Late Seizure Recurrence after Multiple Subpial Transections

*Darren Orbach, †Pantaleo Romanelli, *†Orrin Devinsky, and †Werner Doyle

Departments of *Neurology and †Neurosurgery, NYU School of Medicine, New York, New York, U.S.A.

Summary: We studied long-term outcome (range, 28–89months; mean, 56 months) after multiple subpial transections(MST) for medically refractory epilepsy. Forty-three (79.6%)of 54 patients had a consistent significant reduction in seizurefrequency, and 27 (50%) of the 54 were either entirely seizurefree or virtually so. However, 10 (18.5%) patients sustained

an increase in seizure frequency several years after surgery,after showing initial postoperative improvement. This suggeststhat late seizure recurrence is a more important problem incases in which MST has been performed than for pure resec-tions.Key Words: Intractable seizures—Epilepsy surgery—Multiple subpial transections—Resection.

Morrell et al. (1) developed multiple subpial transec-tions (MST) to treat surgically intractable epilepsy withseizure foci in primary sensorimotor or language areas.Given the columnar organization of cerebral cortex, ver-tical transections should theoretically disrupt only hori-zontally oriented axons while preserving the verticallyoriented architecture and cortical function. AlthoughMSTs appear effective (2–5), long-term outcome dataare not available.

After standard cortical resection for intractable epi-lepsy, patients’ postoperative outcome can be largelypredicted by their status 2 years after surgery (6,7). Sev-eral small series (2–5) reported on seizure outcome afterMST, followed for #2 years after surgery. We reporthere on our long-term follow-up of a large cohort ofMST patients.

METHODS

Fifty-four patients with medically refractory epilepsyhad presurgical evaluation with video-EEG, neuropsy-chological testing, Wada testing, and magnetic resonanceimaging (MRI), supplemented with ictal/interictal single-photon emission computed tomography (SPECT), positronemission tomography (PET), or magnetoencephalography(MEG). After subdural grid and strip placement and oc-casionally depth electrodes, cortical mapping was doneto identify primary sensorimotor or language cortex. If aseizure focus was found to be overlying eloquent cortex,

MSTs were made. Three patients had MST alone; 51patients with lesions partially localized to noneloquentcortex had both resections and MST. An attempt wasmade in each of these 51 cases to limit the resection tocortex that was demonstrably epileptogenic on EEGmonitoring. Fourteen (25.9%) patients had very smallresections involving at most a single gyrus or a tumor,and 37 (68.5%) patients had resections involving muchor all of a cortical lobe. Details concerning patient se-lection, presurgical evaluation, and the placement ofMST are discussed elsewhere (4). We excluded patientswith a progressive neurologic disorder from this analysis.

Patients were followed up for an average of 55.8months after surgery (range, 28–89 months). All patientswere continued on antiepileptic medication (AEDs) im-mediately postoperatively, but their regimens were indi-vidualized over time based on their clinical status,ranging from eventual discontinuation of medication tothe use of experimental AEDs or vagus nerve stimulatorimplantation, as appropriate.

RESULTS

Outcome is expressed using a modified Engel scale:grade I, patients are seizure free or had only nondisablingsimple partial seizures; grade II, rare seizures (>85%reduction); grade III, >50% reduction in seizure fre-quency; and grade IV, no meaningful reduction in sei-zure frequency. Grade I outcome was achieved in 37%,grade II in 13%, grade III in 29.6%, and grade IV in20.4% of patients. Three patients in our cohort had MSTalone, with one patient in each of grades I, II, and IV.

Several temporal patterns were apparent. Two (3.7%)patients had a higher frequency of seizures during the

Revision accepted.Address correspondence and reprint requests to Dr. O. Devinsky at

NYU–Mount Sinai Comprehesive Epilepsy Center, 403 E. 34th St.,New York, NY 10016, U.S.A. E-mail: od4@is4.nyu.edu

Epilepsia,42(9):1130–1133, 2001Blackwell Science, Inc.© International League Against Epilepsy

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immediate postoperative period and then a much lowerseizure frequency over the long term. Thirty-nine(72.2%) patients achieved their long-term postoperativeseizure pattern within 1 year of surgery, and 44 (81.5%)patients did so within 2 years, regardless of their eventualgrade.

Significant worsening of seizure control occurred in10 (18.5%) of 54 patients between 2 and 5 years aftersurgery. Five of the patients with late worsening had agrade I outcome at 2 years; four of these regressed tograde III, and one, to grade IV. The other five patientshad a grade II outcome at 2 years, which deteriorated tograde III in four cases, and to grade IV in one case.

Focusing exclusively on those patients with very goodoutcomes (i.e., Engel grades I and II), after 1 year hadpassed from the date of surgery, 19 (35.2%) patientswere entirely seizure free. After 2 years had passed fromthe date of surgery, 16 (29.6%) of the 54 patients re-mained entirely seizure free, while the remaining threeexperienced only rare auras or simple partial seizures.One additional patient who had been seizure free at2 years after surgery experienced rare auras or simplepartial seizures between postoperative years 2 and 3.Similarly, at 1 year after surgery, 11 (20.4%) patients hadonly rare auras or simple partial seizures, whereas at2 years after surgery, 12 (22.2%) patients did so. Two ofthe original 11 had regressed to Engel grade II, whereasthree patients who had been entirely seizure free at the1-year mark were now experiencing auras or simple par-tial seizures.

