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Jose Augusto Burattini
Pedro Paulo Mariani
Cristine Mella Cukiert
Cássio Roberto Forster
Valeria Antakli Mello
Epilepsy Surgery Program, Hospital Brigadeiro, São Paulo SP, Brazil
Purpose: We report the outcome of patients with refractory IGE that were submitted to extended one-stage callosal section.
Methods: Eleven patients with IGE who were submitted to extended one-stage callosal section were studied. Pre-operative work-up included history and neurological examination, interictal and ictal EEG recording, high resolution 1.5T MRI and IQ testing . All patients were submitted to extended one-stage microsurgical callosal section, leaving only the splenium intact.
Results: Preoperative ictal patterns included repetitive spike and wave or polispike and wave discharges or fast epileptic recruiting rhythm. MRI showed no focal lesions. Preoperatively, mean general IQ was 85. Postoperatively, at least a 75% reduction in the frequency of generalized tonic-clonic seizures was noted in all patients. In 3 patients absences disappeared completely and the others had at least 90% reduction in seizure frequency. Only one patient had myoclonic seizures preoperatively and these seizures disappeared after callosal section. After surgery, mean general IQ was 89. A very clear increase in attention level was noted in all patients. Postoperative interictal EEG recordings showed rupture of bilateral synchrony in all patients.
Discussion: This paper reports on a large and homogeneous series of patients with refractory IGE submitted to callosal section. There was a marked decrease in generalized seizure frequency and increase in the attention level in this patient population. Our results suggest that cortico-cortical interaction might have a role in IGE pathogenesis. Callosotomy is a very safe, effective and underused palliative procedure in these well selected patients with refractory IGE.
Callosotomy has been used with good results as a palliative procedure in patients with refractory secondary generalized epilepsy (SGE), especially in those patients with Lennox-Gastaut or Lennox-like epileptic syndromes (Cukiert et al, 2006; Jenssen et al , 2006; Oguni et al, 1994) with multiform seizures including tonic, atonic, atypical absences, myoclonic and generalized tonic-clonic types. High seizure frequency reduction rates have been reported in some series and vary among these different seizure types. Although the majority of these patients were mentally retarded, improvements in cognitive function and level of attention have been documented in patients with SGE.
Childhood and juvenile idiopathic generalized epilepsy (IGE) is usually a benign condition, treated with low dose anti-epileptic drug regimens including valproate, lamotrigine, ethosuximide and phenobarbital (Wheless and Bourgeois, 2004). On the other hand, a subset of patients with IGE might be refractory to medical treatment and are potential candidates for surgery.
Widespread cortical generators or multifocal cortical abnormality are usually considered to be involved in the pathogenesis of SGE while genetic factors might prevail in the pathogenesis of IGE. On the other hand, there are clinical and basic data that suggest that these two apparently different entities might share some common pathological pathways (Musgrave and Gloor, 1980). The role of the corpus callosum in the genesis of bilateral synchrony in both SGE ande IGE has already been emphasized (Marcus and Watson, 1966). More extensive callosal sections have been shown to yield higher bilateral synchrony rupture and seizure reduction rates (Spencer et al,1993; Rahimi et al, 2007). We report on the results obtained after extended callosal section in patients with refractory IGE.
Eleven patients with IGE who were submitted to extended callosal section between 1998 and 2004 at the Hospital Brigadeiro Epilepsy Surgery Program were studied. Diagnostic criteria for IGE included: a) typical absence, generalized tonic-clonic and myoclonic seizures as the only seizure types; b) General IQ higher then 75; c) MRI showing mild atrophy or no changes; d) Diffuse generalized interictal spike-and-wave (SW) or poly-spike-and-wave (PSW) discharges prevailing over the frontal lobes; e) Ictal repetitive SW or PSW or epileptic fast recruiting rhythm pattern; f) No focal neurologic or neurophysiologic finding; g) No background slowing on EEG.
