323 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2003.013706 on 23 January 2004. Downloaded from

SHORT REPORT Collateral damage, a potential source of cognitive impairment after selective for control of mesial temporal lobe C Helmstaedter, D Van Roost, H Clusmann, H Urbach, C E Elger, J Schramm ......

J Neurol Neurosurg Psychiatry 2004;75:323–326

caused by the surgical approach. This turns out to be a Background: Highly selective epilepsy surgery in temporal potential source of postoperative cognitive impairment.6 lobe epilepsy is intended to achieve freedom at a lower cognitive risk than standard en bloc resections, but bears the risk of collateral cortical damage resulting from the METHODS surgical approach. The study originally comprised 38 patients with left hemi- sphere language dominance who had been randomly Objective: To investigate cortical damage associated with assigned to selective amygdalo-hippocampectomy for mesial selective amygdalo-hippocampectomy (SAH). temporal lobe epilepsy, using either a transsylvian14 or a Methods: 34 epileptic patients were evaluated. They were transcortical approach.15 Informed consent was obtained randomly assigned to SAH using either a sylvian (9 left/10 from the patients for randomisation and the study was right) or a transcortical surgical approach (5 left/10 right). approved by the ethics commission of the university clinics, Postoperative MRI signal intensity changes adjacent to the Bonn. In our centre, SAH is generally indicated where there is approach were correlated with performance changes in a clinical diagnosis of mesial temporal lobe epilepsy and serial word and design list learning. suspicion of mesial temporal sclerosis or atrophy as the sole Results: Losses in verbal learning and recognition pathology. were positively related to signal intensity changes, indepen- Transsylvian amygdalo-hippocampectomies are done

dent of the side of the resection, the surgical approach, or the through a pterional craniotomy of approximately 5 cm in copyright. extent of the mesial resection. Losses in consolidation/ diameter. After microsurgical dissection of the sylvian fissure retrieval (memory) were greater after left sided surgery. (2.5–3 cm), the temporal horn of the lateral ventricle is Losses in design learning were related to right sided surgery entered through the temporal stem, thus enabling resection and signal intensity changes. Seizure outcome (85% seizure- of the mesial structures (amygdala, hippocampus, parahip- free) did not differ depending on the side or type of surgery. pocampus). The collateral sulcus is the intended lateral Conclusions: Collateral damage to cortical tissues adjacent resection border, while the area of maximum brain stem diameter is the dorsal border. to the surgical approach contributes to postoperative verbal In transcortical amygdalo-hippocampectomies only the and figural memory outcome after SAH. Controlling for approach to the temporal horn is different: a 3 cm collateral damage may clarify the controversial memory craniotomy is centred on the projection of the middle outcomes after SAH reported by different surgical centres. temporal gyrus. After a 2 cm corticotomy, the temporal horn is approached through the white matter with the aid of http://jnnp.bmj.com/ neuronavigation, followed by a hippocampal resection, as described above. espite advances in the pharmacological management of Three patients after left amygdalo-hippocampectomy had location related epilepsy, remain refractory to to be excluded from the because their magnetic resonance medical treatment in approximately 15–30% of D 12 imaging (MRI) results were not available for review. One patients. For these patients epilepsy surgery can be a 3 patient developed a postoperative space occupying intra-axial successful treatment option. Epilepsy surgery, however, haematoma after left amygdalo-hippocampectomy, which bears an undeniable risk of causing additional cognitive on September 25, 2021 by guest. Protected 4 was removed surgically. This patient was excluded because of impairment. Temporal lobe resections still represent the persisting dysphasia and mild . There was no most frequent type of surgery and, accompanying progress in mortality in the series. Minor complications which did not neuroimaging and electroencephalographic monitoring, there lead to exclusion were evident in two patients with signs of is a ‘‘new wave’’ in epilepsy surgery away from standard en meningeal inflammation, one patient with an asymptomatic bloc resections towards tailored and highly selective small choroidal , and one patient with some blood 56 approaches. Restricting the resection to already damaged in the resection cavity, which did not require specific and epileptogenic tissue was originally thought to spare treatment. Visual field defects (contralateral upper quad- 56 unaffected brain areas and their associated brain functions. ranopias), if present, were not encountered as complications. However, there have been contradictory findings relating to Thus 34 patients were evaluated for this study. Nineteen had memory loss after left selective amygdalo-hippocampectomy a sylvian (nine left, 10 right) approach, and 15 a transcortical 7–10 (SAH). The same is true of studies comparing the outcome approach (five left, 10 right). of selective surgery versus standard two thirds anterior temporal lobectomy.6 11–13 In this report we call to a factor that has not been ...... considered so far in discussions on cognitive outcome after Abbreviations: AVLT, auditory verbal learning test; SAH, selective selective epilepsy surgery—collateral damage to brain tissue amygdalo-hippocampectomy; FLAIR, fluid attenuated inversion recovery

