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REVIEW ARTICLE
AED Strategy after Refractory Epilepsy Surgery Andreas Zigouris1, George A. Alexiou1, Marios S. Themistocleous2 and SpyridonVoulgaris1 1
Department of Neurosurgery, University Hospital of Ioannina, Ioannina, Greece, 2Department of Neurosurgery, Children’s Hospital ‘’Agia Sofia’’, Athens, Greece Abstract: Post-epilepsy surgery antiepileptic drug discontinuation (AED) practices remain unclear and little ARTICLE HISTORY
evidence about the optimum timing exists. In the present study, we reviewed the types of surgery for epilepsy and their outcome. The current concepts for discontinuation of AED after surgery are presented and all contributing
Received: September 28, 2017 Accepted: October 25, 2017
factors that should be taken into consideration are discussed.
DOI: 10.2174/1381612823666171030154449
Keywords: ??????????????. 1. INTRODUCTION The second most common cause of mental health disability is epilepsy, a clinical entity that mainly affects young adults [1]. The ILAE classification of seizure types is based on onset (focal, generalized and unknown) with a basic and an expanded version [2]. During an epileptic episode, patients may experience psychic, olfactory, gustatory and autonomic symptoms. During the latter ones, patients lose awareness and usually have automatisms repetitive and involuntary movements, such as lip smacking, scratching, chewing or gesturing [3]. While anti-epileptic drugs (AEDs) are the lynchpins of treatment in most cases, as many as one-third of patients will have a refractory form of disease indicating the need for a neurosurgical evaluation [3]. The present study analyzes the factors that affect a decision of postoperative discontinuation of AEDs including age, underlying pathology, type of surgery, type of medication, quality of life, EEG findings and persistent postoperative symptoms. 2. TYPES OF SURGERY Surgery for temporal lobe (TL) epilepsy, one of the most common syndromes, may not only control seizures, but also prevent sudden unexplained death [5]. Mesial temporal lobe epilepsy (MTLE) is the most common surgically treated epilepsy syndrome, and hippocampal sclerosis (HS) is the most frequently encountered lesion in patients with MTLE [6, 7]. The goal of temporal lobectomy is the resection of mesial structures, such as the amygdala, hippocampus, and parahippocampal gyrus, while preserving as much of the neocortex as possible and the best seizure control with minimal neurological deficits [8]. There are four types of temporal lobectomy: a) the classic type, where during the resection, all temporal lobe, including the mesial structuresare removed, 5-7 cm from the tip, b) the anterior temporal lobe resection, where the anterior part of the temporal lobe is resected, andthereafter the medial parts (hippocampus and lateral amygdala) are removed, c) the Spencer type, where, in order to *Address correspondence to this author at the PO BOX 103, Neochoropoulo, Ioannina, Greece; Tel: +30 26510 48795; +30 6948 525134; Fax: +30 26510 99700; Email:
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preserve possibly functioning temporal cortex, a minimal resection of the medial and inferior temporal gyrus is performed, creating a key-hole to continue with the medial resection, and d) the selective amygdalohippocampectomy, carried out with a selective resection of lateral amygdala, hippocampus, uncus, and the parahippocampal gyrus [9]. Extratemporal lobe epilepsies are characterized by the epileptogenic foci outside the temporal lobe. They have a spectrum of presentation depending upon the site of origin. This type of seizures is predominantly associated with frontal lobe epilepsy. The surgical treatment is a focal cortical resection with excision of the epileptogenic zone [10]. 3. POSTOPERATIVE OUTCOME The superiority of surgery over medical therapy in refractory epilepsy seems clear in the quality of life, and the rates of employment and school attendance [3]. After epilepsy surgery, 64 to 70% of patients with drug-resistant temporal lobe epilepsy will be without seizure with continued antiepileptic drug (AED) treatment [11, 12, 13]. For Kim et al, TL carries a (33-93) % range of seizure-free period [8]. Additionally, only about 3.8-14% of patients that underwent epilepsy surgery required a second operation. The average time interval for reoperation ranged between 2 and 5.5 years. However, in patients with unfavorable outcomes reoperation rates ranged between 35.9 and 65.2%. Major causes for failure are improper localization of the seizure location, partially retained epileptogenic lesion or both incorrect localization and subtotal resection of the seizure focus, progression of the underlying pathology or presence of other seizure foci [12]. 4. AED DISCONTINUATION POSTOPERATIVE Nearly in all cases, patients continue at least one or more antiepileptic drugs (AEDs), when discharged from the hospital after surgery. Seizure recurrence may appear if AEDs discontinued prematurely. This may have a direct impact on patient’s psychological status, raising concerns about subsequent seizure control. On the other hand, AED-related side effects should also be considered when administrated for long periods. In addition, continued use of AEDs imposes afinancial and social burden on the patientsand their caregivers [6, 7]. It is not uncommon some patients to prefer AEDs © 2017 Bentham Science Publishers
