Lennox-Gastaut Syndrome and Palliative Surgical Treatment: Bibliographic Review.
Lennox-Gastaut Syndrome (LGS) is one of the most severe forms of epilepsy in childhood (1) due to the high frequency of seizures, drug resistance and associative frequency with cognitive impairment.
It is characterized by recurrent polymorphic epileptic seizures, neuropsychomotor retardation or involution and a characteristic electroencephalographic pattern, consisting of slowing in the base activity, presence of slow complexes spike--wave (1.5 Hz to 2.5 Hz) of diffuse projection and previous predominance and discharges of diffuse projection polyspikes in electroencephalographic record performed during sleep (1).
Its incidence is about 1 to 10% of childhood epilepsies (2) and 3 to 17% of all patients with epilepsy and psychomotor retardation (3). It is associated with various etiologies in, at least, 70% of cases, such as brain malformations, hypoxicischemic encephalopathy, central nervous system infections, neurocutaneous syndrome and genetic diseases, particularly chromosome abnormalities (4). It is more frequent in males (5:1)(5) and its onset occurs up to 8 years of age, with a peak between 3 and 5 years (2).
The most common seizures in LGS are tonic and atonic seizures and atypical absences, but other types of epileptic seizures may be associated, such as myoclonic seizures, partial seizures and generalized tonic-clonic seizures (1,6). Prolonged episodes of atypical absence, with fluctuation of consciousness, occur and have duration of minutes to hours (4). Drop attacks are common, are most often atonic seizures and may result in repeated craniofacial traumas. Overall, 80% of children will develop tonic seizures, 65% atonic seizures, 60% atypical absences and 55% tonic-clonic seizures (7).
Due to its encephalopathic nature and the multiple types of epileptic seizures present, LGS is a disease of difficult drug control. Many drugs initially reduce the frequency of seizures, but over time, they lose their efficacy.
The International League Against Epilepsy (ILAE) have emphasized the importance of early detection of children who are candidates for surgical procedures in LGS treatment and have recommended the immediate referral of them to specialized surgical centers (8).
There are three options in the surgical approach to epilepsy in children: surgical resection, callosotomy, and vagus nerve stimulation.
The main purpose of surgical resection is to remove the brain region where the seizures originate. Surgery may be considered when there is a failure in the control of epileptic seizures, with the use of at least two or three appropriate antiepileptic drugs (AED), or when these crises affect the patient's quality of life8. However, because of the multifocal characteristics of the disease or the difficulty in locating a single crisis focus, most patients are not candidates for resection surgery and may undergo two palliative surgeries: callosotomy or vagus nerve stimulation.
Callosotomy aims to partially disconnect the cerebral hemispheres, thus helping to prevent the spread of epileptic discharge between the hemispheres. Currently, it is a particularly effective surgical option for patients with LGS who present atonic, tonic and tonic-clonic seizures, even if it is a palliative treatment (7,8).
The vagus nerve stimulation consists of the implantation of a programmable electric pulse generator attached to electrodes that are connected to the left cervical vagus nerve. It is an adjunct treatment option that was approved in 1997 by the Food and Drug Administration (FDA9) and since then has been accepted in clinical practice to decrease the frequency and severity of generalized seizures, especially atonic seizures, although its efficacy in the treatment of other types has also been recognized (10).
This bibliographic review aims to review which palliative treatment for LennoxGastaut syndrome, such as callosotomy and vagus nerve stimulation, presents the best response in the aspect of seizures remission.
A bibliographic review was performed through PubMed platform, LILACS, Scientific Electronic Library Online (SciELO) and Periodical Portal CAPES. Preferably, articles were chosen in the English language, published from the year 2000 and covering LGS palliative surgical treatment. The terms used were: Lennox-Gastaut syndrome, vagus nerve stimulation, callosotomy and surgical treatment, and preferably with search through index terms.
The data collected were organized into tables (Tables 1 and 2) containing: author, type of treatment (VNS or callosotomy), sample of patients with LGS and seizures reduction rate, categorized according to Engel's classification when available in the article (Figure 1) or their percentages in the articles that did not use this classification
First, 30 articles were selected, 15 about callosotomy and 15 about vagus nerve stimulation. However, 13, in total, were excluded because they did not present enough data for this study or because they were only review articles. Thus, at the end, 17 articles (8 callosotomy and 9 VNS) were analyzed. All were published between the years 2000 and 2016.