Of the three patients who had MST and no resections,one had only rare postoperative seizures, and another hada >50% decrease in seizure frequency. The third patientwas a late regressor: he initially had a >50% reduction,only to return close to his baseline between postoperativeyears 2 and 5. As mentioned earlier, of the 51 patientswith resections in addition to MST, 14 had small resec-tions involving at most a single gyrus or a tumor, and37 had resections involving much or all of a cortical lobe.Outcome did not differ between these two groups.

Surgical sites were classified as being restricted to thetemporal lobe, restricted to extratemporal lobe(s), orcombined temporal and extratemporal. Patients were al-most uniformly distributed among the three classes, andthere was little difference in the likelihood of achievingan excellent outcome (grades I or II) as a function of

surgical site (46.7% for temporal lobe sites, 47.4% forextratemporal sites, and 52.6% for combined surgery).However, patients whose surgery was restricted to thetemporal lobe were markedly less likely to have a pooroutcome (grade IV) than those whose surgery includedextratemporal regions (6.7% for temporal surgery vs.20% and 26.3% for extratemporal and combined surgery,respectively). These data are summarized in Table 1.

MRI results were available in the records of 50 of the54 patients. Scans were classified as normal, as showingevidence of an intracranial tumor, or as showing evi-dence of another lesion type (i.e., cortical dysplasia, in-farct, mesial temporal sclerosis, vascular lesion, cyst,nonspecific white matter abnormality). Patients with ei-ther an excellent outcome (grades I and II) or a satisfac-tory outcome (grade III) were approximately evenlydistributed among the three MRI results. However, of the11 patients with poor outcome (grade IV), eight (72.7%)had normal MRI scans. These data are summarized inTable 2.

Of the 51 patients who had resections (and thus tissuespecimens for analysis), pathology reports were availablefor 44. Results were distributed into four classes, asshowing evidence of (a) tumor, (b) structural dysplasia(cortical heterotopy, white matter extending to the pia,etc.), (c) hippocampal gliosis, or (d) unremarkable orshowing only Chaslin gliosis (thought to result fromchronic seizure activity rather than serving as an irrita-tive lesion). Similar to the MRI results, grade I, II, and IIIoutcomes were approximately evenly distributed amongthe various lesion types, but of the 11 patients with pooroutcome (grade IV), seven (63.6%) had unremarkablepathology. These data are summarized in Table 3.

The 10 patients with late seizure recurrence were ap-proximately as likely to have undergone purely temporallobe surgery (five of 10) as purely extratemporal surgery(four of 10); the last patient had combined temporal andextratemporal surgery. MRI findings among the 10 lateregressors were notable for the presence of tumor ononly one scan, with five of the 10 being normal, and theremaining four showing evidence of a nontumorouslesion.

DISCUSSION

MST can benefit patients with medically intractableepilepsy: almost 50% of our cohort were either entirely

TABLE 1. Seizure outcome as a function of cortical site of surgery

Seizure outcome(Engel grade)

Temporal lobesurgery

Extratemporallobe surgery

Combined temporal andextratemporal surgery

Grade I 7 6 7Grade II 1 2 3Grade III 7 6 4Grade IV 1 5 5Total 16 patients 19 patients 19 patients

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or virtually seizure free (grades I and II), and >80% hada long-term significant reduction in seizure frequency(i.e., grades I–III). Approximately 82% of our patientsachieved their long-term seizure outcome within 2 yearsafter surgery, but the rest had increased seizure fre-quency between postoperative years 2 and 5. In twocases, seizure frequency immediately after surgery washigh and then declined to its long-term frequency withinseveral weeks, likely an effect of widespread surgicalirritation of the cortex, which resolved with healing.

Of the 19 patients who were entirely seizure free at1 year after surgery, three (15.8%) experienced rare au-ras or simple partial seizures by the 2-year mark, and anadditional one (5.3%) did so between years 2 and 5.None of these patients regressed beyond Engel grade Iduring the time of our follow-up, and thus freedom fromseizures at the 1-year mark after surgery is a strong in-dication of an outstanding surgical outcome.

Spencer (8), reporting on temporal and extratemporalresections, found that seizure relapse rates >1 year aftersurgery ranged from 1% in patients with gliomas or nor-mal brain to 25% in those with developmental abnor-malities. In contrast, we found a higher tendency towardpoor outcome among patients with unremarkable pathol-ogy (63.6% of all grade IV patients), whereas patientswith structural dysplasia (likely subsuming Spencer’scategory of developmental abnormalities) had outcomessimilar to those with tumors. This difference probablyreflects the fact that patients undergoing MSTs harbormore widespread epileptogenic cortex, which may ap-pear normal on pathologic examination.

