connection with measles; two had encephalitis caused by mumps accompanied by orchitis ; two had encephalitis following vaccination against whooping cough; one had encephalitis caused by whooping cough, and one by rubella; and one encephalopathy was of possibly uremic pathogenesis in a patient with a very severe haemorrhagic nephritis caused by a streptococ-infection; and lastly there was one patient with a pneumococcal meningitis, and one with a Pfeiffer meningitis. A s can be seen from Table 3, the presence of a cerebral infection per se does not give a significantly unfavourable prognosis with regard to either the surgical result or the psychiatric status at follow-up. One patient had suffered from recurrent attacks of iritis. In the analyses this has not been considered to be an etiological factor, but in the pathological specimens definite postencephalic changes were found, and no other etiological factor was to be found in the history.
Miscellaneous Postnatal Etiology Three patients had had severe postnatal cerebral injuries, which could not be placed in the previously mentioned groups. The first was a patient in whom an ipsilateral sphenoidal wing meningeoma had been removed 22 years previously. Her first psychomotor attacks occurred a few months after this operation. One patient, when aged 4 years, was admitted unconscious and in status epilepticus, probably due to poisoning caused by eating laburnum. The last patients was, at the age of 12 years, described as moribund due to severe shock from bleeding during a tonsillectomy. Her epilepsy started 6 months after this incidence. She had also suffered a severe birth trauma, and when she was 1 year old probably also had an encephalitis. There was no effect from the temporal lobectomy, and she died in status 4 years later.
Febrile Convulsions The absence of febrile convulsions can be definitely stated in 64 patients. In three patients febrile convulsions are not definitely excluded; their parents had died, but all three were familiar with the noti0.n of febrile convulsions and doubted whether they had ever suffered from these. In the remaining seven patients, one or more
111 febrile convulsions have been recorded. A febrile convulsion seems to give a good surgical prognosis, and also a normal psychiatric status, but this trend is not statistically valid.
No Known Natal or Postnatal Etiology
For only 12 patients were neither natal or postnatal injuries recorded; nor was any information on complications in the mother’s pregnancies o r previous pregnancies obtained. Three of these patients had a family history of neurological diseases, and another four of severe psychiatric disorders. One patient had, as mentioned before, suffered from recurrent iritis. Another was a precipitate birth, but, apart from this, the perinatal circumstances were normal and she was the fifth child. Prenatal Etiological Abnormalities Complications in actual pregnancg. Seventeen patients, 23 per cent of the total material, have a positive history of prenatal complications, which is a significantly higher frequency than in the general population. These complications will be described in detail in connection with the perinatal complications, and only the main conclusions will be mentioned here. Four mothers had had preeclamptic symptoms; two had vaginal haemorrhage late in pregnancy; two had severe infections ; two experienced labour pains in the last months before delivery; two had suffered severe trauma to their abdomen; and three were extremely nervous and were treated with various medications- and of these, two had had hyperemesis and vomiting in a degree exceeding the “permissible”, and of these three nervous mothers, two had also fainted
Table 4 . Abnormalitu in previous a n d / o r actual pregnancu correlated to e f f e c t o f operation and psychiatric status at follow-up.
Effect of operation Total
N = 74 Previous pregnancy Actual pregnancy Previous or actual Previous and actual 1)
16 (36%)1) 17 (23%) 27 ( 3 7 % ) 6 (13%)‘)
Psychiatric status a t follow-up
No seizures
Seizures
Normal
Abnormal
N = 45
N = 29
N = 22
N = 52
10
6
10 17 3
7 10 3
2 3
4 1
14
14 23 5
Calculated on a total of 44 multigravida mothers, plus one formerly sterile mother.
112 frequently during pregnancy. In a further three cases a marked hydramnion had been recorded. The presence of complications in pregnancy apparently does not influence the surgical prognosis, as can be seen from Table 4; but complications in pregnancy are recorded in one-third of the patients in the group “no change”, compared with one-fifth of the patients who became free from seizures. Previous miscarriages, stillbirths, unexplained perinatal mortality and sterility. Forty-four of the 74 patients’ mothers had had one or more previous pregnancies and six (i.e. 8 per cent) of the total number of mothers had been pregnant five times or more. Pregnancies terminating in provoked abortions have naturally been counted in the numbers of pregnancies, but are disregarded in the following analyses. For 15 of these multigravida mothers one pregnancy or more resulted in a miscarriage, a stillbirth, or unexplained death of the child within the first few days. That is: the frequency of mothers with previous complications is 34 per cent, which is much higher than in the general population of multipara, where the expected incidence of abortions is 7.5-12 per cent (as quoted by Willuinsen 1970). The 44 multipara mothers in this material have a total of 116 previous pregnancies. Twenty-six of these terminated in still births or miscarriages, giving a frequency of 22.4 per cent. This is significantly higher than those in the Canadian material by Mefrakos & Mefrakos (1960), which records frequencies of 9.8 per cent and 7.2 per cent in an unselected group of patients afflicted with epilepsy and in an unafflicted control group, respectively; the difference being statistically significant at the 0.2 per cent level (0.0018) and 0 per cent level (O.OOOO), respectively.
Table 5 . Abnormal outcome of previous pregnancy correlated to effect o f operation and to psychiatric status at f o l l o w - u p .
