Acta Neurol. Scandinav. 54, 391-414, 1976

University Clinic of Neurosurgery, Rigshospitalet, and Institute of Neuropathology, University of Copenhagen, Denmark.

TEMPORAL LOBE EPILEPSY AND NEUROPATHOLOGY

Histological Findings i n Resecfed Temporal Lobes Correlated to Surgical Results and Clinical Aspects INGEJENSEN and L. KLINKEN ABSTRACT Neuropathological findings were studied i n 74 patients with drugresistant temporal lobe epilepsy who underwent unilateral temporal lobe resection i n 1960-1969 i n Denmark. I n 60 per cent of the patients a well-defined neuropathological abnormality was revealed ( i x . 13 cases of focal lesions, including four small tumours, 21 cases of gliosis, and 10 cases of perivascular infiltration), i n 23 per cent the findings were either questionably abnormal or without structural abnormality, while i n t h e last 18 per cent scquelae of a previous operation dominated t h e histology. The general trend was for the postoperative clinical outcome to h e better, the more specific a n d circumscrihed t h e histological ahnorrnality. There was no correlation between the neuropathological findings and the preoperative types of seizures. Postoperative recurrence of seizures was more often observed in patients w i t h gliosis t h a n i n those w i t h other histological diagnoses. A positive corrclation existed hetween a history of cerebral infection and thc presence of perivascular lymphocytic and histioeytic infiltration, a n d gliosis was a frequent finding i n patients w i t h epilepsy of unknown aetiology. No other significant correlation was found between the neuropathological abnormalities and t h e clinical, hereditary, aetiological, and social aspects.

Unilateral temporal lobe resection has, since first applied in 1948, proved to be a n excellent treatment of drug-resistant temporal lobe epilepsy of unilateral or predominantly unilateral origin. By the end of 1975 surveys from neurosurgical clinics all over the world covering more t h a n 2,000 operations were available (Znge Jensen 1975 a, Soureli 1974, V a n Buren e f QZ. 1975). Generally, a t follow-up one to ten years This study was supported b y grants from The Danish Foundation for the Advancement of Medical Science and t h e Danish Epilepsy Association.

392 postoperatively, almost two-thirds of the patients had no or few seizures, and in more t h a n three-quarters of the patients the operation could be characterized as “worthwhile”. Furthermore, preoperative psychiatric disorders disappeared o r improved markedly postoperatively in more t h a n half of the patients. I n the second quarter of this century surgical treatment of temporal lobe epilepsy consisted of a n excision, provided a visible abnormality was present (Penfield et al. 1961). T h e progress in electroencephalographic technique made i t possible to diagnose localized abnormalities which were not visible macroscopically, and on hiarch 12th, 1947, the first unilateral excision of temporal lobe cortex under guidance of electrocorticography was performed (Bailey & Gibbs 1951, Bailey 1954). Within a few years temporal lobe surgery was taken up by neurosurgeons all over the world. I n general the operative techniques now employed follow one of two somewhat divergent principles : 1) Excision with suction under the guidance of electric stimulation and electrocorticographical recording to ensure that all abnormally discharging cortex is resected, with the preservation of as much normal brain as possible (Rasmrrssen 196‘3); 2 ) Removal in one piece, anterior to the vein of LabbC, of the affected temporal lobe together with the uncus, the major part of the amygdala, and the anterior 2 to 3 cm of the hippocampus, to obtain a specimen that can be adequately studied histologically; the superior temporal gyrus, apart from the anterior 2 cm, is preserved in order to minimize the risk of postoperative dysphasia (Falconer 1965). T h e surgical treatment of drug-resistant temporal lobe epilepsy was instituted in Denmark in 1960, and by the end of hiarch 1975 n total of 106 patients had been submitted to a n anterior temporal lobectomy. This paper covers the neuropathological findings in the first 74 patients, and the correlations between these findings and various clinical, genetical and aetiological observations ; hitherto such correlations have been studied only by the Guy’s-Rlaudsley group (e.g. Cauanagh & Meyer 1956, Falconer & Serafetinides 1963, Falconer et al. 1961, Falconer & Taylor 1968, Dauidson d? Falconer 1975, Engel et al. 1975).

PRESENT INVESTIGATION CASE MATERIAL The present material comprises the first 74 patients with drug-resistant temporal lobe epilepsy, who during t h e period 1960-1969 were treated w i t h unilateral temporal lobe resection a t Rigshospitalet, Copenhagen. Neither before nor during the operation was a n y t u m o u r o r gross vascular malformation recognized in any