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continuation after surgery, because they believe that they will never become seizure free or have a past experience of seizure recurrence after withdrawal [14, 15]. In the study presented by Schmidt et al.for the AED discontinuation after epilepsy surgery, research should be focused on the frequency and timing of seizure relapse after planned discontinuation of AEDs in the seizure free period that is adequate and safe for AED discontinuation and if patients with seizure recurrence regain seizure control with reinstitution of AEDs. These questions are not easily answered, creating a therapeutic dilemma after epilepsy surgery that has been widely studied over the last 20 years. In general, seizure recurrence is seen in nearly 30% of patients after epilepsy surgery [15, 16]. Rathore et al. reported a 25% risk of seizure recurrence after AED withdrawal, and more than half of patients became at last seizure- and AED-free [6, 7]. A metaanalysis showed that in patients that received all types of surgery, 20% achieved long-term AED discontinuation, 31% remained on polytherapy and 41% were on monotherapy [17]. AED withdrawal did not affect long-term seizure outcomes, but could reveal unsuccessful surgical intervention, identifying patientsof need for drug treatment [17]. Considering the above the decision to stop or continue AED therapy is excessively complex requiring careful evaluation of the risk/benefit ratio in individualized basis [18]. The most important issue for these patients is the aftermath of surgery, where there must be discrimination between remission and relapse of seizures. Remission is considered as, at least, 1 year period without seizures with or without auras. A relapse has been defined to be the occurrence of a seizure after a patient had achieved remission. It is not uncommon patients to have multiple remissions and relapse episodes. Patients that demonstrated relapse during AED reduction were more likely to regain remission than patients who relapsed for other reasons (persistent auras after decrease of clinical seizures, delayed reduction after discharge from hospital, cortical developmental disorders). A randomized trial will be required to answer that question satisfactorily [16]. In general, AED treatment should last for at least 2 years before discontinuation. Almost all neurologists (98%) in a US study,were not willing to discontinue AEDs earlier than one year after asuccessful surgery, and 62% of them would only discontinue AED2 years later[19, 20]. From the patient’s perspective 9 out of 10 patients believethat surgery will allow discontinuation of the medications, and, after extensive education,6 out of 10 still held this belief [19].In seizure-free patients after surgery discontinuation of AED is justified. In case of recurrent seizures there isthe risk of clinical, social, and psychological consequences, and on the otherhand, the low, but significant probability that restarting AEDs may no longer control seizures [19, 20]. Τhe optimum time point in the postoperative period to begin AED reduction is unknown. Rathore et al. reported that, in patients one two or multiple AEDs, tapering can be initiated at the end of the third postoperative month and, in those, who are on monotherapy, after completion of the first postoperative year [6, 7]. Overall, the reviewed studies support one year of postsurgical seizure freedom prior to AED tapering or discontinuing, since safety should be the main aspect of decision-making. 5. DECISION MAKING FOR AED DISCONTINUATION The discontinuation of AEDs may induce changes in the quality of life, including physical changes, due to side effects of medications, changes in driving status, and other potential adverse outcomes for the patient. Almost all the studies considered that AED withdrawal is a safe procedure, but careful selection of patients should be made. The rate of postoperative recurrence of epilepsy after AED withdrawal showed a tendency in patients with a normal MRI appearance and a lack of obvious abnormality preoperatively according to the work of Schiller et al. [21]. On the other hand, the riskiest and most vulnerable group for discontinuation after surgery is that
Zigouris et al.