Type of abnormality Miscarriage Still birth Perinatal death Miscarriage/ still birth/ perinatal death Total
Total
Effect of operation No seizures
Seizures
Psychiatric status Normal
Abnormal
6 3 2
4
2 1 1
0 0 0
6
2 1
4
3
1
2
2
15
10
5
2
13
3 2
113 The various abnormalities are recorded in Table 5. Six mothers had pregnancies terminating in miscarriages, one a total of five all occurring in the third or fourth month of pregnancy; the delivery of the patient was extremely difficult, and she was advised against becoming pregnant again. For another mother, five of her 11 previous pregnancies terminated in miscarriages in the fourth or fifth month. For the remaining four mothers the miscarriages were solitary. Three mothers had stillborn children: one had two previous stillbirths; and another had stillbirths both before and after the birth of the patient. In two families, a child had died within a few days after birth. Three mothers gave a history of multiple abnormality. The parents in one of these families divorced a few years after the birth of the patient, who is severely handicapped, being a psychotic idiot, even though he now is free from seizures. Both the father and the mother later remarried and have had normal children. One mother, an X-ray nurse, had been sterile for more than 8 years, and arduous attempts after the birth of the patient did not result in further pregnancies. As can be seen from Table 4, the presence of abnormality in a previous pregnancy does not p e r se influence the surgical prognosis regarding abolition of seizures; but even if the difference is not statistically significant, it should be mentioned that five of the six patients who still have seizures belong in the “no change” group, so that the incidence of previous abnormality is 35.7 per cent in this group, compared with 22.2 per cent in the seizure-free group. The psychiatric status at follow-up is u n f a v o u r d k influenced by a recorded previous abnormal pregnancy, with an incidence of 26.9 per cent in the mentally abnormal patients compared with 9.1 per cent in the mentally normal, the difference falling just short of statistical significance.
All Etiological Factors For a total of 27 patients (i.e. 37 per cent), there was information about prenatal abnormality in the actual or in the outcome of a previous pregnancy or sterility, as can be seen from Table 6 ; but this does not influence the surgical prognosis. On the other hand, a prenatal abnormality is apparently the only etiological factor which unfavourably influences the psychiatric status, even if the difference falls just short of statistical significance at the 5 per cent level. Three-quarters of the patients have a history of a possible peri- or 8
ACTA NEUROL. SCAND.
53, 2 \\
114 Table 6. Summary of possible etiological factors correlated to effect of operation and psychiatric status a t follow-up. Prenatal
Peri- and/or postnatal
No etiology
n
n
n
No seizures Marked reduction No change
17 3 7
33 12 10
Total
27 (37%)
55 (74%)
Normal Markedly improved Unchanged/deteriorated
4 8 15
17 16 22
Total N
(%)
45 15 14
(61) (20)
~
8 2 2
(19)
74 (100)
12 (16%)
3 2 7
22 20 32
(30) (27) (53)
postnatal etiological injury, but neither the presence or the absence influences the surgical prognosis or the psychiatric status. The total number of etiological factors does not significantly influence either the surgical prognosis or the psychiatric status at follow-up, as can be seen from Table 7. When comparing the various combinations of etiological factors, no significant prognostic information can be extracted, with the possible exception of combinations including a postnatal cerebral infection; and even in that case this is not true of the psychiatric status at follow-up. Table 8 records the four different combinations, including infection, which significantly influence the surgical prognosis. The 60 patients
Table 7. Numbers of non-genetic etiological factors correlated to effect of operation and psychiatric status a t follow-up. Effect of operation Numbers
Total
No seizures
Marked reduction n
No change n
Psychiatric status a t follow-up Normal Abnormal n n
N
(%)
n
0 1 2 3 4
12 28 19 11 4
(16) (38) (26) (15) (5)
8 17 11 8 1
2 8 4 1 0
2 3 4 2 3
3 10 5 4
0
9 18 14 7 4
0-4
74 (100)
45
15
14
22
52
Table 8 . Combinations of etiological factors correlated to effect of operation and psychiatric status at follow-up. Effect of operation
Psychiatric status at follow-up
Marked reduction
No change
Normal
N=74
No seizures N=45
N = 15
N = 14
N
n
n
n
n
n
n
5
2
0
3
1
4
7
2
1
4
2
5
complication or postnatal trauma
9
3
1
5
3
6
d prenatal abnormality and perinata1 complication o r postnatal trauma
3
0
0
3
0
3
Total Type of etiology
Infection and : a prenatal abnormality
= 22
Abnormal
N = 52
b perinatal complication c perinatal
who became free from seizures or obtained a reduction in their seizure frequency by at least 75 per cent are compared with the remaining 14 patients. In the five patients with infection and a prenatal abnormality, the difference falls short of statistical significance at the 5 per cent level (0.0438). In the seven patients with perinatal complications, the difference is significant at the 5 per cent level (0.0211) ; in the nine patients with either a perinatal complication and/or a postnatal head trauma the difference is significant at the 2 per cent level (0.0098) ; and lastly in the three patients with both prenatal and peri- and/or postnatal injury the difference is significant at the 1 per cent level (0.0056). No significant differences could be found when correlating the etiological factors to biological variables such as sex, age at onset of epilepsy, duration of epilepsy until operation, and age at operation. Apart from the fact that 80 per cent of the patients with postencephalic neuropathological abnormalities had a positive history of a cerebral infection, no significant correlation could be found between the various etiological factors and the neuropathological findings. These will be described in detail in collaboration with L. Klinken (Inge Jensen & L . Klinken, in press). 8'
116 CONCLUSION
In this investigation the observation of an increase in the number of birth injuries, postnatal head injuries, and cerebral infections in a population of patients with epilepsy compared with the population in general has been supported. The distribution of the various etiological factors varies from survey to survey, largely dependant on the age groups represented, especially with regard to the incidence of birth injuries; marked variations are also noticed from country to country, where for instance the high frequency of otitis, mastoiditis, and sinusitis recorded in the French surveys has not been observed in surveys from other countries. The high incidence of febrile convulsions observed in the materials from England, France, and Australia is not reproduced in the Danish survey. This might be due to the fact that in Denmark febrile convulsions have for many years been regarded as “emergency cases”, and accordingly anticonvulsant medication is administered very early in the convulsive attack. It must also be added that two of the seven patients with febrile convulsions had suffered from encephalitis prior to their first attack of febrile convulsions. In more than one-third of the patients a history of a moderate to severe perinatal complication is recorded. This is an incidence greatly exceeding that recorded in a normal population and this observation strongly supports the view that the improvement of the obstetric service is an important aspect in the prevention of the epileptsies. In the Danish material an abnormal outcome of a previous pregnancy is an unexpectedly frequent observation. The incidence is not only extremely high compared with that in the general population, but also markedly increased in comparison with the incidence recorded in the Canadian epilepsy material by Metrakos & Mefrakos (1960). Even if this observation diverges significantly from the findings in general population and from that in an unselected group of epileptics, it is only a solitary observation, on the basis of which it would not be fair to advise unfortunate parents against further pregnancies ; nevertheless I find it an observation of obstetric and eugenic interest. None of the etiological factors per se prognostically influences the surgical results, but apparently if a brain which has previously sustained a prenatal and/or postnatal injury is afflicted with epilepsy following a cerebral infection, the postoperative prognosis regarding relief from seizures is highly unfavourable.