of the patients. All patients suffered from psychomotor and/or focal seizures originating from the temporal lobe, and 55 of them also had grand mal. Their cpilepsy was extremely severe and preopcratively all were socially handicapped due t o frequent and severe seizures and/or psychiatric disturbances. I n all patients a unilateral o r predominantly unilateral spike-discharging temporal focus was rcvealed through routine EEG scalp recordings including sleep recordings or through recordings with sphenoidal electrodes. The operation consisted of an anterior temporal lobectomy, usually estcnding 5.5 to 7 cm backwards to the vein of IAabbC.Where this vein could not he used f o r reference, the line of resection was 6 cm behind the pole of the temporal lobe in a dominant hemisphere, and 7 cm in a non-dominant. All operations but c ~ n ewere performed by the same surgeon ( K . V a e r n e t ) , who followed the principles laid down a t the Guy’s-Maudsley Hospital by Falconcr ( F a l c o n e r at al. 1955, Falconer 1965), resecting the tip of the temporal lobe en bloc including the mesial structure so that the whole specimen was available for histological examination. The present series consists of 43 males and 31 females. At the time of the operation the ages of the patients ranged from 4-54 years, including 1 4 of 15 years or younger. The median postoperative follow-up periud was 5.1 years. In 60 of the patients the preoperative duration of epilepsy was more than 4 years. A retrospective follow-up investigation was undertaken in 1970-1971, and covered various clinical, genetical, aetiological, social, psychological and electroencephalographical aspects (Inge Jensen 1975 b, c, 1976 a, h, c, Inge Jenscn & S e e d o r f f 1976, lnge Jcnsen h Vaernet 1976).

Table 1 . E f f e c t of temporal lobe resection on seizures correlated to psflchiatric status at f o l l o w - u p .

Psychiatric s t a f u s Normal (pre- and postop.) (only postop.) Abnormal markedly improved improved unchanged/deteriorated (abnormal preop.) (normal preop.) Total

No seizures

Marked reduetion

Some reduction

change

4 11

2 4

0 0

0 1

0 0

6 8% 16 22%

13 3

5 1

1 1

1 0

0 0

20 5

27% 7%

11 3

3 0

2 1

2 1

4 0

22 5

30% 7%

5 7%

5 7%

4 5%

74 100%

45 61%

1 5 20%

Death

Total

The overall effect on scizures of the operation was (Table 1) : 61 per cent had no more seizures; 20 per cent had their seizure frequency reduced by at least 75 per cent; the remaining 19 per cent (including the four who died) had no or little reduction of seizure frequency. Table 1 also indicates t h a t unilateral temporal lobcctomy also may improve psychiatric disorders. Before operation only 12 per cent were psychiatrically normal; a t follow-up this applied to 30 per cent.

KEUIIOPATHOLOGICAL TECIINIQLJE AND FINDINGS

I n order to obtain uniform descriptions all the primary microscopic sections were studied by the present authors, and in most cases the original slides were supplemented with new sections. T h e individual neuropathological diagnosis was made in blind by one of u s (L. K.) aiid only after the final classification was the neuropathology comparcd with the case history. T h e amount of tissue available for histological examination varicd widely. I n several cases the most medial structures were not present, as they had bcen removed by suction due to adhesions a n d / o r herniation below the tentorium. All the specimens were cut in frontal scctions aiid embcddcd in paraffin. T h e sections were stained with hacmatoxylin-cosin, by van Gieson’s, Einarson’s, and Kliiver-Barrera’s methods. Initially the neuropalhological findings were classified into the following ninc groups: 1) Small tumours, 2) Focal well-defined nonneoplastic changes; 3) Nodular gliosis; 4 ) Diffuse gliosis with satcllitosis and loss of nerve cells; 5) Perivascular infiltration with lymphocytes and histiocytes; 6 ) Questionable diffuse gliosis; 7 ) Questionable perivascular lymphocytic a n d / o r histiocytic infiltration; 8 ) No abnormality; and 9) Sequelae of a previous iatrogenic insult (operation).

1)

Small Tuinours (case nos. 11, 47, 54 and 74)

This group includcd a total of four small tumours, which had not been recognized macroscopically a s tumours. I n two cases, however, small intracerebral cysts were obscrvcd when the tempera1 lobe was cut. Case no. 11, oligo-astrocytoma (Kernohan type I ) , localized to the uncits and reaching t h e t i p of the temporal horn. It was composed of a mixture of oligodendroglial a n d astrocytic cells without nuclear polymorphism ; small calcospherites were situated between these cells (Figure 1 ) . Case no. 47, cystic astrocytoma (Kernohan type I), composed of fihrillary astrocytic t u m o u r cells without nuclear polymorphism. When the temporal lobc w a s cut a small cyst, localized to t h e tip, was found (Figure 2). Case no. 54, ganglioma. T h e tumour was composed of ependgmal and/or astrocxtic cells; between these cells gangioid cells w i t h distinct nucleoli and Kiss1 granules were observed (Figure 3 ) . Case no. 74, fihrillary and cystic astrocytoma (Kernohan type I ) , cornposed of astrocytic cells with uniform nuclei and numerous fihrils. Small cysts, some Roscnt h a l fibres, and small calcospherites were also observed.

