doi:10.1684/epd.2012.0497 Italy Catanzaro, 88100 Europa, Viale Germaneto, Universitario Campus Græcia”, “Magna Studi degli Università Neurologia, di U.O. ed Cattedra Labate Angelo Correspondence: plpi iod o.1,N.2 ue2012 June 2, No. 14, Vol. Disord, Epileptic ABSTRACT 3 2 1 Labate Angelo study open-label an epilepsy: lobe temporal and Topiramate e words: well Key very TLE. and mild effective with particular patients is in TPM tolerated TLE. in effectively frequency mg/day 50-600 seizure of reduces doses at discontinued therapy add-on patient or monotherapy one either effects. and adverse well to respond due TPM not a did showed patients Two achieved 10 quency. patients 41 whereas of 28 freedom, total, In seizure (n=12). switch the recorded. treatment. before after therapy were years add-on mg/day, two 50-600 antiepileptic events least TPM, at received other adverse of Patients Results period . taken a and (TLE) for having conducted changes epilepsy was after Follow-up frequency lobe or Seizure temporal directly drugs. monotherapy with as years) received Patients Italy. TPM Catanzaro, 54+18 of University Unit, age Epilepsy the to referred study. mean seizures female, observational epileptic (20 lobe an temporal on with patients based for monotherapy as (TPM) eevdNvme 2 01 cetdFbur 9 2012 29, February Accepted 2011; 12, November Received met Aguglia Umberto lncltil fTMa adjunc- as TPM of trials clinical Jette 2002; al., et receptor (Kaminski glutamate acid AMPA/kainate propionic methyl-4-isoxazole amino-3-hydroxy-5- and of neurons, antagonism into influx GABA-mediated chloride increasing tance, an conduc- sodium as on effect such inhibitory TPM actions that multiple exerts indicated models these models animal (Park anti- in striking action novel having have epileptic to a (AED) shown is been an drug It as antiepileptic drug. used antidiabetic initially from derived D-fructose, is (TPM) Topiramate nttt fNuooia cecs ainlRsac oni,Csna Italy Cosenza, Council, Research National Sciences, Cosenza Neurological Hospital, of Annunziata Institute Division, Neurology Neuroscience, of Catanzaro Department Græcia, Magna University Neurology, of Institute rgnlarticle Original plpi iod21;1 2:163-6 (2): 14 2012; Disord Epileptic ,20) h s of use The 2008). al., et – oiaae eprllb plpy niplpi drugs antiepileptic epilepsy, lobe temporal topiramate, ,20;Herrero 2004; al., et oeaut h fcc n oeaiiyo topiramate of tolerability and efficacy the evaluate To Purpose. ,20) Several 2008). al., et 1 noi Siniscalchi Antonio , 1 loQuattrone Aldo , u eut ofimta P as TPM that confirm results Our Conclusions. eeautd4 patients 41 evaluated We Methods. nybe vlae naut with adults in evaluated been mono- only has AEDs, as other many TPM for as of therapy, For efficacy monotherapy. the as TLE, used be also could drug this that suggested epilepsy (TLE), epilepsy, lobe temporal for with refractory mainly therapy with adjunctive results patients as excellent TPM The of 2000). al., et (Glauser generali- syndrome with Lennox-Gastaut associated seizures (Bergey, primary and seizures 2005), 2008), tonic-clonic sed al., et ieaantprilostseizures partial-onset (Giannakodimos against effec- actions, tive has of spectrum TPM AEDs broad a that standard demonstrated with have therapy tive 0 euto fsiuefre- seizure of reduction ≥50% 1 2 noi Gambardella Antonio , ar Mumoli Laura , enovo de 2)o ntal as initially or (n=29) 05 Jette 2005; al. et 1 , 163 3 A. Labate, et al.