117 REFERENCES Aird, R. B., A. M. Venturini & P. M. Spielman (1967) : Antecedents of temporal lobe epilepsy. Arch. Neurol. (Chic.) 16, 67-73. Bengzon, A. R. A., T. Rasmussen, P. Gloor, J. Dussault & M. Stephens (1968): Prognostic factors in the surgical treatment of temporal lobe epileptics. Neurology (Minneap.) 18, 717-731. Bray, P. F. (1962) : Temporal lobe syndrome in children. Pediatrics 29, 617-628. Dalby, M . A. (1969) :Epilepsy and 3 per second spike and wave rhythms. Acta neurol. scand. 45, Suppl. 40, pp. 183. Davis, E. (1963) : A review of the features and treatment of temporal lobe epilepsy, with special reference to surgery. Proc. Aust. Ass. Neurol. 1, 27-30. Earle, K. M., M. Baldwin & W. Penfield (1953): Incisural sclerosis and temporal lobe seizures produced by hippocampal herniation at birth. Arch. Neurol. Psychiat. (Chic.) 69, 27-42. Falconer, M. A. (1971): Genetic and related aetiological factors in temporal lobe epilepsy. Epilepsia 12, 13-31. Falconer, M. A., E. A. Serafetidines & J. A. N. Corsellis (1964): Etiology and pathogenesis of the temporal lobe epilepsy. Arch. Neurol. (Chic.) 10, 233-248. Gastaut, H. & Y. Gastaut (1951) : Correlations CIectroencCphalographiques et cliniques B propos de 100 cas d’Cpilepsie dite “psycho-motrice” avec foyers s u r l a region temporale du scalp. Rev. Oto-neuro-ophtal. 23, 257-282. Green, J. R. (1967): Temporal lobectomy, with special reference to selection of epileptic patients. J. Neurosurg. 26, 584-593. Hassan, A. H., A. El-Banhawy, T. El-Gengaihy & E. El-Gengaihy (1966) : A study of Egyptian epileptics with temporal lobe focus. J. Egypt. med. Ass. 49, 529-541. Hullay, J. (1965): Surgical treatment of temporal lobe epilepsy. Acta med. Acad. Sci. hung. 7 , 295-320. Jensen, Inge (1975) : Temporal lobe surgery around the world. Results, complications and mortality. Acta neurol scand. 52, 354-373. Jensen, Inge (1975) : Genetic factors i n temporal lobe epilepsy. Acta neurol. scand. 52, 381-394. Jensen, Inge & I.. Klinhen: Neuropathology i n temporal lobe epilepsy. To he published. Jensen, Inge & K. Vaernet : Temporal lobe epilepsy. Follow-up investigation of 74 temporal lobe resected patients. To be published. Lennox, W. G. & Margaret A. Lennox (1960): Epikpsy and Related Disorders. Little, Brown and Co., Boston, Mass. Metrakos, J. D. 9: K. Metrakos (1960) : Genetics of convulsive disorders 1. Introduction, problems, methods, and base lines. Neurology 10, 228-240. Ounsted, C., J. Lindsay & R. Norman (1966): Biological Factors in Temporal Lobe Epilepsy. Heinemann, London. Paillas, J. E. (1958) : Aspects cliniques de 1’Cpilepsie temporale. Temporal Lobe Epilepsy, ed. M. Baldwin & P. Bailey, pp. 411-439. Charles C Thomas, Springfield, 111. Penfield, W. & K. Paine (1955): Results of surgical therapy for focal epileptic seizures. Canad. med. Ass. J . 73, 515-531. Kasmussen, T. (1969) : The role of surgery in the treatment of focal epilepsy. Clin. Neurosurg. 16, 288-314. Rodin, E. A. (1968): The prognosis of patients with epilepsy. Charles C Thomas, Springfield, 111.
118 Stepieh, L., J. BidziAski & W. Mazurowslri (1969) : The results of surgical treatment of temporal lobe epilepsy. Pol. med. J. 8, 1184-1190. Talairach, J. & J. Bancaud et al. (1974) : Approche nouvelle de la neurochirurgie de 1’Cpilepsie. Neuro-chirurgie 20, Suppl. 1, 183-205. Temkin, 0. (1971) : The Falling Sickness. 2nd ed. The Johns Hopkins Press, Ltd., London. Vorobiev, S. P. (1968) : The role of the etiological factor in the clinical picture of temporal epilepsy. Zh. Nevropat. Psikhiat. (Rus.) 68, 1637-1641. Willurnsen, A. L. (1970) : Environmental Factors i n Congenital Malformations. F.A.D.L.’s Forlag, Copenhagen. Received April 21, 1975
Inge Jensen, M.D. Neuromedicinsk afd. Ksbenhavns Amts Sygehus DK-2600 Glostrup Denmark
University Clinic of Neurosurgery, Rigshospitalet, Copenhagen, Denmark.