Pre-operative work-up included history and neurological examination, interictal and ictal EEG recording, high resolution 1.5T MRI and IQ testing (WAIS: general IQ, verbal IQ and executive IQ). Seizure’s frequency and type were recorded pre- and postoperatively by the patients or families in a diary. The anti-epileptic drug regimen was kept unaltered during the first postoperative year. IQ testing was repeated one year after surgery. No patient was submitted to any invasive recording.
All patients were submitted to extended microsurgical callosal section through a parasagittal craniotomy, leaving only the splenium of the corpus callosum in place. Post-operative MRI documented the extent of the section in each patient.
When needed, mean values were analyzed using the Student T-test.
Follow-up time ranged from 24 to 98 months (mean= 49 months). The age of seizure onset ranged from 4 to 8 years and the age by the time of operation from 21 to 53 years. The association of typical absences and generalized tonic-clonic seizures was common, but not all patients with absences had generalized tonic-clonic seizures; additionally, not all patients with generalized tonic-clonic seizures had absence seizures. Overall, ten patients had generalized tonic-clonic seizures prevailing on awakening and 10 patients had typical absences; only one patient had myoclonic seizures. No patient had isolated generalized tonic-clonic seizures on awakening (without absences). All patients were receiving high dose polytherapy. Preoperatively, 10 patients had been treated with high dose valproate therapy, 6 were taking lamotrigine, 8 were taking phenobarbital, 3 were taking clonazepan and 1 was taking etosuximide. Patient V was the only one not receiving valproate; he presented valproate related encephalopathy and was receiving etosuximide, lamotrigine and clonazepan. Preoperative interictal EEG showed diffuse generalized SW(5 patients) or PSW discharges (6 patients), ranging from 2.5 to 3.0Hz, prevailing over the frontal regions. Preoperative ictal patterns included repetitive SW (5 patients) or PSW (5 patients); in 2 patients seizures consisting of a fast epileptic recruiting rhythm were also noted, together with seizures consisting of repetitive PSW discharges. MRI was normal in 7 patients and disclosed mild atrophy in 4 patients. Preoperatively, general IQ ranged from 75 to 100 (mean=85); verbal IQ ranged from 71 to 98 (mean=84) and executive IQ ranged from 77 to 101 (mean=86) (Table I).
A post-operative MRI documented an adequate extended callosal section sparing only the splenium in all patients. There were no other lesions seen in the postoperative scans. Postoperatively, at least a 75% reduction in the frequency of generalized tonic-clonic seizures was noted in all patients who had this type of seizure (n=10); 70% of them had at least 85% reduction and 40% of them had at least 90% reduction in tonic-clonic seizure frequency. Ten patients had typical absences: in 3 patients absences disappeared completely and the others had at least 90% reduction in seizure frequency. Only one patient had myoclonic seizures preoperatively and these seizures disappeared after callosal section. After surgery, general IQ ranged from 80 to 98 (mean=89); verbal IQ ranged from 78 to 98 (mean=87) and executive IQ ranged from 79 to 98 (mean=89). There was a mean increase in 5 points of general IQ postoperatively (Table II). There was no statistically significant modification in the neuropsychological functioning of these patients postoperatively.
All patients presented an acute postoperative syndrome characterized by apathy, urinary incontinence, left hemineglect and lower verbal output; these symptoms disappeared completely after 3 weeks in all patients. In a single patient, severe intermanual conflict was noted postoperatively and lasted for 3 months. There was no other postoperative sign or symptom of hemispheric disconnection. There was no other morbidity or mortality in this series. A very clear increase in attention level was noted in all patients, although we were not able to quantitatively document this phenomenon. At the last follow-up visit, 4 patients were receiving high dose valproate monotherapy; the other patients remained on high dose polytherapy. Postoperative interictal EEG recordings showed rupture of bilateral synchrony in all patients during wakefulness; in seven patients, bilateral synchrony was rebuilt during slow wave sleep. Both hemispheres retained the ability to generate epileptic discharges during wakefulness and hemispheric discharges prevailing over the frontal lobe could be seen independently over each hemisphere.