www.jnnp.com 324 Helmstaedter, Van Roost, Clusmann, et al J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2003.013706 on 23 January 2004. Downloaded from

Verbal learning and memory were assessed preoperatively quadrigeminal plate (fig 1A, 1B, left side); and second, the and three months after surgery by parallel versions of a serial extent of post-surgical brain tissue signal changes along the word list learning test, which requires learning and immedi- transsylvian or transcortical path to the mesial temporal lobe ate recall of a word list (A) of 15 words over five trials, (‘‘collateral damage’’), quantified by the mean diameter on delayed recall after distraction (learning a second list (B) in coronal T2 weighted or FLAIR fast spin echo images (fig 1A, one trial) and after a delay, and recognition of list A items 1B, right side). ‘‘Collateral damage’’ was considered on the from among alternatives (German pendant of the auditory one hand as a continuous variable, ranging from 0 to 22 mm, verbal learning test (AVLT)16). The chosen measures of and on the other as a dichotomous variable. Defining a ‘‘learning over five trials,’’ ‘‘loss of learned items in delayed diameter greater than the median (10 mm) as a significant free recall,’’ and ‘‘recognition memory (correct minus , 15 of the 34 patients were classified as showing errors)’’ differentially assess aspects of verbal short term/ greater collateral temporal cortical damage, and 19 as having working memory and verbal long term consolidation/retrie- lesser or no such damage. val, and reflect more temporo-cortical or temporo-mesial functioning, respectively.17 Figural memory was assessed using a revised version of a serial design list learning test Statistics which requires learning and reproduction of nine abstract Data were analysed by repeated measurement analysis of designs.18 Each design consists of five lines of equal length, covariance (MANCOVA), which included preoperative/post- and the designs have to be reproduced using five wooden operative memory testing as the ‘‘within subject’’ factor, and sticks. Learning over four trials was chosen as the dependent side of surgery, surgical approach, and the diameter of the measure. This test has been shown to be sensitive to right MRI signal intensity changes (dichotomous variable) as temporal lobe function and surgery.19 20 between subject factors. The extent of the mesial resection High resolution MRI was undertaken a week after surgery, was controlled by covariance analysis. A prediction model of using a 1.5 Tesla system (Gyroscan ACS-NT, Philips Medical memory outcome (difference score: post2pre) was calculated Systems, Best, Netherlands). Results of post-surgical MRI by backward multiple regression analysis (p for removal (axial and coronal FLAIR and T2 weighted fast spin echo ,0.1). Regression analysis took into consideration baseline images) were assessed by two independent examiners with performance, side of surgery, surgical approach, seizure respect to, first, the extent of hippocampal resection (defined outcome, age, age at the onset of epilepsy, the degree of the negatively by measuring the distance from a line through the mesial resection, and the degree of signal intensity changes dorsal resection border to a line along the dorsal border of the (continuous variable). copyright. http://jnnp.bmj.com/ on September 25, 2021 by guest. Protected

Figure 1 (A) T2 weighted fast spin echo images in axial (left) and coronal (right) orientation after left amygdalo-hippocampectomy (transsylvian approach). The axial slice shows the measurement of the extent of hippocampal resection (211 mm). On the coronal slice only a small area of decent postoperative ‘‘damage’’ (9 mm in transverse diameter) can be seen adjacent to the sylvian fissure. (B) T2 weighted fast spin echo images in axial (left) and coronal (right) orientation after right transsylvian amygdalo-hippocampectomy with a much larger zone of postoperative alterations. The axial (left) image shows a similar extent of hippocampal resection (210 mm), but note the hypointense signal alterations in the right lateral temporal lobe. The quantification of ‘‘collateral damage’’ results in a 22 mm zone adjacent to the sylvian fissure.