TEMPORAL LOBE EPILEPSY
Etiological Factors and Surgical Results INGEJENSEN ABSTRACT Seventy-four patients with temporal lobe epilepsy, resistant to medication, who i n 1960-1969 underwent unilateral temporal lobe resection at Rigshospitalet, Copenhagen. In only 12 patients was no etiological factor found. In three-quarters of the patiehts a peri- or postnatal injury was the suspected etiology of the epilepsy; and in one-third, a history of complications i n the actual and/or abnormal outcome of a previous pregnancy was recorded. Only seven patients had experienced febrile convulsions. Patients with certain combinations of etiological factors, including encephalitis, have a poor prognosis regarding relief from seizures. Patients in whom a n abnormal outcome of the mother’s previous pregnancies is recorded have a poor prognosis as regards psychiatric normalization. Apart from this no correlation has been found between the surgical results and the numbers o r types of the various etiological factors.
One of the most important factors in the prevention of a disease is a knowledge of its etiology, and numerous attempts have been made throughout the centuries to elucidate the etiology of epilepsy, as described by Temkin (1945 and 1971) in “The Falling Sickness”, by Lennox & Lennox (1960) in “Epilepsy and Related Disorders”, and by Rodin (1968) in “The Prognosis of Patients with Epilepsy”. Gastaut & Gastauf (1951) were the first to publish a review of etiological factors related to temporal lobe epilepsy. In 100 patients, predominantly adults, with psychomotor epilepsy and with a temporal EEG focus they recorded that there was a recognized possible etiological factor in 69 per cent of the patients. Half of these patients had suffered from sinusitis, otitis, mastoiditis or a cerebral infection; while birth injury was recorded in only three patients, as can be seen in Table 1. The cause of the cerebral infection was stated in 12 patients: ~~
This study was supported by a grant from The Danish Foundation for the Advancement of Medical Science and from The Danish Epilepsy Association.
Table I . Etiological factors in various surveys o f temporal lobe epilepsy.
Children
Birth injury Postnatal injury Infection Febrile convulsion Miscellaneous Unknown
Ounsted et al. N = 100 p.c.
Bras N = 20
10 6 15 32 4 33
20 10
p.c.
-
Children and adults Hassan et al. N = 34 p.c.
1
Aird
Gastaut & Gastaut N = 100 p.c.
Gibbs & Gibbs N = 678 p.c.
et al. N = 193
3 35 31
11 3 6
21 37 12
p.c.
-
38
-
-
-
5
-
-
65
32
31
4 76
6 23
four syphilis, three tuberculosis, three brucellosis, and two malaria. Lennox & Lennox (1960) did not examine the etiological factors of epilepsy themselves, but relied on the material from the Gibbs’ “Atlas of Encephalography” from 1952. A cause of epilepsy was assigned in only 23.7 per cent (161/678) of the patients suffering from psychomotor seizures alone, as can be seen in Table 1. Eleven per cent of these 678 patients had suffered from postnatal trauma, 6 per cent from infections, and 3 per cent from perinatal trauma. In the groups of patients with either pure focal seizures or pure Jacksonian seizures the percentage of assigned causes were 52 and 59 per cent respectively, with almost equal distribution between the three above-mentioned causative conditions. Bray (1962) in a study of 20 epileptic children with a clearly defined electroencephalographic temporal focus found four patients with neonatal asphyxia, all born prematurely, and one patient in whom a serious head injury occurred in early infancy. These patients all had localized EEG changes without propagation beyond the temporal lobe. One patient with a head injury and four of five patients in whom genetic factors were suspected all had EEGs with propagation to other parts of the brain. In nine patients, the etiology was unknown, but in one of these a cystic astrocytoma was later removed. Ounsfed e f al. (1966), in their survey of 100 children with temporal lobe epilepsy, recorded that the nature of the etiological organic insult was known in 35 patients; that in a further 32 patients the epilepsy had its onset in status without any recognized organic insult; while in the remaining 33 patients neither an insult nor an initiating status was recorded. The organic insult group comprised 10 birth injuries, six head injuries, 15 cerebra1 infections, and four miscellaneous. Hassan et al. (1966) published a review of 135 patients with temporal
lobe epilepsy. In 101 patients with an onset of epilepsy after the age of 18 years, definite etiological factors were recognized in only 13 patients: 10 head injuries, one fever, and two with a genetic predisposition. In the remaining 34 patients, the onset of epilepsy was at 11 years or younger. Thirteen of these patients had a history of febrile convulsions, in ten patients an intranatal or a postnatal trauma was recorded, and in three there was a hereditary factor. In only eight patients could no definite etiological factor be demonstrated. Vorobiev (1968) in his survey of 200 patients with temporal lobe epilepsy found severe birth complications in the form of protracted labour with asphyxia as the etiological factor in half of the patients; in a further 25 per cent of the patients, other birth complications or postnatal head injury were considered to be the cause of the epilepsy. A specially severe type of epilepsy with early onset was observed in patients with natal asphyxia, who were also premature and/or whose mothers had suffered from toxaemia of pregnancy. He further found that 60 per cent of the patients were first-born, compared with 37 per cent of patients with other types of epilepsy. Dalby (1969), in his survey of 346 patients with different types of epilepsy, but all with spike-wave rhythms in the EEG, recorded a known etiological diagnosis in only 49 patients (i.e. 14 per cent). Aird et al. (1969), in a survey of 193 patients with temporal lobe epilepsy, also examined the etiological factors. One hundred and fourteen patients had a trauma in their history, including 42 birth abnormalities. In 24 patients, the epilepsy was caused by infection; in 11, other causes were suspected; and in 44 patients, or almost one-quarter, no etiology was known or suspected.