395

396

2)

Focal W e l l - d r f i n c d hron-~zeoplrrslicClmn~gcs(case no\. 3, 4, 17, 23, 27, 31, 51, 6 7 31ld 7 2 )

This g rou 1, conil)r i w s 11 i n c (1 iff ercn t 11e I I r op a t h ol og i c a1 I c s i ( ) n 4 : Vn scular malformation, porcnccphaly, athcrosclerosis in llic i i n c i i s , sequclac of toxoplasniosis, cortical dysplasia, hctcrotopia o f ncrve cells, meningoccrehral scar, eiicc~~halornalaci~i (seqiiclac of a 1 ) l : t t i o i i of :i mcningeoma) and cystic gliosis. Case no. 5, artcriovcnoiis malformation. 'Jhe lesion \vas not recojinizctl ni:ic'roscopically, probably due t o its s m a l l extent; i t w a s localized to the siipcrfici:il parts of t h e cortex a n d to the leptomeninges. The vessels \vei-c siirroundcd 1)y diffuse gliobis. (:(IS(, no. 4 , porencephaly. Macroscopically t h e tcmporal lobe \vas atrophic. The cerebral h r i m was only a few m m thick a t o n e end of t h e specimcBn, anti 8 m m :it t h e other. hlicroscopically there was m a s s i l c cortical atrophy with almost tl)t:il loss of nerve cells, pronoiinced cystic gliosis and proliferation of conncctivc tissue. (:use no. 17, atherosclerosis i n t h e I I I I C I I S . I n t h e uiiciis m:irlicdly hyalinizcd arteries \vcre ohservctl in t h e grey anti nrltitc mattc*r, togctlicr with slight depletion of nerve cells a n d slight diffuse gliosis. ( : m e no. 23, calcified focal meninjio-cnccp1i:ilitis iscquc.lnc of tiisoplnsmosis). hlacroscopically t h e area around thc t i p of tlie fcmporal horn a n d tlie cbntirc hippoc a mp a l gy rus w a s t r a n sf o r m c' tl t n a ycl 1ow-1v 13 it e, avasc 111:I r s i i h t :( ncc \vh ich w n s almost a s hard a s cartilage. The 1iistologic:il findings lverc pr.olifer:iting pilocytic astrocytcs, which were arrayed i n long streaks l)et\vc,cn siibpial :iud m o r e p r o f o u n d l y sit II at etl c alc i f i c a t i o n s, m a s sivc dcgen er at i on of o I i g( )(I c 11d rog1 i a i n t he \vh i t e

.

397

matter. Two y-cars p r i o r t o the lohectomy. tosoplasmosis had hcrn diagnosed 11y glandular biopsy (Figure 4). Case n o . 27, cortical tlysplasia. hIacroscopically nothing ahnormal l v a s noted. 'l'hcre were numerous very l a r g e nerve cclls, eloscly rcscml)ling pyramidal cells, confined t o t h e intermediary tcmporal g y r u s ; they had large nurlcoli, ahundnnt cytoplasm a n d Xissl granules in the periltaryon. The nerve cells w c r c arr:rngcd i n clnsters i n t h e cortex. B fcw were also found in t h e white mattcr. Cnscp no. 3.4, hetcrotopia of ganglion cells. BIacroscopically nothing nhnormal xvas noted. T h e histiological findings in t h e nucleus nmygdalac n e at rop h ic gn rig1ion cells, which were replaced by satcllitosis a n d clusters of glia cells. I n the remainder of t h e temporal lobe the cyto-architecture w a s normal a p a r t from a small area at t h e tip, where t h e stratification of t h e ganglion cclls w a s compromised; in the white m a t t e r numerous ganglioid cells were ohserved. These dislocated ganglion cells were surrounded h y proliferating glial tissue. (:ascp no. 5 1 , meningocerehral scar (scqiielae of cerehral contusion). Pronounced cicatricial changes a n d localized cortical atrophy in t h e resected remnant f r o m a previously lacerated temporal lobe w i t h intraccrehral hacmatoma. (,'use no. 67, cystic encephalomalacia, occupying t h e greatcr part of t h e temporal lobe. The onset o f psychomotor epilepsy following removal of a sphenoidal wing meningcoma h a d occurred 22 years previously to t h e temporal lohectomy. Cnsc no. 72, cystic gliosis. h1acrt)scopically t h e temporal lohe w a s completely atrophic, transformed into a cyst w i t h a t h i n \vall. The microscopical changes wcrc very massive, with destruction of nerve cclls, which were replaced hy proliferating glial cells. Calcifications were diffusely scattered throughout t h e tissue and pigmented histiocytes a n d proliferating \vessels werc ohserved il'igurc 5).

26

ACTA NF:l'ROI..

SCAND.