Foldvary et al. (7) found that after temporal lobec-tomy, 80% of patients had a grade I–II outcome; 11%,grade III; and 9%, grade IV. Only six (7.6%) of 79 pa-

tients had seizures recur after 24 months of follow-up.Salanova et al. (9) reported that for temporal lobe resec-tions, patients who were seizure free at 1 year after sur-gery had an 83% probability of remaining so, and thosewho were seizure free at 2 years, a 92% probability.Eliashiv et al. (10) reported that after temporal lobec-tomy, 80% were seizure free at 6 years, with only three(5%) of 60 patients having late recurrence (two >10years and one, 15 years after surgery).

Previous reports on outcome after MST have divergedwidely. Wyler et al. (2) reported that one (16.7%) of sixpatients failed to derive any benefit from pure MST,whereas Rougier et al. (3) reported that two (28.6%) ofseven patients did not benefit from pure MST. Hufnagelet al. (5) reported that two (33.3%) of six patients un-dergoing pure MST failed to improve, whereas only one(6.3%) of 16 patients undergoing both resection andMST failed to improve. Pacia et al. (4) reported that two(9.5%) of 21 patients had no benefit from MSTs (18 ofthe 21 had also had resections). In contrast, our longerfollow-up study revealed 20.4% grade IV patients, re-flecting a subgroup whose seizure frequency increasedagain several years after surgery.

Our data suggest that the surgical site (pure temporallobe vs. extratemporal involvement) was not a relevantfactor in determining the likelihood of an excellent out-come after surgery. In contradistinction, patients whosesurgery was restricted to the temporal lobe were far lesslikely to have poor outcome (i.e., no significant improve-ment) than were those whose surgery included or waslimited to extratemporal regions. Semah et al. (11) re-ported that, in patients with partial epilepsy managednon-surgically, if the seizure focus was located in thetemporal lobe, outcome tended to be significantly worse(as defined by seizure freedom for >1 year) than it wasfor seizure foci located elsewhere; there were no differ-ences between various extratemporal sites in terms ofoutcome. Most important, they found that the presence orabsence of an lesion on MRI was tightly correlated withoutcome, with 45% of those with cryptogenic partial epi-lepsy achieving freedom from seizures, but only 3–24%of those with identifiable lesions doing so. This resultdiffers significantly from our finding that patients withpoor outcome after surgery (grade IV) were, in >72% of

TABLE 3. Seizure outcome as a function of pathological findings

Seizure outcome(Engel grade) Unremarkablea

Hippocampalgliosis Tumor

Structuraldysplasia Total

Grade I 3 2 4 5 14Grade II 2 0 3 1 6Grade III 3 3 3 4 13Grade IV 7 2 1 1 11Total 15 patients 7 patients 11 patients 11 patients 44

a “Unremarkable” pathology denotes the presence of Chaslin gliosis only, thought to be secondary tothe presence of chronic seizure activity, rather than an irritative lesion.

TABLE 2. Seizure outcome as a function of MRI result

Seizure outcome(Engel grade)

MRI:Tumor

MRI:Other lesion

MRI:Normal Total

Grade I 6 6 8 20Grade II 3 1 1 5Grade III 2 9 3 14Grade IV 1 2 8 11Total 12 patients 18 patients 20 patients 50 patients

MRI, magnetic resonance imaging.

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cases, likely to have a normal MRI. One important dif-ference between our cohort and that of Semah et al. wasthat their patients were not treated surgically, and theirdata may thus reflect the natural history of seizure-inducing lesions, whereas ours reflects the effect of sur-gical intervention.

The efficacy of MST is difficult to definitively assessin patients who have also undergone resection (2). How-ever, the paucity of pure MST cases in our cohort (aswell as the absence of any other large series monitoringoutcome after pure MST) is indicative of the fact thatalmost all patients have some resectable epileptogenicregion. Moreover, comparison of our patients’ outcomeswith published outcomes on those who have undergonepure resections is a valid means of assessing what MSTadds to the surgical management.

The etiology of the late seizures after MST is unclear.Cortical injury and gliosis caused by MST may causenew seizure foci in some patients. As Kaufmann et al.(12) demonstrated, histologic analysis of cortex that hadundergone MST revealed parenchymal injury that ex-tended as deep as the gray–white junction, with neuronalpyknosis and adjacent myelin pallor. Alternately, giventhat MST disrupts epileptogenic cortical circuits ratherthan removing them, alternate circuitry may eventuallybe recruited. In particular, ideal placement of MST mightnot have been possible if the gyri were not perfectlyperpendicular to the cortical surface, as Kaufmann et al.(12) demonstrated occurs de facto as well.

Our results suggest that MST is a valuable surgicaltherapy, but that its efficacy is more limited than previ-ously suggested and that seizures can relapse several

years after surgery. Patients with extratemporal surgery,those with normal MRI scans, and those with unremark-able pathological findings may represent a subgroup par-ticularly vulnerable to long-term seizure recurrence.

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9. Salanova V, Markand O, Worth R. Longitudinal follow-up in 145patients with medically refractory temporal lobe epilepsy treatedsurgically between 1984 and 1995. Epilepsia1999;40:1417–23.

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