Surveys of Temporal Lobe Resections Earle et al. (1953) from Montreal, in their survey of 157 patients with seizures originating i n temporal lobe, observed that i n approximately 63 per cent of the cases the pathological findings suggested that compression o r anoxia during birth or infancy was the cause of epilepsy. The etiological factors suggested by the clinical history showed a different scatter: 16 per cent had a history of difficult birth and consistent pathological findings. Thirty-one per cent had a history of a postnatal head injury, but only 29 of these 49 patients had adequate pathological findings. Seventeen per cent had a relevant infection in their history, but only eleven of these 26 patients had pathological findings consistent with the history. In 11 per cent, a neoplasm was suspected and found, and i n 22 per cent no related history was recorded; in these 35 patients, the pathological findings were similar to the birth injury group, as was the case with the patients with pathological findings not consistent with their clinical history. A further two patients had a history of severe anoxia during general anaesthesia, and in the last two the epilepsy was related to injection of pertussis toxoid.
106 Penfield & Paine (1955) found i n a group of 67 patients with seizures due t o birth injury that the patients with lesions i n their temporal lobe had a later age of onset of epilepsy than those with lesions elsewhere i n the brain. Th. Rasmussen (1969), i n the survey of 583 epileptic patients treated with temporal lobectomy a t t h e Montreal Neurological Institute up to 1966, found that the presumed cause was birth trauma in 36 per cent, postnatal brain trauma i n 16 per cent, postinflammatory scarring i n 16 per cent, miscellaneous i n 5 per cent, and unknown in 26 per cent of the patients. Bengzon et al. (1968) selected from the 650 patients who had been treated with a temporal lobectomy a t the Montreal Neurological Institute since 1928 a group with therapeutic success and compared these patients with a group with slight or no improvement. They concluded that a presumed etiology of seizures was a prognostic factor of no statistical significance. Falconer e f al. (1964) recorded a postnatal head injury in 19 per cent of their patients, and found that the incidence was lowest i n the pathological group characterized by mesial sclerosis. Further they found that the number of miscellaneous factors such as meningitis, mastoid disease, febrile illness without convulsions, and encephalitis was small. A history of prolonged febrile convulsions usually amounting to status epilepsicus was obtained in 23 patients i n the first series and i n 17 patients in the second series (overlapping of about 50 patients). They found that 40 per cent of the patients in the group characterized by mesial sclerosis (i.e. 47 patients) in the first series of 100 patients had suffered from febrile convulsions. Falconer (1971), who used the large materials from the Guy’s-Maudsley Hospital as the basis for his review of genetic and etiological factors, concluded: The birth was likely to have been injurious to the baby whenever there was a history of prolonged labour, instrumental birth o r precipitate birth. He could not tell from the case records which babies had been horn asphyxiated, but considered that this information would be parallelled by the history of a difficult birth. He found no significance i n the incidence of difficult birth among the various pathological groups. Paillas (1958) i n his surgical series of 50 temporal lobe resected patients correlated the pathogenesis to the operative result, and found that there were significant differences between the various etiological factors. A comparatively large number of patients (i.e. 38 per cent) had convulsions of infancy as the assigned cause. Nineteen per cent had a birth injury, 1 4 per cent an infection, 2 per cent a hamartoma, and i n 27 per cent the etiology was unknown. Talairach e f al. (1974), in their survey of 146 patients with drug-resistant epilepsy, treated operatively (but only i n 68 cases with a temporal lobectomy), have recorded the ctiological factors for the total material. In 56 per cent of the cases the cause was recorded, but without correlation to the effect of the operation: i n 38 cases there was a neonatal complication; in 16 an infection; in 12 a postnatal injury; and lastly in 16 miscellaneous causes, comprising 10 astrocytomas, one glioma, three aneurysms, and two phacomatosis. H u l l a y (1955), i n his survey of 25 patients, records t h a t 10 of these gave a history of a postnatal head injury, but only four of these exhibited gross lesions consistent with the trauma. Stephieri e f al. (1969) correlated the effect of temporal lobectomy to etiology i n their survey of 54 patients with drug-resistant epilepsy of non-tumourous origin. They concluded that in patients with evident birth injury in the history there were
Table 2. Etiological factors in various surveys of patients treated with unilateral temporal lobe resection. Montreal Gny’s-M. Marseille Paris Warsaw Phoenix N = 583 N = 100 N = 37 N = 146 N = 54 N = 88 p.c. p.c. p.c. p.c. P.C. p.c.
Place Birth injury Postnatal injury Infection Febrile convulsion Miscellaneous2 ) Unknown 1)
36 16 16 -
5 26
Including miscellaneous.
28 19 201) 23 17 2)
19 -
14 38 3 27
26 8 11
15 22
25 24
-
24 2 37
}16 17 18
11 44
Sidney N r 30 p.c.