chronic, refractory partial-onset seizures (Sachdeo were labelled as unilateral if confined to one temporal et al., 1997), despite some forms of epilepsy having a side at least 95% of the time. All patients had a conven- mild course. Recent studies described clinical features tional MRI (1.5 Tesla) examination, based on a protocol and outcome of TLE patients who had a benign form of routinely used for patients with epilepsy (Labate et al., TLE (bTLE) (Aguglia et al., 1998; Gambardella et al., 2003; 2006), including T2-weighted images, and a coronal Labate et al., 2011). Furthermore, MRI evidence of hip- 3D sequence with contiguous slices, with and with- pocampal sclerosis (HS) in about 40% of these patients out administration of gadolinium. Exclusion criteria with bTLE has pointed out that the presence of HS itself were: extratemporal epilepsies, generalised epilep- does not necessarily indicate intractable epilepsy with sies, status epilepticus, epilepsia partialis continua, a worse outcome as previously thought (Labate et al., non-epileptic seizures, clinically significant laboratory 2006; Labate et al., 2008; Labate et al., 2011). abnormalities, nephrolithiasis, mental retardation, To evaluate the efficacy of TPM in a population of TLE poor compliance, pregnancy, alcohol or drug abuse patients with mild and refractory partial epilepsy, we within the past years, hypersensitivity to carbonic conducted an observational open-label study in adults anhydrase inhibitors or sulfonamides, and suicide and children taking TPM as monotherapy or as a sec- attempt or psychiatric disorder requiring therapy. Each ond AED choice due to inefficacy of the first AED. patient received a starting dose of 12.5 mg TPM nightly for a week and a following increment to at least 50 mg/day over four weeks, while withdrawl of any anti- Patients and methods convulsant being used previously without efficacy was initiated. This open-label study was conducted at an epilepsy Patients were clinically observed every three months outpatient clinic at the University of Catanzaro from during a follow-up of more than two years. Firstly, June 2009. Patients were eligible for the study if they the efficacy was assessed by measuring changes in were at least three years of age. The study group con- seizure frequency and secondly, side effects and tole- sisted of 41 consecutive patients (20 females; mean rability were observed. We classified patients after age: 54+18 years) referred to our clinic and recruited treatment into four categories: seizure freedom, ≥50% prospectively. The study was approved by the Uni- seizure reduction; <50% seizure reduction, and those versity Hospital Ethics Committee and all subjects that withdrew from the trial. Diagnosis, treatment deci- and their guardians, in the case of children, gave sion and grading the efficacy were made by a single informed consent to participate. For all patients, the trained neurologist with special expertise in epilepsy diagnosis of epilepsy was based on the International (AL). Classification of Epilepsies (Commission, 1989). The Categorical variables were reported as counts and following features were noted: sex, age, history of percentage. Frequency distributions among patient migraine, seizure type, AEDs used prior to TPM, age groups were compared using the ␹2 test and Monte at epilepsy onset, seizure frequency, abnormal phy- Carlo or Fisher exact test, as appropriate, when the sical and neurological examination, family history of expected frequencies were low. The unpaired t-test epilepsy or febrile convulsions (FC), and laboratory was used to evaluate differences in mean of conti- and neuroimaging findings. Seizure types were identi- nuous variables among groups. Statistical analysis was fied according to the classification of epileptic seizures performed using the Statistical Package for Social and syndromes by the International League Against Science software (SPSS, version 17.0, Chicago, IL) for Epilepsy (Commission, 1989). The diagnosis of TLE was Windows. made on the basis of a constellation of clinical, EEG, and MRI criteria which are considered to be reliable inter- ictal indicators of TLE (Commission, 1989). The diagno- Results sis of TLE was mainly based on typical temporal auras or interictal EEG discharges, maximum over the tempo- Clinical characteristics of patients are summarised in ral lobes. Any suggestion of seizure onset outside the table 1. In detail, 29 (70%) of 41 subjects had benign mesial temporal structures by semiology or EEG find- TLE with very mild epilepsy (bTLE), i.e. seizure-free ings was an exclusion criterion. All patients underwent patients or patients with either occasional auras or not several interictal EEGs including routine EEGs while more than two disabling (complex partial or secondary awake and asleep. The interictal EEGs were recorded generalised) seizures per year for at least two follow- according to the 10-20 international system with sup- ing years. The remaining 12 subjects had symptomatic plementary T1 and T2 electrodes (Gambardella et al., epilepsy (sTLE); four of these patients had HS, four 1998). The EEG abnormalities (spikes, spike waves, and patients had vascular lesions, two patients had a brain runs of sharp theta/delta waves of temporal intermit- tumour, and three had post-traumatic gliosis. The diag- tent rhythmic delta activity over one temporal region) nosis of both bTLE and sTLE was made before starting

164 Epileptic Disord, Vol. 14, No. 2, June 2012 Topiramate and TLE

Table 1. Features in patients with bTLE or sTLE. 40

35 Clinical Features bTLE sTLE (n=29) (n=12) 30 25 ± ± ± Age (Mean SD) 57 17 52 19 20 bTLE

± ± ± 15 Age at onset (Mean SD) 48 18,7 34,7 21,3 N° Patients 10 sTLE Sex (n, %) bTLE 5 sTLE Male 13 8 sTLE bTLE Female 16 4 0 Seizure freedom ≥50-99% Seizure <50% Seizure Drop out frequency reduction frequency reduction Familial history of epilepsy (n,%) 5 (17) 3 (25) Response to TPM therapy Febrile convulsions (n,%) 1 (3,4) 1 (8,3) Figure 1. Overall response to TPM treatment in patients with Mean dose of TPM (mg/day) 197±13 379±13 bTLE and sTLE.