54, 5

398

3)

Norlulnr Gliosis (case nos. 16, 20, 29, 32, 11, 16 and 6 3 )

'I'his group includcs cases will1 nodular collections of cclls s c a t L c r c ~ i throughout t h e cortex and subpial tissue. Somc of the collcclions \vcrc rel:ited to blond vessels. They consisled mainly o f hisliocytic cclls atid prolifcrating glial elements, sometimes wi l h (1 is Iinc L shrub form :I Iion. No calcification was found in these areas. Slight pcrivusciilar inf'illratioii of lymphocytes and histiocylcs \vas ohserved in some palicnts (FiSurc 6 ) .

4)

Diffiisc Gliosis, Safelliiosis and I l c p l t ~ t i o nof Ganglion C c l l s (case nos. 2, 6 , 12, 13, 22, 25, 26, 28, 3 1 , 35, 38, 40, 15 und 50)

Depletion of ncrvc cells of varying degree was observed :is heiiig more pronounced in the medial structures. Apart from t h e loss of iicr\c cells there was a massive isomorphic gliosis, satellilosis, and areas i n which nerve cells had been rcplaced by glial cells. Proliferation of oligodcndroglia was observed in many cases. In some of the sprciincns a slight perivascular infiltration of lymphocyles and histiocylcs was nolc~l. Cases where this infiltration dominated have been classified us k)cIoi~ging to the following group.

399

5)

P eri nascdar I,yniphocylic arid Ilisliocyl ic Iiifilfrcrf ion (case nos. 19, 21, 24, 3 5 , 311, 41, 62, 68, 71 ant1 76)

I n thesc C ~ S C Sa massive pcrivasculnr infillralion o f Iyiil)hocylc\ ant1 histiocytcs w a s observed. Alany of the hisliocylic cells coiil:iincti a yellowish pigment which was colotiretl rcd w i t h S~idnn111. 111 adtlilion sonic of the sections also showed gliosis indicaling loss of I I C I I I ' O I I S . Thcsc changes wcre diffuse and cvciily dislrihutccl.

ti)

Questionable Gliosis (case nos. 5, 18, 3 0 , 36, 3 7 , 43, 4!1 ant1 5 5 )

I n these palicnts gliosis was suspectcd as dcscri1)cd in group 4, b u t the findings c o d d not lie characterized a s definitely :il)normal. 7)

Questionable Perivascular Infilfraliorz (case nos. 9, 10, 13, 42, 73 and 7 7 )

I11 these patients slight perivascular infillration of lyniphocytcs and histiocytes was ohscrveti; the changes wcre regarded as insignificant, and the patients were placed in this group in accordance wilh lhe criteria riicritioncd in group 6.

8)

N o Definite Structural AbriorniaIifrJ (case nos. 1, 7 a n d 8 )

400 9)

Sequelae o f a Previous Iatrogenic Insult (case nos. 15, 48, 52, 53, 56, 57, 58, 60, 64, 65, 70, 75 and 78)

I n these patients marked changes, such as loss of neurons, satellitosis, subpial gliosis, a n d / o r pcrivascular infiltration of lymphocytes and histiocytes were found; but a s stereotactic coagulation of the amygdaloid nucleus or another iatrogenic insult in this area had been performed prior to the temporal lobe resection, it could not bc decided whether these abnormalities were related to the epilepsy or caused hy the previous operation. These neuropaihological findings were correlated with various clinical, hereditary, acliological, social and other aspects. I t turned out that some of the ncuropalhological groups had approximately the same correlations to these parameters ; acordingly, we decided to combine them, which resulted in five major groups, as shown 1)elow:

1)

2) 3) 4)

5)

Focal lesion (small tumours and focal xvell-defined non-neoplastic changes). Gliosis (nodular gliosis and diffuse gliosis). Perivascular infiltraiion of lymphocytes antilor histiocytes. Equivocal changes (questionable gliosis, questionable perivascular infiltration, and n o abnormality). SequeIac of previous iatrogenic insult.

NEUI~OPATIIOI.OGICA1, COIiHEI,A?'IONS TO TIIE CLINICAI, FINDINGS

Operative Findings A t operation the temporal lobe w7as described by the stirgeori as definitely abnormal i n 46 patients, and as questionably abnormal in further 23 patients. I n seven patients the findings were either normal o r described as a n anatomical variant. I n 49 of the 74 patients the medial p a r t of the resected temporal lobe appeared sclerotic and tough on palpation and/or was herniated below the tentorium. T h e remaining macroscopic abnormalities were : one tumour-like lesion, which histologically proved to be gliosis, three cysts, seven localized atrophies, and seven cases with sequelae of previous operations. By comparing the macroscopic observations with the histological findings it was not possible to find any reliable correlations except in the few cases with very marked macroscopic changes.