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RESULTS The patient groups (transsylvian/transcortical) did not differ with respect to demographic variables (sex, age, intelligence quotient), clinical variables (age at onset, duration of epilepsy), seizure outcome (84% v 87% completely seizure- free), or the extent of the mesial resection (remaining hippocampus (mean (SD)), 1.8 (1.7) v 1.6 (1.8) cm). Surgical approaches were not associated with a different mean degree of ‘‘collateral cortical damage’’ (10 (7) mm v 9 (6) mm). With respect to verbal memory, multivariate analysis of variance revealed an effect of the MRI measure on postoperative memory change independent of the chosen approach (interaction effect: test repetition 6 collateral temporal damage, F = 3.4, p = 0.03). This effect was obtained only with respect to the more cortical aspects of verbal memory (learning/data acquisition, p,0.001; recognition memory, p = 0.05). In multivariate analysis of variance the Figure 2 Regression showing a significant relation between the extent observed interaction effect overshadowed the known effects (diameter) of the collateral temporal cortical damage indicated by postoperative magnetic resonance imaging signal intensity changes and of the side of surgery on verbal learning and memory. This the postoperative change in verbal learning, independent of the surgical effect became evident only in univariate analysis of variance approach and the side of surgery (r = Pearson’s correlation coefficient, and here only for verbal recognition memory (analysis of p = two tailed significance). Negative values on the y axis represent variance: F = 6.5, p = 0.01) (see also table 1). losses, positive values gains in the absolute number of words learned Differences between the surgical approaches only margin- over five trials. ally disfavoured the transcortical approach. Regression analysis showed that only the degree of signal intensity changes (t = 3.5, p,0.01) together with the preoperative (t = 3.0, p,0.01), with continuance of seizures (t = 2.6, baseline performance (t = 0.26, p,0.05) remained in the p,0.05), and with better baseline performance (t = 2.0, regression model and explained about 40% of the post- p,0.1). Together, these variables explained 48% of the operative change in verbal learning (F = 9.6, p,0.01). The variance in recognition memory change (F = 6.3, p = 0.001). respective correlation between the degree of signal intensity With respect to figural memory, multivariate analysis of changes and postoperative change in verbal learning is variance indicated a significant two way interaction (test shown in fig 2. Performance in the more mesial function of repetition 6 side of surgery, F = 5.2, p = 0.03) and a verbal memory consolidation/retrieval (delayed free recall) significant three way interaction (test repetition 6 side of copyright. was not affected by the degree of collateral damage, but in surgery 6collateral damage, F = 5.9, p = 0.02). Patients with multiple regression analysis the expected effect of the side of right sided surgery showed greater losses in design learning surgery became evident (t = 2.3, p,0.05); according to this, than patients with left sided surgery, particularly when there greater losses were observed after left sided surgery. Together was evidence of collateral cortical damage (table 1). with the baseline performance (t = 5.9, p,0.001), the side of According to regression analysis, right sided surgery surgery explained 54% of the variance in performance (t = 3.0, p = 0.005), better baseline performance (t = 22.0, changes in this measure (F = 18.1, p,0.001). Greater losses p = 0.04), continuing seizures (t = 2.1, p = 0.04), and older in recognition memory, which also reflects mesial and age (t = 1.7, p = 0.09) were predictive of greater losses in cortical aspects of memory, were observed after left sided design learning. Altogether the remaining variables explained resections (t = 3.6, p,0.01), with greater collateral damage 43% of variance. http://jnnp.bmj.com/

Table 1 Pre- and postoperative memory as a function of side of surgery and collateral damage

RTLE LTLE

CD2 CD+ CD2 CD+

Verbal memory* on September 25, 2021 by guest. Protected Learning Pre- 46.5 (10.3) 49.5 (14.2) 41.2 (8.4) 48.0 (7.5) Post 46.3 (9.0) 42.0 (14.0) 40.2 (9.8) 40.5 (8.9) Loss in delayed recall Pre- 2.3 (2.0) 2.8 (2.1) 4.0 (1.7) 2.6 (2.0) Post 3.6 (1.9) 2.3 (2.0) 4.8 (1.9) 4.7 (2.3) Recognition Pre- 11.2 (3.7) 11.0 (6.4) 9.4 (3.6) 11.1 (1.6) Post 11.1 (2.9) 14.6 (7.7) 8.5 (3.8) 4.1 (7.6)