EEG (n, %) Normal 8 0 between sex (p=0.240), age at onset (p=0.097), and Left spikes or/and sharp waves 7 7 family history of epilepsy (p=0.240). Right spikes or/and 11 2 No changes on interictal EEGs were observed during sharp waves the follow-up. Bilateral spikes or/and 33 sharp waves Discussion

Previous drugs (n, %) To our knowledge, this is the first open-label study that Carbamazepine 6 reports on the efficacy and safety of TPM as mono- Clobazam 2 therapy for the treatment of temporal lobe epileptic Lamotrigine 2 patients regardless of their seizure frequency. Fenobarbital 2 TPM has been extensively reported to be effective as None 29 add-on therapy for refractory partial epilepsy in sev- bTLE benign temporal lobe epilepsy; sTLE: symptomatic temporal eral placebo-controlled studies (Sachdeo et al., 1997; lobe epilepsy; TPM: topiramate. Giannakodimos et al., 2005; Jette et al., 2008). However, we have recently showed that many patients with TLE TPM treatment. The vast majority (36 patients, 87%) have a benign evolution and very good response to reported a history of migraine. AEDs, regardless of the presence of HS (Labate et al., All patients with bTLE (70%) received TPM as de novo 2006; Labate et al., 2008; Labate et al., 2011). Our results monotherapy while 12 with sTLE received TPM initially further confirm that TPM, even at low doses, is very as add-on therapy to other drugs (carbamazepine, effective and well tolerated in partial-onset epilepsy lamotrigine, and valproate) before the switch. The with mild outcome. In fact, the dosage evaluated in mean dose of TPM achieved was 250±109 mg. As this work ranged from 50 to 600 mg/day. shown in figure 1, seizure frequency was dramati- We observed, over a period of more than two years, cally reduced for the great majority of our population 41 consecutive patients who were referred to our (93%). Of 41 patients, 28 (93%; 19 with bTLE and clinic with either benign or symptomatic temporal lobe nine with sTLE) reached seizure freedom. Ten patients epilepsy. TPM was administered at a common dosage (25%; seven with bTLE and three with sTLE) showed on average of 200 mg daily. Simple and complex par- reduction in seizure frequency by more than 50%. tial seizures dramatically improved in response to TPM Only two subjects had an unsatisfactory response and in fact 38 patients achieved seizure reduction. with less than 50% reduction of seizures. One patient Of these, 28 subjects obtained seizure freedom and dropped out from the study because of side effects the remaining 10 patients achieved more than 50% (excessive somnolence), and a gradual and not exces- reduction in seizure frequency. Interestingly, seizure sive decrease (average of 2 kilograms) in body weight freedom was experienced mainly among patients with occurred during TPM therapy in four patients. Some bTLE (19 of 28 patients) who received TPM de novo. patients (three with bTLE) during the follow-up spon- Moreover, for nine of 12 patients with sTLE, seizure taneously reduced the dose of TPM because of very freedom was observed. The efficacy of TPM was consis- rare simple partial auras (one per year). Between the tent even as add-on therapy. In this small subgroup of two groups, we did not observe statistical difference patients (n=12) taking different concomitant AEDs that

Epileptic Disord, Vol. 14, No. 2, June 2012 165 A. Labate, et al.