Table 2. NeuropatlioloyU correlated t o effect o f o p e r a t i o n o n seizures and psychiatric s t a t u s a t f o l l o w - u p . 72 p a t i e n t s w i t h a f o l l o w - u p period o f o n e !]ear or more. Operative results

1

Psychiatric status

Good improved Focal lesions Gliosis Perivasc. infiltr. Equivocal changes Iatrogenic insult

16 8 13 12

11 92% 80% 80% 76% 9270

1 8% 4 20%

Total

60 83%

12 17%

2 20% 4 24% 1 8%

1

1

I

No change/ deteriorated

9 75yo 13 65% 5 50c/, 6 35% 9 69%

3 7 5 11 4

42 58%

30 42%

Total

12 1 7 % 20 28v0 10 14%

25% 35% 5070 65% 31%

1 7 2470 72 100%

1

13 18%

Surgical Results Table 2 is a condensed survey of the correlations between the neuropathological findings and the effect of the operation on seizures and the psychiatric status a t the follow-up. T h e term “good operative result” signifies an abolition of seizures or reduction in seizure frequency by a t least 75 per cent. T h e two patients who died in the immediate postoperative period from a pulmonary embolism and from meningitis have been excluded ; their neuropathological diagnoses were gliosis and porencephaly, respectively. Apparently the final result is better the more specific the histological abnormality; with regard to relief from seizures this is merely a trend, while the difference a r e statistically significant a t the 5 per cent level with regard to the psychiatric normalization a n d / o r iinprovemcnt ( R a n k sum test, t = 2.22).

T a b l e 3. N e u r o p a t h o l o y y correlated t o preoperative t!jpes o f seizures.

Psychomotor

Focal lesion Gliosis Perivasc. infiltr. Equivocal changes Iatrogenic insult

Total

1 5 1 5 2 14 19%

rsycnomoror and/or focal

1

9

3

8 7 9

0 0 1 5 7%

5 38 5170

2 5 2 3 5

1 7 237‘

13 21 10

17 13 74 100%

402

Clinical Aspects of Epilepsy As shown in Table 3, n u correlations can be found between the neuropathological findings and the preoperative types of seizures. The neuropathological findings in the seven patients who had expcricnccd one o r more febrile convulsions covered almost all the groups : three cases of gliosis, two cases of perivascular infiltration, one equivocal lesion, and one previous coagulation. A further 12 patients had before the onset of their chronic epilepsy experienced a solitary epileptic seizure in close connection with a cerebral infection, a severe head injury, or a uraemic crisis. The neuropathological findings in these patients were nodular gliosis, perivascular infiltration, and Coagulation, with an equal distribution over the groups. Only six patients experienced the onset of their epilepsy in status. Four of these had changes from previous amygdaloid coagulation, and the other two gliosis and perivascular infiltration.

Table 4. Neuropathology correlated to length of postoperative seizure-free period until recurrence of seizures.

Focal lesion Gliosis Perivasc. infiltr. Equivocal changes Iatrogenic insuIt

>

_ 20

years

years

years

years

years

2 6 2 2 6

6 3 3 4 2

0 4 4 4 1

4 4 1 5 3

Focal lesion Gliosis Perivasc. infiltr. Equivocal changes Iatrogenic insult

18 24%

Total

Total

0-4

18 24%

13 18%

17 23%

Table 5 indicates that no specific conclusions can be drawn when correlating the neuropathological groups to the age at onset of epilepsy. The observations on the preoperative duration of epilepsy and on the age at operation display the same diffuse scatter. A s a curiosity, the following might he mentioned: If the gliosis group is split into the primary groups “nodular gliosis” and “gliosis and/or satellitosis” (“mesial sclerosis”) and these are compared to the group with perivascular infiltration, the third group with definite diffuse and disseminated changes, i t is observed that the patients with nodular gliosis have onset of their epilepsy a t an early age, that they have a relatively short preoperative duration of epilepsy, and consequently

0

’:j

NODULAR GLlOSlS PERIVASC. INFILTR.

MESLAL SCLEROSIS

2o

30

10

0-4

5 - 9 10-14

1-19 20-24 25-2930-34 235 YEARS

Figure 7. Neuropathological findings correlated to age at operation.

404 are young a t the time of the operation; on t h e other hand, “the mcsial sclcrosis” group were old a t onset, had a long duration of epilepsy, and were relativeIy old a t operation, while the patients with perivascular infiltration constitute an intermediary group. These findings are illustrated in Figure 7.

Heredity An examination of the genetic factors revealed a massive heredity burden in 76 per cent of the patients, not only regarding epilepsy, but especially regarding other neurological diseases or major psychiatric disorders. W h e n correlating the neuropathological findings to various genetic aspects n o statistically significant conclusions can be drawn even if 86 per cent of the patients with gliosis have a predisposition to the neurological and/or psychiatric diseases as compared to 68 per cent of the remaining patients without previous iatrogenic insults.

