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Lennox-Gastaut Syndrome and Palliative Surgical Treatment: Bibliographic Review.

Introduction

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).

Objective

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.

Methodology

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

Results

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

Discussion

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.

Conclusion

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

References

(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 [1], Gustavo Estevam [1], Paulo Henrique Pires de Aguiar [2,3], Samuel Simis [2]

[1] Medicine Academics of Pontificial Catholic University of Sorocaba, Sao Paulo, Brazil.

[2] Department of Medicine, Division of Neurology, Pontificial Catholic University of Sorocaba, Sao Paulo, Brazil.

[3] Division of Neurology and Neurosurgery of Santa Paula Hospital, Sao Paulo, Brazil.

Correspondence:

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. phpaneurocir@gmail.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
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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
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