of patients with hippocampal sclerosis or a diffuse pathology or a multifocal disease in preoperative MRI [6, 7, 11, 15, 16, 20, 22]. The postoperative clinical condition also plays a crucial role. In patients who became not seizure-free postoperative (e.g. persistence of postoperative auras) or after AED discontinuation the risk is higher [11, 15, 17, 22]. Patients with behavioral problems or those who do not tolerate not driving during the period of their AED tapering are not the best candidates for discontinuation [6, 7, 15, 17]. Two studies reported that the period of greatest risk for seizure recurrence was within the first 6 months after surgery, when a 2537% of patients, who were seizure free for two postoperative years, experienced, on average, a recurrence during the period of 8.4-10 postoperative years [10, 22, 23]. In the study carried out by McIntosh et al., the presence of preoperative secondarily generalized seizures and the transition from high to low doses of AEDs carried a greater risk of discontinuation [22]. Continued EEG indications of seizure susceptibility is reported from other studies as an important marker that could make the discontinuation after surgery, difficult [6, 16, 20]. The postoperative intraparenchymal conditions in terms of secondary epileptogenesis mechanisms are still under investigation. A predetermination to recur independently from discontinuation has been suggested, persistence of epileptogenic network or multiple unidentified lesions [13, 15, 24]. Discontinuation of AEDs after surgery is preferred in patients who were operated in an earlier age, until 30 years old or in children, according to Ladino et al. [25]. The preoperative duration of epilepsy is an important positive factor, especially when it is less than 20 years [6, 7,17]. Some studies reported that a safe period before discontinuation is a 2-year seizure-free interval which can be 1 year in children population [6,7,17]. Kim et al. concluded that patients without seizures or auraswithin1 year or more was the 20% [24]. Overall, the reviewed studies support one year of postsurgical seizure freedom prior to AED tapering or discontinuing, since safety should be the main aspect of decision-making [17]. Especially, the patients without seizures or aurasfor one or two postoperative years are reported as “cured” in some studies [10, 22, 24]. On the other hand, recurrent seizures or auras, months or years after surgery for epilepsy, remain unclear having a percentage of 11-14%, giving evidence of what is called “running down phenomenon” [24]. In any case, the reinstitution of AEDs is more effective to control seizures in adults [6, 7, 15]. After temporal lobectomy for epilepsy, the discontinuation of AEDs is safer also where there are no other extra-temporal neuronal assemblies with pathways to non-resected areas [6, 7]. Anterior temporal lobe resection or amygdalohippocampectomy did better than neocortical or multilobar resections in order to control seizures [26]. According to Kanchanatawan et al, the use of gabapentin was a significant predictor variable for a worse outcome, when gabapentin was not the first AED choice for seizure treatment and was used in refractory seizures that failed to respond to treatment with other AEDs. This may show that use of gabapentin should not be regarded as a real explanatory variable. In a few patients, the increased use of levetiracetam post-surgery may be associated with a better outcome at 24 months, whereas in most of the patients no specific characteristics were detected [13]. Evidence is lacking in the area of how many years of seizure freedom are needed prior to a withdrawal in adults. There are no data supporting the withdrawal of AEDs prior to 2 years of remission in adults, when a seizure remission period of 2 years is reasonable before attempting a drug withdrawal in children [27]. CONCLUSION The strategy of AEDs administration or discontinuation after surgery for epilepsy has many unclear aspects, according to the mechanisms of epileptogenesis, the behavior of the neural pathways postoperatively and the complicated association with the outcomes [11, 22]. The majority of studies reports that AEDs withdrawal can manage seizures and does not continue uncontrolled seizures [6, 7,
AED Strategy after Refractory Epilepsy Surgery
17, 18]. The decision to stop treatment should be considered in the light of thesocial, personal and, of course, medical complications of a relapse [18]. The risk of epilepsy after surgery is largely unpredictable appearing in a significant number of patients. Any future randomized controlled trial of AEDs withdrawal in adults should include a minimum follow-up period of 2 years, when in children the known evidence supports more clearly a seizure-free period of 2 years before attempting a discontinuation trial [28]. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENTS The authors thank Miss EleniDimoka for English language editing.
Current Pharmaceutical Design, 2017, Vol. 23, No. 00 [12] [13]
[14] [15] [16] [17]
[18] [19]
REFERENCES [1] [2] [3] [4] [5] [6]
[7] [8] [9] [10] [11]
Kale R: Bringing epilepsy out of the shadows. BMJ. 1997 July 5; 315(7099): 2-3. Fisher RS, Cross JH, D'Souza C et al: Instruction manual for the ILAE 2017 operational classification of seizure types. Epilepsia. 2017 Apr; 58(4): 531-542. Wiebe S: Epilepsy: Outcome patterns in epilepsy surgery—the long-term view. Nature Reviews Neurology 8, 123-124 (March 2012) Trinka, E, Cock H, Hesdorffer D: A definition and classification of status epilepticus—Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia 2015, 56, 1515–1523. Sperling MR, O'Connor MJ, Saykin AJ et al.Temporal lobectomy for refractory epilepsy.JAMA. 1996 Aug 14; 276(6): 470-5. Rathore C, George A, Kesavadas C et al. Extent of initial injury determines language lateralization in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) Epilepsia. 2009 Oct; 50(10): 2249-55. Rathore C, Panda S, Sarma PS et al. How safe is it to withdraw antiepileptic drugs following successful surgery for mesial temporal lobe epilepsy?Epilepsia. 2011 Mar; 52(3): 627-35. Ramey WL, Martirosyan NL, Lieu CM et al. Current management and surgical outcomes of medically intractable epilepsy. ClinNeurolNeurosurg. 2013 Dec; 115(12): 2411-8. Spencer D, Burchiel K: Selective amygdalohippocampectomy. Epilepsy Res Treat. 2012; 2012: 382095. Cascino GD: Surgical Treatment for Extratemporal Epilepsy. Curr Treat Options Neurol. 2004 May; 6(3): 257-262. McIntosh AM, Wilson SJ, Berkovic SF: Seizure outcome after temporal lobectomy: current research practice and findings.Epilepsia. 2001 Oct; 42(10): 1288-307.