30 17 3 23 23 3
Including possible genetics.
up to 87.5 per cent with good results; while when there were causes other than birth injury there were only 33 per cent with good results. John R . Green (1967), in his survey of 88 patients without space-occupying lesions treated with temporal lobectomy i n 1948-1965, records the following scatter of etiologies : 22 difficult births including anoxia; 14 febrile convulsions during infancy (but including encephalitis and meningitis) ; 16 obscure causes; and 15 neoplasms, of whom 1 0 later died from recurrences. Ifauis (1963), in his survey of 30 temporal lobe resected patients, found nine with perinatal brain damage, seven with postnatal serial convulsions, one infection, five postnatal cranio-cerebral trauma, two glioma, four hamartoma, one postnatal anoxic episode, and one not ascertained. PRESENT INVESTIGATION The Danish material consists of 74 patients with temporal lobe epilepsy, resistant to medication, who during the period 1960-1969 underwent unilateral temporal lobe resection at Rigshospitalet, Copenhagen. Neither before nor during the operation was any tumour o r gross vascular malformation recognized i n any of the patients. A thorough follow-up investigation was undertaken 1970-1971, described in detail by the author (1975) and by the author and K . Vaernet (1975). Even though this investigation was retrospective, the patients’ birth histories and the details of the mothers’ pregnancies are well elucidated for all 74 patients. This information is dealt with in an independent article and only the main items will be summarized here. Information regarding the remaining etiological factors has been obtained from the patients, their parents, and from the 1,174 hospital records.
Perinafaf Compfications As can be seen from Table 3, 37.8 per cent of the patients had a birth injury, with a total of 61 complications recorded i n these 28 patients. In 13 patients this t r a u m a is considered to be the main etiology of the epilepsy; i n a further eight patients it is considered to be a major factor; and i n only seven patients to be of minor importance. A low
1)
No prenatal, natal, o r postnatal etiological factor.
~
5 11 12
Psychiatric status Normal Markedly improved Unchanged/deteriorated
~~
26 (35%)
28 (38%)
Total
9 7 10
13 8 5
17 4 7
n
n
Effect of operation No seizures Marked reduction No change
Postnatal head trauma
Birth trauma
8 3 7
1 1 1
3 (4%)
1
5
18 (24%)
1
1
n
Miscellaneous
10 3
n
infection
4 1 2
7 (9%)
1
6 -
n
convulsions NO
3 2 7
i
12 (16%)
2
8 2
n
etiologyl)
22 (30%) 20 (27%) 32 (53%)
74(100%)
45 (61%) 15 (20%) 14 (19%)
N
Total
TabIe 3. Possible natal and postnatal causes of temporal lobe epilepsy correlated to effect of operation and psychiatric status at follow-up.
co
109 birth weight is not in itself considered a birth complication. Five patients had a birth weight of 2500 g or less, and all of these had accompanying complications. A total of 13 patients were “small for dates”, and eight patients weighed 4000 g or more; both these figures are very high compared with the distribution in the general population. Three patients were twins, compared with an expected one. In eleven patients artificial assistance was necessary; in three of these forceps were applied. Intrauterine and/or neonatal asphyxia was recorded in nine patients. The presence of a birth injury does not p e r se significantly influence the surgical prognosis, even if the patients in the “no change” group apparently have a higher frequency of perinatal complications than the remaining patients. The patients found to be psychiatrically abnormal at follow-up also seem to have an increased complication rate compared with the psychiatrically normal patients.
Postnatal Head Trauma Altogether 43 patients had suffered a head trauma prior to their epilepsy; but in only 26, or roughly one-third of the total group, is it considered severe enough to be of any importance: i.e. the patient must either have been unconscious in immediate connection with the trauma or have displayed some major cerebral symptoms post-traumatically. In 16 of these 26 patients, the trauma was considered to be the main cause of the epilepsy, and the remaining 10 patients were equally distributed in the groups of major and minor etiological importance. As can be seen from Table 3 the presence of a postnatal head trauma does not influence the surgical prognosis o r the psychiatric status at follow-up. In the period from onset of epilepsy to unilateral temporal lobectomy, nine patients had one o r more moderate to severe head traumas; and a further 24 patients had head traumas without unconsciousness or other cerebral symptoms. Patients with no head trauma in the preoperative period had a better prognosis than the patients with such trauma, this difference being significant at the 5 per cent level (0.0250). The prognostic difference between the patients with no or a slight head trauma and the patients with moderate to severe head traumas falls just short of statistical significance. The patients with poor operative results have significantly (0.0006) more head traumas postoperatively than the patients who became free from seizures or who had a reduction in their seizure frequency of at least 75 per cent (i.e. 8/12 compared to 9/60, as the two patients who died in the immediate postoperative period have been disregarded).
110 Cerebral Infections In 18 patients a cerebral infection is recorded; for 11 of these it is considered to be the main cause of their epilepsy; and for a further four patients, of major etiological importance. Six patients had encephalitis of unknown origin. Of the remaining 12 patients: three had encephalitis in connection with measles; two had encephalitis caused by mumps accompanied by orchitis ; two had encephalitis following vaccination against whooping cough; one had encephalitis caused by whooping cough, and one by rubella; and one encephalopathy was of possibly uremic pathogenesis in a patient with a very severe haemorrhagic nephritis caused by a streptococ-infection; and lastly there was one patient with a pneumococcal meningitis, and one with a Pfeiffer meningitis. A s can be seen from Table 3, the presence of a cerebral infection per se does not give a significantly unfavourable prognosis with regard to either the surgical result or the psychiatric status at follow-up. One patient had suffered from recurrent attacks of iritis. In the analyses this has not been considered to be an etiological factor, but in the pathological specimens definite postencephalic changes were found, and no other etiological factor was to be found in the history.
Miscellaneous Postnatal Etiology Three patients had had severe postnatal cerebral injuries, which could not be placed in the previously mentioned groups. The first was a patient in whom an ipsilateral sphenoidal wing meningeoma had been removed 22 years previously. Her first psychomotor attacks occurred a few months after this operation. One patient, when aged 4 years, was admitted unconscious and in status epilepticus, probably due to poisoning caused by eating laburnum. The last patients was, at the age of 12 years, described as moribund due to severe shock from bleeding during a tonsillectomy. Her epilepsy started 6 months after this incidence. She had also suffered a severe birth trauma, and when she was 1 year old probably also had an encephalitis. There was no effect from the temporal lobectomy, and she died in status 4 years later.