Figural memory* Learning Pre- 10.7 (7.7) 14.6 (7.7) 12.2 (6.6) 13.1 (6.5) Post 9.9 (7.3) 9.3 (5.2) 10.8 (7.5) 17.5 (9.0)

Values are mean (SD). *Raw scores. CD+, collateral cortical damage .10 mm, CD2, collateral cortical damage ,11 mm; LTLE, left temporal lobe excision; RTLE, right temporal lobe excision.

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DISCUSSION D Van Roost, H Clusmann, J Schramm, Department of , Our results replicate the known specific effect of left sided University Clinic Bonn selective surgery on verbal long term consolidation/retrieval, H Urbach, Department of Radiology/Neuroradiology, University Clinic which appears to be associated with left temporo-mesial Bonn structures.10 11 17 Right sided surgery, in contrast, had a Competing interests: none declared negative effect, particularly on design list learning. SAH in patients with mesial temporal lobe epilepsy with hippocam- Correspondence to: Dr C Helmstaedter, University Clinic of Epileptology Bonn, Sigmund Freud Str 25, 53225 Bonn, Germany; pal sclerosis as the sole pathology was originally intended to [email protected] spare the unaffected temporal cortex and associated func- tions. However, as in our recent study on SAH,10 we observed Received 4 March 2003 not only losses in verbal consolidation/retrieval but also in In revised form 5 June 2003 verbal learning and recognition memory. In addition a Accepted 9 June 2003 significant correlation between collateral cortical damage and changes in verbal learning and recognition was evident, REFERENCES indicating an effect of temporal cortical damage from the 1 Mattson RH, Cramer JA, Collins JF, et al. Comparison of carbamazepine, surgical approach, particularly on the short term and working phenobarbital, phenytoin and primidone in partial and secondarily memory aspects of verbal memory performance. The effect on generalized tonic clonic seizures. N Engl J Med 1985;313:145–51. verbal learning appeared to be non-specific, as it was 2 Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342:314–319. observed independently of the side of surgery and the 3 Wiebe S, Blume WT, Girvin JP, et al. A randomized, controlled trial of surgery surgical approach (transsylvian v transcortical). This is for temporal-lobe epilepsy. N Engl J Med 2001;345:311–18. consistent with findings that the short term and working 4 Lee TM, Yip JT, Jones-Gotman M. Memory deficits after resection from left or memory aspects of verbal memory can be impaired non- right anterior temporal lobe in humans: a meta-analytic review. Epilepsia 2002;43:283–91. specifically by of different location and lateralisation 5 Stefan H, Halasz P, Gil-Nagel A, et al. Recent advances in the diagnosis and if these affect receptive or executive components of memory treatment of epilepsy. Eur J Neurol 2001;8:519–39. processing.16 With design list learning we were never able to 6 Clusmann H, Schramm J, Kral T, et al. Prognostic factors and outcome after differentiate mesial from cortical damage qualitatively.19 20 different types of resection for temporal lobe epilepsy. J Neurosurg 2002;97:1131–41. However, the present data indicate that right sided temporal 7 Wieser HG. Selective amygdalo-hippocampectomy for temporal lobe collateral cortical damage has a negative effect on this epilepsy. Epilepsia 1988;29:100–13. performance. 8 Goldstein LH, Polkey CE. Short-term cognitive changes after unilateral temporal lobectomy or unilateral amygdalo-hippocampectomy for the relief of We are aware that, in contrast to our previous studies on temporal lobe epilepsy. J Neurol Neuosurg Psychiatry 1993;56:135–40. 10 20 SAH, a rather short follow up interval was chosen in this 9 Regard M, Schiess R, Landis T. Ho¨here Hirnfunktionen und Epilepsie – mit study, so recovery from surgical damage can still be expected. besonderer Beru¨cksichtigung der Leistungen vor und nach The short interval was originally chosen in order to find out Amygdalohippokampektomie. Z EEG-EMG 1996;27:257–62.

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