Our previous results in cats (Cukiert et al, 1989) and in patients with Lennox-Gastaut syndrome (Cukiert et al, 2006) have clearly demonstrated that the corpus callosum was the main anatomical relay for bilateral synchrony generation and that complete or extensive sections of the corpus callosum are much more effective then small sections in the disruption of epileptic bilateral synchrony; this was also noted by others (Spencer et al, 1993). Outcome after callosal section in patients with IGE was poorly discussed in the literature and Jenssen’s paper (Jenssen et al, 2006) was possibly the only one to directly address this issue. Our paper reports on a large and homogeneous series of patients with refractory IGE submitted to callosal section.
Our patient population was extremely homogeneous; all these patients were considered to have IGE from the beginning and the only clinical and neurophysiological difference was their bad outcome regarding seizure control under the standard mono- and polytherapy drug regimens. There was a marked decrease in generalized seizure frequency and increase in the attention level in this patient population. This was very likely related to the rupture of secondary bilateral synchrony seen in these patients. These results were similar to those obtained in patients with SGE submitted to extended callosal section (Cukiert et al, 2006; Gates et al, 1884; Rathore et al, 2007) and were stable over the follow-up years. This led to better quality of life and improvement in general cognitive performance as noticed in daily life activities. Although we were not able to quantify this, since it was not possible to apply standardized quality of life questionnaires, improvement in their quality of life was very clear for all those professionals involved in these patients care. One-third of the patients were able to be maintained on monotherapy after surgery and although the rest of them remained on polytherapy, their regimen was invariably simplified. There was a mean increase of 5 points in general IQ postoperatively in this series; although this did not reach statistical significance, we believe that we would be able show a significant cognitive improvement in a larger series of patients. On the other hand, our data certainly demonstrate that extensive callosal section did not impair global functioning. Increased attention level has also been described in patients with generalized epilepsy submitted to stimulation of non-specific thalamic nuclei and the cortical or subcortical mechanism involved in increased attention after these procedures is not yet clear (Cukiert et al, 2007).
Callosal section was able to disrupt bilateral synchrony in the present patient population with IGE, suggesting that although epileptogenesis might be modulated by subcortical structures as shown in some human studies (Prevett et al, 1995; Theodore et al, 1985), cortico-cortical interaction might have an important role in its pathogenesis (Berkovic et al, 1987). The re-synchronization of epileptic activity during slow-wave sleep seen in our patients suggests a subcortical modulatory influence in the pathophysiology of patients with IGE (Steriade and Contreras, 1998). Clearcut focal activity is very rarely documented after callosal section, although diffuse epileptic activity is restrained to each hemisphere after the procedure. Cortical resection in this patient population (with or without previous callosal sections) systematically yielded bad results. We had the opportunity to study 2 patients with SGE of the Lennox-Gastaut type with extensive coverage of the all available cortical surface bilaterally and although multifocal epileptic activity could be documented, ictal onset remained truly generalized. The pathogenesis of both SGE and IGE is very likely different from that of classical focal epilepsy, which is mainly a cortical disease.
More recently, vagus nerve stimulation (VNS) has been used to treat patients with both SGE and IGE. VNS has actually been effective in some of our patients with generalized epilepsy although seizure frequency reduction did not correlate with neurophysiological improvement as seen in callosotomy. Furthermore, extensive callosal section was more effective regarding seizure frequency reduction in our hands and in other’s experience (Nei et al, 2006). Although callosotomy is an intracranial procedure , compared to VNS which is an extracranial procedure, our current policy is to submit patients to callosal section before undergoing eventual VNS therapy. So far, only one patient with IGE was submitted to VNS at our center.