Febrile Convulsions The absence of febrile convulsions can be definitely stated in 64 patients. In three patients febrile convulsions are not definitely excluded; their parents had died, but all three were familiar with the noti0.n of febrile convulsions and doubted whether they had ever suffered from these. In the remaining seven patients, one or more
111 febrile convulsions have been recorded. A febrile convulsion seems to give a good surgical prognosis, and also a normal psychiatric status, but this trend is not statistically valid.
No Known Natal or Postnatal Etiology
For only 12 patients were neither natal or postnatal injuries recorded; nor was any information on complications in the mother’s pregnancies o r previous pregnancies obtained. Three of these patients had a family history of neurological diseases, and another four of severe psychiatric disorders. One patient had, as mentioned before, suffered from recurrent iritis. Another was a precipitate birth, but, apart from this, the perinatal circumstances were normal and she was the fifth child. Prenatal Etiological Abnormalities Complications in actual pregnancg. Seventeen patients, 23 per cent of the total material, have a positive history of prenatal complications, which is a significantly higher frequency than in the general population. These complications will be described in detail in connection with the perinatal complications, and only the main conclusions will be mentioned here. Four mothers had had preeclamptic symptoms; two had vaginal haemorrhage late in pregnancy; two had severe infections ; two experienced labour pains in the last months before delivery; two had suffered severe trauma to their abdomen; and three were extremely nervous and were treated with various medications- and of these, two had had hyperemesis and vomiting in a degree exceeding the “permissible”, and of these three nervous mothers, two had also fainted
Table 4 . Abnormalitu in previous a n d / o r actual pregnancu correlated to e f f e c t o f operation and psychiatric status at follow-up.
Effect of operation Total
N = 74 Previous pregnancy Actual pregnancy Previous or actual Previous and actual 1)
16 (36%)1) 17 (23%) 27 ( 3 7 % ) 6 (13%)‘)
Psychiatric status a t follow-up
No seizures
Seizures
Normal
Abnormal
N = 45
N = 29
N = 22
N = 52
10
6
10 17 3
7 10 3
2 3
4 1
14
14 23 5
Calculated on a total of 44 multigravida mothers, plus one formerly sterile mother.
112 frequently during pregnancy. In a further three cases a marked hydramnion had been recorded. The presence of complications in pregnancy apparently does not influence the surgical prognosis, as can be seen from Table 4; but complications in pregnancy are recorded in one-third of the patients in the group “no change”, compared with one-fifth of the patients who became free from seizures. Previous miscarriages, stillbirths, unexplained perinatal mortality and sterility. Forty-four of the 74 patients’ mothers had had one or more previous pregnancies and six (i.e. 8 per cent) of the total number of mothers had been pregnant five times or more. Pregnancies terminating in provoked abortions have naturally been counted in the numbers of pregnancies, but are disregarded in the following analyses. For 15 of these multigravida mothers one pregnancy or more resulted in a miscarriage, a stillbirth, or unexplained death of the child within the first few days. That is: the frequency of mothers with previous complications is 34 per cent, which is much higher than in the general population of multipara, where the expected incidence of abortions is 7.5-12 per cent (as quoted by Willuinsen 1970). The 44 multipara mothers in this material have a total of 116 previous pregnancies. Twenty-six of these terminated in still births or miscarriages, giving a frequency of 22.4 per cent. This is significantly higher than those in the Canadian material by Mefrakos & Mefrakos (1960), which records frequencies of 9.8 per cent and 7.2 per cent in an unselected group of patients afflicted with epilepsy and in an unafflicted control group, respectively; the difference being statistically significant at the 0.2 per cent level (0.0018) and 0 per cent level (O.OOOO), respectively.
Table 5 . Abnormal outcome of previous pregnancy correlated to effect o f operation and to psychiatric status at f o l l o w - u p .
Type of abnormality Miscarriage Still birth Perinatal death Miscarriage/ still birth/ perinatal death Total
Total
Effect of operation No seizures
Seizures
Psychiatric status Normal
Abnormal
6 3 2
4
2 1 1
0 0 0
6
2 1
4
3
1
2
2
15
10
5
2
13
3 2
113 The various abnormalities are recorded in Table 5. Six mothers had pregnancies terminating in miscarriages, one a total of five all occurring in the third or fourth month of pregnancy; the delivery of the patient was extremely difficult, and she was advised against becoming pregnant again. For another mother, five of her 11 previous pregnancies terminated in miscarriages in the fourth or fifth month. For the remaining four mothers the miscarriages were solitary. Three mothers had stillborn children: one had two previous stillbirths; and another had stillbirths both before and after the birth of the patient. In two families, a child had died within a few days after birth. Three mothers gave a history of multiple abnormality. The parents in one of these families divorced a few years after the birth of the patient, who is severely handicapped, being a psychotic idiot, even though he now is free from seizures. Both the father and the mother later remarried and have had normal children. One mother, an X-ray nurse, had been sterile for more than 8 years, and arduous attempts after the birth of the patient did not result in further pregnancies. As can be seen from Table 4, the presence of abnormality in a previous pregnancy does not p e r se influence the surgical prognosis regarding abolition of seizures; but even if the difference is not statistically significant, it should be mentioned that five of the six patients who still have seizures belong in the “no change” group, so that the incidence of previous abnormality is 35.7 per cent in this group, compared with 22.2 per cent in the seizure-free group. The psychiatric status at follow-up is u n f a v o u r d k influenced by a recorded previous abnormal pregnancy, with an incidence of 26.9 per cent in the mentally abnormal patients compared with 9.1 per cent in the mentally normal, the difference falling just short of statistical significance.