Aetiological Factors Records of the possible aetiological factors revealed a n increased frequency of birth injuries, post-natal head traumas, and cerebral infections as compared to the general population, at the same level as recorded in other surveys of epileptic patients. An investigation of the outcome of the mothers’ previous pregnancies and of complications in the actual pregnancy disclosed a markedly increased incidence of abnormalities, this also correlates to other epileptic surveys. Only 12 patients had no recorded non-genetic aetiological factor. A survey of the neuropathological findings correlated l o the nongenetic aetiological factors is recorded in Table 6. Apart from a positive correlation between the occurrence of perivascular infiltration and a positive history of infection, no correlations could be found between the neuropathological findings and possible aetiological factors. Of the 10 patients with perivascular infiltration seven had a history of encephalitis and/or meningitis prior to the onset of their epilepsy, and one without known aetiological factor had suffered from recurrent iritis. To these must be added a patient from the focal lesion group, who had toxoplasmosis verified by biopsy. This gives a n incidence of 82 per cent infections in the case histories of patients with perivascular infiltration (9/11) as compared to a n incidence of 16 per cent in the remaining patients, regardless of whether or not patients with previous iatrogenic insults are included. These differences are highly significant a t the 0 per cent level ( P = 0.0000). Gliosis o r equivocal changes were the neuropathological diagnoses in 10 of the 12 patients without recognized aetiological factors, as com-

5 3 3 4 2

17 23%

2 7 2 3 2

16 36%

Focal lesion Gliosis Perivasc. infiltr. Equivocal changes Iatrogenic insult

Total

i.e. including all pcrinatal complications.

Actual

Previous

P r e n a t a l aetiology. .4hnormality in pregnancy

I 28 38%

9 11 2 1 5

Birthl)

26 35%

5 7 2 6 6

Trauma

18 24%

1 5 7 1 4

Infection

7 9%

0 3 2 1 1

convulsion Fchr.

P o s t n a t a l aetiology

3 470

1 1 0 0 1

laneous Miscel-

Table 6 . Neuropathological f i n d i n g s correlated t o uarious non-genetic aetiological factors.

12 l S 7 0

None

74 l o o y o

13 21 10 17 13

Total

cn

0

406 pared to 28 of the remaining 62 patients. This difference is statisticallly significant a t the 5 per cent level ( P = 0.0312). Many patients with focal lesions o r gliosis have a recorded birth i n j u r y in their case history, but neither in this case, nor when correlating the neuropathological findings to single perinatal aspects such a s maternal age, parity, course of delivery, birth weight, o r postnatal complications, a r e any statistically significant differences observed.

Miscellaneous Neither statistically significant differences nor possible trends are observed when the neuropathological findings a r e correlated to : 1 ) side of operation (right versus left, dominant versus non-domi n a n t ) ; 2 ) handedness; 3) milestones; 4 ) intellectual level; a n d 5 ) various social aspects such as : birth place, rank, social distribution of parents a n d patients, schooling, further education, and working capacity pre- and postoperatively. W i t h regard t o the presence of psychiatric disturbances before the onset of epilepsy and in the preoperative period, no differences can be found between the various neuropathological groups, whereas the 11 patients, who were characterized preoperatively as psychotic were unevenly distributed: 39 per cent of the patients with focal lesion (5/13) were psychotic as compared to 10 per cent of the remaining patients ( 6 / 6 1 ) , the difference being significant a t the 5 per cent level ( P = 0.0394). This finding is i n full accordance with TayZor (1975).

DISCUSSION

Surveys have been published on unilateral temporal lobe epilepsy a s a treatment of drug-resistant temporal lobe epilepsy from a total of 34 neurosurgical clinics all over the world. Information concerning neuropathological abnormalities is available from about one-third of these clinics, and even fewer record correlations of histology l o surgical results and other clinical aspects. Earle et al. (1953), in their report on the first 157 patients operated on a t the Montreal Neurological Institute 1928-1950, found gross and microscopic abnormalities i n all cases. I n the vast majority of these patients one of the main indications for operation was “the presence of macroscopically abnormal brain localized to the temporal lobe”. I n 63 per cent the abnormality consisted of sclerotic areas in the inferior and medial temporal lobe cortex including the uncus, the hippocampal gyrus and the first temporal gyrus. Histological examination revealed

a ::

' d m

R

Y

0,

z 3

B 0 c,

d

P

c I .

rn

z

Falconer & Taylor (1968) 1 2

0

Falconer et al. (1964) 1 2

0 0

L

CL

m y

W N

t.

Haberland (1958)

0

D

Maspes & Marossero (1953)

i

Currie et al. (1971) 1 3

N

c,

Davis (1963)

ca

Morris (1956)

ca

Scharenberg (1957)

0

a

Bhatia & Kollevold (1976)

cn

w

W

N

N

1

Van Buren et al. (1975) 3

4 N

Dill & Gullota (1970)

ED

Y

CL

Present investigation

3

Shih et al. (1966)

30

Goldensohn (1962)