Eight articles were selected that addressed the performance of callosotomy, preferably by previous route. In total, the response of 327 patients was evaluated, with average age at surgery ranging from 6 to 12 years of age. After the procedure, these patients were monitored on average for 2 to 4.7 years. Of the total articles selected, 7 reported that the free of epileptic seizures (Engel 1) status, in relation to all types of seizures, had been reached in 74 patients (22.62%). In addition, 3 articles mentioned that an improvement of more than 50% in epileptic seizures occurred in 70.84%. While in relation to atonic seizures, one of the articles reported that there was an improvement of over 50% in 92% of the patients studied.
In relation to vagus nerve stimulation, 9 articles were selected. The total patients presenting LGS in these articles was of 983, and this sample number was submitted to VNS treatment. They achieved reduction of more than 50% in epileptic seizures of 57.8% of patients
Callosotomy is often oriented to resolve drop attack in children with LGS, leading to a free-falling condition in 10-15% of patients, although effectiveness on other types of seizures has also been recognized. Complications associated with the procedure include: bruising and cerebral infarctions, infections (meningitis and ventriculitis), hydrocephalus, acute disconnection syndrome and neurological deficits, which may be transient (8).
In a retrospective study with seventy-six patients with LGS or Lennox-like who underwent complete callosotomy, the researchers concluded that improvement (> 50%) was achieved in sixty-nine patients (91%). In addition, fifty-two patients (68%) had a [mayor que o igual a] 90% reduction in the frequency of seizures after surgery and seven (9%) were free of seizures. The reduction in the frequency of specific types of seizures was: atonic (92%), atypical absence (82%), tonic (51%) and tonic-clonic (57%). A consistent increase in the level of attention was also observed in 65 patients (86%) (11).
Su Jeong You (12) et al., described that 5 (35.7%) of 14 patients had an improvement greater than 75%. Likewise, Cukiert et al evaluated the patients' improvement specifically in relation to the decrease in the frequency of atonic seizures, and 92% of the patients in this study (69 people) showed an improvement of more than 50% of atonic seizures after one year of monitoring.
Asadi-Pooya (13) et al., addressed the tonic seizures reduction after callosotomy and found that 6 (46.1%) of the 13 patients were free of seizures after one year. Curkiert et al found a reduction of tonic seizures greater than 50% in 38 patients (51%).
Lancman (10) et al concludes that callosotomy is significantly better compared to VNS in achieving reduction of 50 to 75% in atonic seizures. In this study, a reduction greater than 50% of atonic attacks was observed in 80% of the patients after callosotomy and in 54% after the VNS, whereas a reduction of more than 75% in atonic seizures was observed in 70% after callosotomy and in 26% after VNS.
Authors suggest that VNS should be performed before callosotomy, as it presents a lower morbidity and is a less invasive and reversible procedure and as it presents reduction of the different seizures types similar to callosotomy. Regarding the financial aspects, it is estimated that the costs of VNS are compensated in 2 to 3 years (7).
This device is activated one to two weeks after its implantation and is adjusted periodically. On average, each stimulation lasts 30 seconds, with a frequency of 30 Hz, pulse width of 500 ps, initial output of 0.25 mA, with frequent increases, if tolerated, up to 2.0-2.5 mA. It is considered a useful alternative in patients older than 12 years who are refractory to the use of AED and who are not candidates for surgical treatment. The improvement in seizure control is gradual and continues over time with weekly increments in the stimulation intensity. In addition, improvement in cognition and mood may be associated (7). The occurrence of adverse effects is low and includes: infections at the site of incision, hoarseness, persistent cough, trachea paresthesia, voice alteration and, most serious, vocal paralysis.
Cukiert (14) et al., describe that both procedures were not effective in controlling tonic seizures and both were effective in controlling atypical absences and generalized tonic-clonic seizures. Callosotomy was more effective in controlling the frequency of atonic seizure while VNS proved to be better for myoclonic seizure control.
Frost (15) et al., evaluates changes in patients' quality of life after VNS. There was improvement in alertness in more than half of patients investigated after 3 to 6 months of treatment. After 6 months, a quarter of patients showed improvement in verbal communication, school performance and post ictal recovery. Some patients also showed improvement in mood, memory and ambulation.
Both procedures are effective in decreasing the frequency and severity of seizures in LGS.
According to the reviewed articles, callosotomy seems to be more effective in decreasing atonic seizures. In addition, no significant difference was observed in reducing all types of seizures.
Recibido: 17 de julio de 2017
Aceptado: 20 de agosto de 2017
(1.) Rizzutti S, Muszkat M, Vilanova LCP. Epilepsias na Infancia. Neurociencias. 2000;8(3):108-16.