were quickly withdrawn throughout the follow-up, the firing of dentate granule cells to a sustained rhythmic mode effect of TPM cannot be attributed to pharmacokinetic in temporal lobe epilepsy. J Neurosci 2011; 31: 10811-8. or pharmacodynamic interactions. Bergey GK. Evidence-based treatment of idiopathic gene- The present study reinforces the awareness of the ralized epilepsies with new antiepileptic drugs. Epilepsia safety profile of TPM, similar to previous reports. 2005; 46: 161-8. Indeed, side effects were not observed in any patients Commission on Classification Terminology of the Inter- except for one patient, demonstrating that TPM was national League Against Epilepsy. Proposal for revised very well tolerated. Nevertheless, as in other TPM classification of epilepsies and epileptic syndromes. Epilepsia trials (El Yaman et al., 2007), a gradual and not exces- 1989; 30: 389-99. sive decrease (average of 2 kilograms) in body weight occurred during TPM therapy in four patients. No El Yaman SH, Mroueh SM, Sinno DD, Mikati MA. Long-term patterns of weight changes during topiramate therapy: an clinical noteworthy findings were reported based on observational study. Neurology 2007; 69: 310-1. clinical laboratory tests, neurological examinations, or physical examinations. Gambardella A, Pucci F, La Piane E, et al. Usefulness of TPM is effective for a broad spectrum of epileptic syn- latero-orbital electrodes in detecting interictal epileptiform activity-a study of 60 patients with complex partial seizures. dromes and our data suggest that TPM might be a very Electroencephalogr Clin Neurophysiol 1998; 107: 174-6. good alternative to other AEDs such as carbamazepine commonly used for the treatment of partial-onset Gambardella A, Manna I, Labate A, et al. GABA(B) receptor 1 seizures, especially for patients with bTLE. Clearly, polymorphism (G1465A) is associated with temporal lobe future studies using a double-blind approach would epilepsy. Neurology 2003; 60: 560-3. strengthen our findings in the same population. Giannakodimos ST, Georgiadis G, Tsounis ST, et al.Add- Interestingly, TPM that is widely used preventively on topiramate in the treatment of refractory partial-onset against migraines also significantly improved migraine epilepsy: clinical experience of outpatient epilepsy clinics attacks in most of our epileptic patients. from 11 general hospitals. Seizure 2005; 14: 396-402. TPM, which acts at different neural transmission levels, Glauser TA, Levisohn PM, Ritter F, Sachdeo RC. Topiramate in has been reported to have a selective antagonist Lennox-Gastaut syndrome: open-label treatment of patients effect on the ␣-amino-3-hydroxy-5-methyl-4-isoxazole completing a randomized controlled trial. Topiramate YL propionic acid AMPA/kainate glutamate receptor Study Group. Epilepsia 2000; 41: S86-90. (Siniscalchi et al., 2010). Previous reports showed that Herrero AI, Del Olmo N, González-Escalada JR, Solís JM. the AMPA/kainate glutamate receptor is involved in Two new actions of topiramate: inhibition of depolarizing temporal lobe epilepsy (Artinian et al., 2011) and GABA(A)-mediated responses and activation of a potassium in the genesis of migraine (Andreou and Goadsby, conductance. Neuropharmacology 2002; 42: 210-20. 2011). Therefore, a possible explanation of the posi- Jette N, Hemming K, Hutton JL, Marson AG. Topiramate add- tive effects of topiramate in our patients could be the on for drug-resistant partial epilepsy. Cochrane Database modulation of AMPA/kainate glutamate receptors. Syst Rev 2008; 3: CD001417. In conclusion, our results show that nearly two thirds Kaminski RM, Banerjee M, Rogawski MA. Topiramate selec- of TLE patients treated with TPM remained seizure-free tively protects against seizures induced by ATPA, a GluR5 during follow-up. Once titrated to an effective dose, kainate receptor agonist. Neuropharmacology 2004; 46: 1097- 104. TPM may therefore be used as a first drug for the treat- ment of patients with TLE, especially with mild course Labate A, Ventura P, Gambardella A, et al. MRI evidence of and associated migraine.
mesial temporal sclerosis in sporadic “benign” temporal lobe epilepsy. Neurology 2006; 66: 562-5. Disclosures. Labate A, Cerasa A, Gambardella A, Aguglia U, Quattrone A. The authors report no conflicts of interest. Hippocampal and thalamic atrophy in mild temporal lobe epilepsy: a VBM study. Neurology 2008; 71: 1094-101. Labate A, Gambardella A, Andermann E, et al. Benign mesial References temporal lobe epilepsy. Nat Rev Neurol 2011; 7: 237-40. Park HJ, Kim HJ, Park HJ, et al. Protective effect of topira- Aguglia U, Gambardella A, Le Piane E, et al. Mild non-lesional mate on kainic acid-induced cell death in mice hippocampus. temporal lobe epilepsy. a common unrecognized disorder Epilepsia 2008; 49: 163-7. with onset in adulthood. Can J Neurol Sci 1998; 25: 282-6. Sachdeo RC, Reife RA, Lim P, Pledger G. Topiramate Andreou AP, Goadsby PJ. Topiramate in the treatment of monotherapy for partial onset seizures. Epilepsia 1997; 38: migraine: a kainite glutamate receptor antagonist within the 294-300. trigeminothalamic pathway. Cephalgia 2011; 31: 1343-58. Siniscalchi A, Gallelli L, De Sarro GB. Use of antiepileptic Artinian J, Peret A, Marti G, Epsztein J, Crépel V. Synaptic drugs for hyperkinetic movement disorders. Curr Neurophar- kainite receptors in interplay with INA shift the sparse macol 2010; 8: 359-66.

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