00

3

6

LOP

a n increase in fibrous astrocytes in the grey and white matter, thickening of the pia, and focal loss of neurones and nerve fibres. They concluded that these findings suggested t h a t the cause was compression o r anoxia during birth or infancy. I n the remaining 57 cases they found evidence of postnatal injury, intracranial infection, o r neoplasm in the temporal region. I n the earlier days, when temporal lobectomy was performed on the basis of EEG criteria alone, the presence o r absence of macroscopic abnormalities was considered a factor of prognostic significance (Meyer et al. 1954, Falconer et al. 1964, Paillas 1958, Haberland 1958, Green & Scheetz 1964, Green 1967). These authors all agreed that the results of surgery were better when the excised specimen contained a definite macroscopic lesion. On the other hand, Morris (1956) staled t h a t the absence of gross abnormality did not impair the operative result. T h e present investigation would seem to support the latter view. T h e outcome of the histological examinations varied grcatly in the various series, as is apparent from Table 7. Most of the surveys did not attempt to make any correlation to the final surgical outcome (Haberland 1958, Ijhatia & Kollevold 1976, Scharenberg 1957, Davis 1963, Currie et al. 1971, Maspes & Marossero 1953, Van Uuren et al. 1975, Shih et al. 1966). By f a r the most elaborate neuropathological studies o n the resected temporal lobe specimens have been performed by the Guy’s-hfaudsley group, during the first years under supervision by Meyer, and later by Corsellis at the Runwell Hospital, Essex. Numerous significant contributions covering various aspects have been published (e.g. Meyer et al. 1954, Falconer et al. 1964, Falconer & Taylor 1968, Corsellis 1970, Tayor et al. 1971). Corsellis (1970) concluded that the trend was for about one-quarter of the specimens to show a circumscribed focus of abnormal, but not reactive, tissue. About one-half showed the classical Ammon’s horn sclerosis, a few gave evidence of cortical scarring, and in about one-fifth on the cases there was nothing conclusively abnormal. Falconer et al. (1964) concluded that the results of surgery were better where the excised specimen contained a definite lesion, best when the lesion was a small cryptic tumour or mesial sclerosis, a n d least satisfactory when only equivocal lesions were found. A conclusion with which the surveys by Goldensohn (1962), Dill & Gulotia (1970), and the present investigation essentially are in accordance. Bengzon et al. (1968), at the Montreal Neurological Institute, compared a group of “surgical successes” t o a group of “surgical failures”, and reached the same conclusion. They found that the majority of patients in both groups had some histological abnormality, with the predom-

inant abnormality being gliosis or sclerosis. However, there was a greater predominance of histological abnormality in the group of “successes” (viz. 92 per cent) t h a n in the group of “failures” (74 per cent). Falconer & Taylor (1968) found that mesial sclerosis was the most common pathological lesion encountered and that removal of this scar tissue was associated with a particularly favourable postoperative prognosis both a s regards relief of epilepsy and improved social a d j ustment. T h e distribution of the ncuropathological abnormalities in the Danish material is to a great extent in accordance with that recorded by V a n B u r e n e f a / . (1975), including fewer cases of mesial sclerosis than observed by the Guy’s-Maudsley group. This might be due to the operative technique, as the mesial structures in the prescnt investigation were removed by suction in the cases in which adhesions or herniations below the tcntorium niade this advisible, a procedure routinely performed a t the NINDS. T h e selection of the patients also influences the distribution of the ncuropathological findings, as, for example thc inclusion of a majority of patients with epilepsy of long standing will tend to increase the incidence of gliosis/mesial sclerosis. I n the series from the Guy’sdIaudsley Hospital almost a quarter of the specimens showed a circumscribed focus of abnormal, but not reactive tissue, in the following denoted small tumours. The composition of these tumours have been described in detail by Cauanacgh (1958) and by Falconer & Cavanagh (1959). Similar nodular collections of cells have been encountered in about the same proportion in the temporal lobectomy series of the Montreal Neurological Institute (Cavanagh 1958). I n the present investigation the share of small tumours is less t h a n the British one, but approximately of the same ratio a s that of other published surveys. We can only explain this by referring to the selection of patients. T h e most common neuropathological abnormality encountered in temporal lobe epilepsy is the lesion known as Ammon’s horn o r hippocampal sclerosis. Already by 1825 Bouchet arid Cazauvieihl reported that a t necropsy in nine out of 18 chronic epileptics the hippocampus was small, indurated, o r otherwise damaged (Falconer 1974). Pf1eqc.r (1880) i n his post mortem examinations of epileptic patients found a positive correlation between the extent of the macroscopic abnormality and the severity and duration of the epilepsy. T h e lesion was first described histologically in 1880 by Sommer. It is characterized by a severe, patterned, loss of nerve cells in the hippocampus, which is accompanied by fibrous gliosis, and possibly by shrinkage and atrophy (Corsellis 1970).