(2.) Hancock EC, Cross JH. Treatment of Lennox Syndrome. Cochrane Database Syst Rev. 2013;28(2).
(3.) Archer JS, Warren AEL, Jackson GD, Abbott DF. Conceptualizing Lennox- Gastaut syndrome as a secondary network epilepsy. Frontiers Neurol. 2014;5(225):1-11.
(4.) Ragazzo PC. Sindrome de Lennox- Gastaut. In: Melo-Souza SE. Tratamento das Doencas Neurologicas. Rio de Janeiro: Editora Guanabara; 2008. p. 478-79.
(5.) Stafstrom CE. Update on the management of Lennox-Gastaut syndrome with a focus on rufinamide. Neuropsychiatr Dis Treat. 2009;5:54751.
(6.) Santos MV, Machado HR, Oliveira RS. Tratamento cirurgico da epilepsia na infancia. Rev Bras Neur Psiq. 2014;18(2):156-64.
(7.) Al-Banji MH, Zahr DK, Jan MM. Lennox-Gastaut syndrome - management update. Neurosciences. 2015;20(3):207-12.
(8.) Douglass LM, Salpekar J. Surgical options for patients with Lennox-Gastaut syndrome. Epilepsia. 2014;55(s4):21-8.
(9.) Katagiri M, Iida K, Kagawa K, Hashizumi A, Ishikawa N, Hanaya R, et al. Combined surgical intervention with vagus nerve stimulation following corpus callosotomy in patients with Lennox-Gastaut syndrome. Acta Neurochir. 2016;158(5):1005-12.
(10.) Lancman G, Virk M, Shao H, Mazumdar M, Greenfield JP, Weinstein S, et al. Vagus nerve stimulation vs. corpus callosotomy in the treatment of Lennox-Gastaut syndrome: a meta-analysis. Seizure. 2013;22(1):3-8.
(11.) Cukiert A, Burattini JA, Mariani PP, Camara RB, Seda L, Baldauf CM, et al. Extended, one-stage callosal section for treatment of refractory secondarily generalized epilepsy in patients with Lennox-Gastaut and Lennox-like syndromes. Epilepsia. 2006;47:371-4.
(12.) You SJ, Kang HC, Ko TS, Kim HD, Yum MS, Hwang YS, el al. Comparison of corpus callosotomy and vagus nerve stimulation in children with Lennox-Gastaut syndrome. Brain Dev. 2008;30(3):195-9.
(13.) Asadi-Pooya AA, Malekmohamadi Z, Kamgarpour A, Rakei SM, Taghipour M, Ashjazadeh N, et al. Corpus callosotomy is a valuable therapeutic option for patients with Lennox-Gastaut syndrome and medically refractory seizures. Epilepsy Behav. 2013;29:285-8.
(14.) Cukiert A, Cukiert CM, Burattini JA, Lima AM, Forster CR, Baise C, et al. Long-term outcome after callosotomy or vagus nerve stimulation in consecutive prospective cohorts of children with Lennox-Gastaut or Lennox- like syndrome and non-specific MRI findings. Seizure. 2013;22:396-400.
(15.) Frost M, Gates J, Helmers SL, Wheless JW, Levisohn P, Tardo C, et al. Vagus nerve stimulation in children with refractory seizures associated with Lennox-Gastaut syndrome. Epilepsia. 2001;42(9):1148-52.
(16.) Liang S, Zhang S, Hu X, Zhang Z, Fu X, Jiang H, et al. Anterior corpus callosotomy in school-aged children with Lennox-Gastaut syndrome: a prospective study. Eur J Paediatr Neurol. 2014;18:670-6.
(17.) Iwasaki M, Uematsu M, Sato Y, Nakayama T, Haginoya K, Osawa S, et al. Complete remission of seizures after corpus callosotomy. J Neurosurg Pediatrics. 2012;10:7-13.
(18.) Kasasbeh AS, Smyth MD, Steger-May K, Jalilian L, Bertrand M, Limbrick DD. Outcomes after anterior or complete corpus callosotomy in children. Neurosurgery. 2014;74(1):17-28.
(19.) Kossoff EHW, Shields WD. Nonpharmacologic care for patients with Lennox- Gastaut syndrome: ketogenic diets and vagus nerve stimulation. Epilepsia. 2014;55(s4):29-33.