Although SGE and IGE clearly have different pathological substrates, they share common neuropathophysiological relays. In these settings, the corpus callosum play an important role in the genesis of bilateral synchrony. Callosotomy is a very safe, effective and underused palliative procedure in these well selected patients with refractory IGE.
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Table I: Summary of the pre-operative clinical findings. G: generalized tonic-clonic seizure; A: typical absence seizure; M: myoclonic seizure; Ma: male; Fe: female; SW: spike and wave discharge; PSW: polispike and wave discharge; ERR: epileptic recruiting rhythm; Nl: normal; VPA: valproate; LMT: lamotrigine; PB: phenobarbital; ETX: ethosuximide; CLN: clonazepan; PHT: phenytoin; Gl: global IQ; V: verbal IQ; E: executive IQ.
Table II: Summary of the post-operative clinical findings. G: generalized tonic-clonic seizure; A: typical absence seizure; M: myoclonic seizure; Gl: global IQ; V: verbal IQ; E: executive IQ.
Patient Seizures (/month) Sex Age Age Sz Onset Interictal EEG Ictal EEG MRI AEDs IG
I G:8; A:D; M:0 Ma 33 7 PSW 3.0Hz ERR nl VPA; LMT Gl:80; V:79; E:79
II G:12; A:D; M:0 Ma 43 8 SW 2.5Hz SW 2.5Hz nl VPA, LMT Gl:85; V:81; E:87
III G:10; A:D; M:0 Fe 39 8 SW 2-2.5Hz SW 2.5Hz nl VPA, LMT, PB Gl:100; V:98; E:101
IV G:20; A:D; M:0 Ma 21 6 SW 2.5Hz SW 2.5Hz nl VPA, LMT, PB Gl:91; V:91; E:90
V G:0; A:D; M:D Fe 53 5 PSW 2.5Hz PSW 2.5Hz atrophy LMT,ETX, CLN Gl:75; V:75; E:77
VI G:20; A:D; M:0 Ma 25 8 PSW 2.5Hz RRE/PSW 2.5Hz atrophy VPA, LMT, PB Gl:82; V:83; E:85
VII G:8; A:D; M:0 Fe 21 4 SW 3.0Hz SW 3.0Hz nl VPA, PB Gl:98; V:95; E: 96
VIII G:12; A:0; M:0 Ma 26 7 PSW 2.5Hz PSW 2.5Hz atrophy VPA, PB Gl:92; V:90; E: 89
IX G:8; A:D; M:0 Ma 28 8 PSW 2.5Hz PSW 2.5Hz atrophy VPA, PHT, PB Gl:89; V:87; E:92
X G:4; A:D; M:0 Ma 27 8 PSW 2-2.5Hz PSW 2.5Hz/ ERR nl VPA, PB, CLN Gl:78; V:77; E:77
XI G:15;A:D; M:0 Ma 31 7 SW 2.5Hz SW 2.5Hz nl VPA, PB, CLN Gl:75; V:71; E:77
Table I: Summary of the pre-operative clinical findings.
Patient Seizures (/month) IQ
I G:1; A:15; M:0 Gl:80; V:78; E:79
II G:0.5; A:0; M:0 Gl:90; V:87; E:92
III G:1; A:15; M:0 Gl:98; V:98; E:98
IV G:3; A:60; M:0 Gl:91; V:91; E:90
V G:0; A:15; M:0 Gl:87; V:85; E:87
VI G:4; A:0; M:0 Gl:90; V:85; E:92
VII G:2; A:0; M:0 Gl:98; V:96; E: 96
VIII G:1; A:0; M:0 Gl:91; V:90; E: 90
IX G:1; A:10; M:0 Gl:95; V:89; E:95
X G:1; A:10; M:0 Gl:85; V:79; E:84
XI G:0;A:10; M:0 Gl:82; V:79; E:83
Table II: Summary of the post-operative clinical findings.
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Disclosure of Conflicts of Interest
None of the authors has any conflict of interest to disclose.