410 Post-mortem clinico-pathological studies by Spielineyer ( 1930), Stauder (1936), Sano & Malarnud (1953), Peiffer (1963), and Margerison & Corsellis (1966) all agree that sclerosis of the Amnion’s horn and the adjacent grey matter is present i n the brain of many of the patients with long-standing epilepsy who die in hospital. However, although the hippocampus is the area most often affected, the damage often extends to other parts of the brain, viz. thalamus, cerebellum, etc. Marqerison & Corsellis (1966) noted that hippocampal sclerosis was present in all their 22 patients with temporal lobe cpilcpsy, and only in five of 1 3 epileptics without temporal lobe seizures. T h e pathogenesis of the hippocampal sclerosis has been and is still a subject of discussion. Spielineyer (1930), and in agreement with him, Stauder (1936), Marx & Heppner ( 1 9 6 0 ) , and Peiffer (1963) concluded t h a t the damagc developed as a sequel to the epileptic attacks, probably caused by the hypoxacmia. Penfield (EarZe et al. 1953), who called the abnormality “incisural sclerosis”, and Gastaut ( 1954-55), who named i t “pararrhinal sclerosis”, both claimed that Ihe hippocampal sclerosis was primary to the epilepsy, and that it was caused by a herniation of the temporal lohc below the tentorium during the head moulding of parturition, leading to compression of t h e anterior choroidal and posterior cerebral arteries ( Penfield), o r by a postnatal head injury ( Gastaut). T h e third major hypothesis is advocated by Falconer (Falconer 1968, 1970, 1971, 1974, Falconer & Serafetinides 1963, Falconer & Taylor 1968, Davidson & Falconer 1975), he named the abnormality “mesial temporal sclerosis” and concluded that two pathogenetic factors appeared to stand out, namely, a family history of epilepsy, and a history of severe febrile convulsions. One intention of this investigation was to try, by elaborate neuropathological examination and careful registration of possible aetiological factors, to supply further information regarding aetiology and neuropathology. Unfortunately, t h e most mesial parts of the temporal region in several specimens had been coagulated or were not present, due to removal by suction, thus preventing a n y statistically valid conclusions. However, our impression is t h a t more patients with a long duration of epilepsy exhibit hippocampal sclerosis, than do patients with a short duration of epilepsy; we also found that a comparatively large number of the patients with gliosis had a positive family history of severe psychiatric disorder. On the other hand, on the basis of the very low incidence of febrile convulsions, i.e. seven out of 7-2 patients, we feel justified i n concluding t h a t the pathogenesis of temporal lobe epilepsy is not primarily a mesial temporal sclerosis caused by febrile convulsions.

41 1 T h e incidence of lymphocytic and/or histiocytic perivascular infiltration in the Danish material is at the same level as recorded by Haberland (1958) and by V a n R u r e n et al. (1975), but, as appears from Tablc 7 , f a r higher t h a t that found in the other materials. This variance could be due to the selection of patients. As staled previously, in the present investigation the presence of perivascular infiltralioii is closely correlated to a history of a cerebral infection. The notion of equivocal changes is a challenge to the ncuropathologist as well as to the clinician, and a wide dispersion between thc various surveys is noted, with the incidence ranging from 0-58 per ccnt. As stated by Corsellis (1970), no definite structural abnormality can be found in about one in five specimens; the equivocal changes lie in the borderland betwccn normal and abnormal, i.e. along a continuum, and the point a t which abnormality occurs cannot be more than arbitrary. Very few surveys correlate tlie neuropathological findings lo the surgical results or to social rehabilitation, and statistically valid conclusions cannot be drawn from a n y of the surveys. I n the various reports from the Guy’s-Maudsley group, mentioned previously, Falconer tends to conclude t h a t patients with a pure mesial temporal sclerosis have the best postoperative prognosis regarding relief from seizures ; however, in the latest survey ( E n y e l et al. 1975) a specific medial focal lesion is found to have a better prognosis t h a n the mesial sclerosis, which again has a better prognosis t h a n a cicatricial or a more nonspecific lesion. Morris (1956), Dill & Gullota (1970) and Goldensohn (1962) express the opinion that the more focal a n d circumscribed the lesion, the better the prognosis. This same impression, but based on gross abnormalities, is advanced by Morris (1956), Paillas (1958), Haberland (195S), and Green & Scheetz (1964). A s stated previously this investigation supports the point of view that the presence of a focal and circumscribed lesion favourably influences the surgical prognosis, not only regarding abolition of or reduction in seizure frequency, but also, and more pronounced, regarding psychiatric normalization and/or improvement. I n the present investigation few conclusive correlations have been disclosed between the neuropathological findings on one hand and tlie various clinical aspects on the other. This may to a large degree be due to the overall good surgical results attained within all the neuropathological groups. From the present study, i t is evident that a careful selection of patients on clinical criteria is prognostically more important t h a n the neuropathological findings.

412 REFERENCES Bailey, P. (1954) : Betrachtungen iiber die chirurgische Behandlung d e r psychomotorischcn Epilepsie. Zhl. Nenrochir. 14, 195-206. Bailey, P. & F. A. Gibbs (1951): T h e surgical treatment of psychomotor epilcpsy. J. Amer. med. Ass. 145, 365-370. Bengzon, A. I