All Etiological Factors For a total of 27 patients (i.e. 37 per cent), there was information about prenatal abnormality in the actual or in the outcome of a previous pregnancy or sterility, as can be seen from Table 6 ; but this does not influence the surgical prognosis. On the other hand, a prenatal abnormality is apparently the only etiological factor which unfavourably influences the psychiatric status, even if the difference falls just short of statistical significance at the 5 per cent level. Three-quarters of the patients have a history of a possible peri- or 8
ACTA NEUROL. SCAND.
53, 2 \\
114 Table 6. Summary of possible etiological factors correlated to effect of operation and psychiatric status a t follow-up. Prenatal
Peri- and/or postnatal
No etiology
n
n
n
No seizures Marked reduction No change
17 3 7
33 12 10
Total
27 (37%)
55 (74%)
Normal Markedly improved Unchanged/deteriorated
4 8 15
17 16 22
Total N
(%)
45 15 14
(61) (20)
~
8 2 2
(19)
74 (100)
12 (16%)
3 2 7
22 20 32
(30) (27) (53)
postnatal etiological injury, but neither the presence or the absence influences the surgical prognosis or the psychiatric status. The total number of etiological factors does not significantly influence either the surgical prognosis or the psychiatric status at follow-up, as can be seen from Table 7. When comparing the various combinations of etiological factors, no significant prognostic information can be extracted, with the possible exception of combinations including a postnatal cerebral infection; and even in that case this is not true of the psychiatric status at follow-up. Table 8 records the four different combinations, including infection, which significantly influence the surgical prognosis. The 60 patients
Table 7. Numbers of non-genetic etiological factors correlated to effect of operation and psychiatric status a t follow-up. Effect of operation Numbers
Total
No seizures
Marked reduction n
No change n
Psychiatric status a t follow-up Normal Abnormal n n
N
(%)
n
0 1 2 3 4
12 28 19 11 4
(16) (38) (26) (15) (5)
8 17 11 8 1
2 8 4 1 0
2 3 4 2 3
3 10 5 4
0
9 18 14 7 4
0-4
74 (100)
45
15
14
22
52
Table 8 . Combinations of etiological factors correlated to effect of operation and psychiatric status at follow-up. Effect of operation
Psychiatric status at follow-up
Marked reduction
No change
Normal
N=74
No seizures N=45
N = 15
N = 14
N
n
n
n
n
n
n
5
2
0
3
1
4
7
2
1
4
2
5
complication or postnatal trauma
9
3
1
5
3
6
d prenatal abnormality and perinata1 complication o r postnatal trauma
3
0
0
3
0
3
Total Type of etiology
Infection and : a prenatal abnormality
= 22
Abnormal
N = 52
b perinatal complication c perinatal
who became free from seizures or obtained a reduction in their seizure frequency by at least 75 per cent are compared with the remaining 14 patients. In the five patients with infection and a prenatal abnormality, the difference falls short of statistical significance at the 5 per cent level (0.0438). In the seven patients with perinatal complications, the difference is significant at the 5 per cent level (0.0211) ; in the nine patients with either a perinatal complication and/or a postnatal head trauma the difference is significant at the 2 per cent level (0.0098) ; and lastly in the three patients with both prenatal and peri- and/or postnatal injury the difference is significant at the 1 per cent level (0.0056). No significant differences could be found when correlating the etiological factors to biological variables such as sex, age at onset of epilepsy, duration of epilepsy until operation, and age at operation. Apart from the fact that 80 per cent of the patients with postencephalic neuropathological abnormalities had a positive history of a cerebral infection, no significant correlation could be found between the various etiological factors and the neuropathological findings. These will be described in detail in collaboration with L. Klinken (Inge Jensen & L . Klinken, in press). 8'
116 CONCLUSION
In this investigation the observation of an increase in the number of birth injuries, postnatal head injuries, and cerebral infections in a population of patients with epilepsy compared with the population in general has been supported. The distribution of the various etiological factors varies from survey to survey, largely dependant on the age groups represented, especially with regard to the incidence of birth injuries; marked variations are also noticed from country to country, where for instance the high frequency of otitis, mastoiditis, and sinusitis recorded in the French surveys has not been observed in surveys from other countries. The high incidence of febrile convulsions observed in the materials from England, France, and Australia is not reproduced in the Danish survey. This might be due to the fact that in Denmark febrile convulsions have for many years been regarded as “emergency cases”, and accordingly anticonvulsant medication is administered very early in the convulsive attack. It must also be added that two of the seven patients with febrile convulsions had suffered from encephalitis prior to their first attack of febrile convulsions. In more than one-third of the patients a history of a moderate to severe perinatal complication is recorded. This is an incidence greatly exceeding that recorded in a normal population and this observation strongly supports the view that the improvement of the obstetric service is an important aspect in the prevention of the epileptsies. In the Danish material an abnormal outcome of a previous pregnancy is an unexpectedly frequent observation. The incidence is not only extremely high compared with that in the general population, but also markedly increased in comparison with the incidence recorded in the Canadian epilepsy material by Metrakos & Mefrakos (1960). Even if this observation diverges significantly from the findings in general population and from that in an unselected group of epileptics, it is only a solitary observation, on the basis of which it would not be fair to advise unfortunate parents against further pregnancies ; nevertheless I find it an observation of obstetric and eugenic interest. None of the etiological factors per se prognostically influences the surgical results, but apparently if a brain which has previously sustained a prenatal and/or postnatal injury is afflicted with epilepsy following a cerebral infection, the postoperative prognosis regarding relief from seizures is highly unfavourable.
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Inge Jensen, M.D. Neuromedicinsk afd. Ksbenhavns Amts Sygehus DK-2600 Glostrup Denmark