(20.) Morris GL, Gloss D, Buchhalter J, Mack KJ, Nickels K, Harden C. Evidence- based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the guideline development subcommittee of the american academy of neurology. Neurology. 2013;81(16):1453-9.
(21.) Zamponi N, Passamonti C, Cesaroni E, Trignani R, Rychlicki F. Effectiveness of vagal nerve stimulation (VNS) in patients with drop-attacks and different epileptic syndromes. Seizure. 2011;20(6):468-74.
(22.) Cersosimo RO, Bartuluchi M, Fortini S, Soraru A, Pomata H, Caraballo RH. Vagus nerve stimulation: effectiveness and tolerability in 64 paediatric patients with refractory epilepsies. Epileptic Disord. 2011;13(4):382-8.
(23.) Labar D. Vagus nerve stimulation for intractable epilepsy in children. Dev Med Child Neurol. 2000;42:496-9.
(24.) Shahwan A, Bailey C, Maxiner W, Harvey AS. Vagus nerve stimulation for refractory epilepsy in children: more to VNS than seizure frequency reduction. Epilepsia. 2009;50(5):1220-8.
(25.) Elliott RE, Morsi A, Kalhorn SP, Marcus J, Sellin J, Kang M, et al. Vagus nerve stimulation in 436 consecutive patients with treatmentresistant epilepsy: long-term outcomes and predictors of response. Epilepsy Behav. 2011;20(1):57-63.
Beatriz de Castro Ribeiro , Gustavo Estevam , Paulo Henrique Pires de Aguiar [2,3], Samuel Simis 
 Medicine Academics of Pontificial Catholic University of Sorocaba, Sao Paulo, Brazil.
 Department of Medicine, Division of Neurology, Pontificial Catholic University of Sorocaba, Sao Paulo, Brazil.
 Division of Neurology and Neurosurgery of Santa Paula Hospital, Sao Paulo, Brazil.
Prof. Dr. Paulo Henrique Pires de Aguiar
Assistant Professor of Neurology, Faculty of Medical Sciences of Sorocaba,Pontifical Catholic University of Sao Paulo, Professor of Post Graduation of Health Science in IAMSPE, Sao Paulo, Brazil. email@example.com
Table 1. Callosotomy Authors Type of treatment Sample Shuli Liang, Shaohui Callosotomy and Drug 60 patients with LGS Zhang, Xiaohong Hu Treatment Average of 9 years et al. (16) of age Masaki Iwasaki, Callosotomy 13 patients with LGS Mitsugu Ue-matsu, Average of 7 years Yuko Sato et al. of age (17) Ali A. Asadi-Pooya, Callosotomy 18 patients with LGS Zahed Malekmohamadi, Average of 9.9 years Ahmad Ka-mgarpour et of age al. (13) Aimen S. Kasasbeh, Callosotomy 58 patients with LGS Matthew D. Smyth, Average of 120.6 Karen Steger May et months al. (18) Su Jeong You, Hoon- Total callosotomy 24 patients with LGS Chul Kang,Tae Sug Ko and VNS el al. (12) Arthur Cukiert, Callosotomy and VNS 44 patients with LGS Cristine M. Cukiert, Average age: 11.2 Jose A. Burrattini years (Calloso- et al. (14) tomy) and 8.6 years (VNS) Arthur Cukiert, Jose Callosotomy 76 patients with LGS A. Burattini, Pedro Average age: 11.2 Paulo Mariani et al. years (11) Callosotomy and VNS 203 patients Lancman G, Virk M, submitted to VNS 145 Shao H et al.10 patients with Callosotomy Authors Results Shuli Liang, Shaohui Callosotomy: Zhang, Xiaohong Hu After 1 year: engel 1 = 17.4% et al. (16) Drug: After 1 year: engel 1 = 2.9% After 2 years: engel 1 = 5.9% Masaki Iwasaki, After 1 year Mitsugu Ue-matsu, Engel 1: 30.7% Yuko Sato et al. Engel 3: 23.07% (17) Engel 4: 46.15% Ali A. Asadi-Pooya, In all types of seizures Zahed Malekmohamadi, After 1 year: engel 1 = 16.6% Ahmad Ka-mgarpour et Generalized tonic-clonic seizures al. (13) After 1 year: engel 1 = 69.2% Tonic seizures After 1 year: engel 1 = 46.1% Absence seizures After 1 year: engel = 88.8% Drop attacks After 1 year: engel 1 = 36.3% Aimen S. Kasasbeh, Previous