[20] [21] [22] [23] [24] [25] [26] [27] [28]
3
Surges R, Elger CE. Reoperation after failed resective epilepsy surgery. Seizure. 2013 Sep; 22(7): 493-501. Kanchanatawan B, Limothai C, Srikijvilaikul T et al. Clinical predictors of 2-year outcome of resective epilepsy surgery in adults with refractory epilepsy: a cohort study.BMJ Open. 2014 Apr 22; 4(4): e004852. Boshuisen K, Schmidt D, Uiterwaal CS: Time to relapse after epilepsy surgery in children: AED withdrawal policies are a contributing factor. Epileptic Disord. 2014 Sep; 16(3): 305-11. Schmidt D, Stavem K: Long-term seizure outcome of surgery versus no surgery for drug-resistant partial epilepsy: a review of controlled studies. Epilepsia. 2009 Jun; 50(6): 1301-9. Berg AT, Vickrey BG, Langfitt JT et al. Reduction of AEDs in postsurgical patients who attain remission.Epilepsia. 2006 Jan; 47(1): 64-71. Téllez-Zenteno JF, Dhar R, Hernandez-Ronquillo L, Wiebe S. Long-term outcomes in epilepsy surgery: antiepileptic drugs, mortality, cognitive and psychosocial aspects.Brain. 2007 Feb; 130(Pt 2): 334-45. Beghi E, Tonini C: Surgery for epilepsy: assessing evidence from observational studies. Epilepsy Res. 2006 Aug; 70(2-3): 97-102. Cole AJ, Wiebe S: Debate: Should antiepileptic drugs be stopped after successful epilepsy surgery? Epilepsia. 2008 Dec; 49 Suppl 9: 29-34. Berg AT, Langfitt JT, Spencer SS et al. Stopping antiepileptic drugs after epilepsy surgery: a survey of U.S. epilepsy center neurologists. Epilepsy&Behavior. 2007 Mar; 10(2): 219-22. Schiller Y, Cascino GD, So EL et al. Discontinuation of antiepileptic drugs after successful epilepsy surgery. Neurology. 2000 Jan 25; 54(2): 346-9. McIntosh AM, Kalnins RM, Mitchell LA et al. Temporal lobectomy: long-term seizure outcome, late recurrence and risks for seizure recurrence.Brain. 2004 Sep; 127(Pt 9): 2018-30. Yoon HH, Kwon HL, Mattson RH et al. Long-term seizure outcome in patients initially seizure-free after resective epilepsy surgery. Neurology. 2003 Aug 26; 61(4): 445-50. Kim DW, Lee SY, Lee SK: Focal Epileptogenic Lesions in Adult Patients with Epilepsy and Generalized Epileptiform Discharges. J Epilepsy Res. 2016 Dec 31; 6(2): 75-78. Ladino LD, Hernández-Ronquillo L, Téllez-Zenteno JF: Management of antiepileptic drugs following epilepsy surgery: a metaanalysis. Epilepsy Res. 2014 May; 108(4): 765-74. Engel J Jr: Clinical neurophysiology, neuroimaging, and the surgical treatment of epilepsy. Current Opinion in Neurology and Neurosurgery. 1993 Apr; 6(2): 240-9. Hixson JD: Stopping Antiepileptic Drugs: When and Why? Curr Treat Options Neurol. 2010 Sep; 12(5): 434–442. Sirven J, Sperling MR, Wingerchuk DM: Early versus late antiepileptic drug withdrawal for people with epilepsy in remission. The Cochrane Library 2010, Issue 4.