callosotomy: Matthew D. Smyth, Engel 1/2: 36% Karen Steger May et Engel 3: 55% al. (18) Engel 4: 9% In 2 stages: Engel 1/2: 27% Engel 3: 64% Engel 4: 9% Complete callosotomy: Engel 1/2: 19% Engel 3: 71% Engel 4: 10% Su Jeong You, Hoon- Callosotomy: Chul Kang,Tae Sug Ko Reduction > 50%: 64.3% el al. (12) Reduction > 75%: 35.7% VNS: Reduction > 50%: 70% Reduction > 75%: 20% Arthur Cukiert, Engel 1 = Cristine M. Cukiert, Callosotomy: 10% Jose A. Burrattini VNS: 0% et al. (14) Arthur Cukiert, Jose In all seizures: A. Burattini, Pedro Engel 1: 9.21% Paulo Mariani et al. Engel 3: 90.78% (11) Atonic seizure: Engel 3: 92% Atypical absence seizure: Engel 3: 82% Tonic-clonic: Engel 3: 57% Tonic seizure: Engel 3: 51% Callosotomy is significantly better Lancman G, Virk M, compared to VNS in achieving 50- Shao H et al.10 75% reduction in atonic seizures Patients who become seizures-free: CC (48%) e VNS (22.8%) Table 2. Vagus Nerve Stimulation Authors Type of treatment Sample Eric HW, Kossoff W, Ketogenic diet and 483 patients with Shields D. (19) VNS LGS without previous surgery Morris GL, Gloss D, VNS 113 patients with Mack KJ et al. (20) LGS Zamponi N, VNS 14 patients with LGS Passamonti C, Cesaroni E. (21) Cersosimo RO, VNS 46 patients with LGS Bartuluchi M, Fortini S et al. (22) Labar D.(23) VNS 5 studies gathering 28 pa-tients with LGS Shahwan A, Bailey C, VNS 9 patients with LGS Maxiner W et al. (24) Elliott RE, Morsi A, VNS 24 patients with LGS Kalhorn SP et al. (25) Frost M, Gates J, VNS 50 patients with LGS Helmers SL et al. (15) Lancman G, Virk M, VNS e CC Meta-analysis with Shao H et al (10) 203 pa-tients with LGS submitted to VNS Authors Results Eric HW, Kossoff W, Of the 483 patients, 55% after Shields D. (19) 18 months reduced seizures in > 50% Morris GL, Gloss D, Seizure decrease of > 50% in Mack KJ et al. (20) 55% of 113 patients with LGS Zamponi N, After 1 year: Passamonti C, Reduction 80 to 100%: 1 pct Cesaroni E. (21) Reduction 50 to 79%: 2 pct Reduction < 50%: 7 pct Without reduction: 4 pct Cersosimo RO, Reduction 80 to 100%: 28 pct Bartuluchi M, Reduction 50 to 79%: 12 pct Fortini S et al. Reduction < 50%: 6 pct (22) Without reduction: 0 pct No patient was completely free of seizures Labar D.(23) Seizure reduction of 55% Shahwan A, Bailey C, 7 of 9 patients with LGS Maxiner W et al. (77.7%) had seizure reduction (24) of > 50% Elliott RE, Morsi A, Seizure reduction of 57.6% Kalhorn SP et al. (25) Frost M, Gates J, After 3 months (43 patients): Helmers SL et al. seizures decreased in >75% (15) in 15 (43%), >50% in 24 (56%) Lancman G, Virk M, VNS Shao H et al (10) Reduction 100%: 142 pct (5.2%) Reduction > 75%: 166 pct (28.6%) Reduction > 50%: 176 pct (49.3%) CC is significantly better com pared to VSN in achieving 50 to 75% reduction in atonic seizures There was no statistically significant difference for other types of seizures between VNS and CC Figure 1. Engel Classification (8) Class I Free of disabling seizures Class II Rare disabling seizures Class III Worthwhile improvement Class IV No worthwhile improvement
|Printer friendly Cite/link Email Feedback|
|Title Annotation:||Revision de Tema|
|Author:||de Castro Ribeiro, Beatriz; Estevam, Gustavo; Pires de Aguiar, Paulo Henrique; Simis, Samuel|
|Publication:||Revista Chilena de Neurocirugia|
|Date:||Jan 1, 2018|
|Previous Article:||Ultimos conceptos de fisiopatologia y diagnostico de la hidrocefalia de presion arterial.|
|Next Article:||Coma y alteraciones del estado de conciencia: revision y enfoque para el medico de urgencias.|