Preliminary reports have suggested a possible 'aetiology-specific' efficacy of tiagabine (TGB) in patients with drug-resistant partial epilepsy (DRPE) related to cerebral glial tumors (GTs). This efficacy should be related to selective blocking of GAT-1 transporter by TGB. We presented our open-label, add-on TGB experience in a group of patients with GTs, compared with other symptomatic DRPEs of different aetiology.eleven patients with DRPE related to oligodendroglioma (six cases), astrocytoma (4) or multiform gliobastoma (1); 12 patients with DRPE related to a miscellanea of CNS lesions. TGB was added to previous AEDs, at dosage of 20-60 mg per die. Responders are defined by seizure frequency reduction >50\% compared with baseline.Seven patients are responders with three seizure-free (SF) in GTs group, a rate of efficacy much higher than in matching group (63.6 vs. 16.6\%). Adverse events have been observed only rarely, not leading to discontinuation, in GTs group.This preliminary observation seems to confirm the high efficacy and tolerability of TGB in DRPE related to GTs

C.  Nocerino

L.  Bilo

P.  Boccella

P.  Striano

S.  Striano

STRIANO, SALVATORE

BILO, LEONILDA

P. Striano

P. Boccella

C. Nocerino

Archivio della ricerca - Università degli studi di Napoli Federico II

Epilepsy Research 49 (2002) 81–85Short communicationTiagabine in glial tumorsSalvatore Striano *, Pasquale Striano, Patrizia Boccella, Cristofaro Nocerino,Leonilda BiloDepartment of Neurological Sciences, Epilepsy Center, ‘‘Federico II’’ Uniersity, Naples, ItalyReceived 4 January 2002; accepted 8 January 2002AbstractRationale and purpose: Preliminary reports have suggested a possible ‘aetiology-specific’ efficacy of tiagabine (TGB)in patients with drug-resistant partial epilepsy (DRPE) related to cerebral glial tumors (GTs). This efficacy should berelated to selective blocking of GAT-1 transporter by TGB. We presented our open-label, add-on TGB experience ina group of patients with GTs, compared with other symptomatic DRPEs of different aetiology. Material and methods:eleven patients with DRPE related to oligodendroglioma (six cases), astrocytoma (4) or multiform gliobastoma (1);12 patients with DRPE related to a miscellanea of CNS lesions. TGB was added to previous AEDs, at dosage of20–60 mg per die. Responders are defined by seizure frequency reduction 50% compared with baseline. Results:Seven patients are responders with three seizure-free (SF) in GTs group, a rate of efficacy much higher than inmatching group (63.6 vs. 16.6%). Adverse events have been observed only rarely, not leading to discontinuation, inGTs group. Conclusion: This preliminary observation seems to confirm the high efficacy and tolerability of TGB inDRPE related to GTs. © 2002 Elsevier Science B.V. All rights reserved.Keywords: Tiagabine; Drug resistant epilepsy; Cerebral gliomaswww.elsevier.com/locate/epilepsyres1. IntroductionTiagabine (TGB) is a new antiepileptic drug(AED), acting through the enhancement ofGABA-mediated inhibition. In detail, it selectivelyblocks GAT-1 type of GABA transporter (Bordenet al., 1994) thus inhibiting the reuptake of GABAand increasing its cerebral concentration in rodent(Fink-Jensen et al., 1992) and in human (Duringet al., 1992) synapses. Recent clinical studiesshowed a long-term efficacy of TGB in about 30%of patients with partial seizures (Loiseau, 1999;Crawford et al., 2001).One preliminary report has suggested TGBcould have a particular efficacy in epilepsy sec-ondary to glial tumors (GTs) of the central ner-vous system (CNS), likely related to its specificmechanism of action (Dean et al., 1998).In this paper, we report about the effect of TGBadd-on therapy in a group of patients with drug-resistant partial epilepsy (DRPE) related to GTs.In the attempt to demonstrate a possible ‘aetiol-ogy-specific’ efficacy, the data are matched with agroup of symptomatic DRPEs related to a miscel-lanea of CNS lesions.* Corresponding author. Tel./fax: +39-81-7463509.E-mail address: sstriano@libero.it (S. Striano).0920-1211/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved.PII: S0920 -1211 (02 )00005 -0S. Striano et al. / Epilepsy Research 49 (2002) 81–85822. Methods2.1. PopulationEleven patients (6 M, 5 F; age: 10–52 years,mean: 32.5) with DRPE secondary to GTs. Clini-cal data of this group are summarized in Table 1.Ten patients had been submitted to surgical resec-tion, and seven also to radiation therapy; thespecific aetiology, according to WHO criteria(Kleihues et al., 1993), was: oligodendroglioma insix cases, astrocytoma in three, and multiformglioblastoma in one. Another patient, with a MRIdiagnosed astrocytoma, was inoperable, becauseof his tumor location. Among the ten operatedpatients, resection had been only partial in eightof them. Epilepsy was characterized by simple(SPS) or complex partial (CPS) seizures, withsecondary generalization in one case. All patientswere resistant to previous therapy, with at leasttwo seizures per month, and more than oneseizure per day in five patients, during the 2-month baseline period. Epilepsy duration rangedbetween 1 and 20 years (mean: 7.36). TGB wasadded with a slow increasing schedule (5 mg everyweek) to previous AED regimen, at dosage of20–60 mg per die, in three daily doses, accordingto clinical response and tolerability. AssociatedAEDs were CBZ in eight patients, PB and PHT infour, LTG in two and VGB in one. Eight patientswere taking two drugs, with an average of 1.72AED per patient.Previous therapy remained unchanged duringbaseline and add-on phase.The GTs group was matched with a smallgroup of patients affected from DRPEs related toa miscellanea of lesional aetiologies, treated withopen-label TGB add-on, and comparable proto-col, in the same period of time. This group wasformed by 12 patients (8 M, 4F; age: 23–60 years,mean: 35); the syndromic diagnosis was temporallobe epilepsy in nine, and frontal (FLE), parietaland occipital lobe epilepsy in the other threepatients. The specific underlying aetiology was:hyppocampal sclerosis in five, perinatal injury inthree, cortical dysplasia (CD) in two, post-surgicalmalacia in one, and Rasmussen encephalitis (pre-viously treated with subtotal callosotomy, too) inanother one. Epilepsy was of long-duration (3–40years, mean: 21.5) and severe in all of them, withat least five seizure per month, and more than 1per day in three cases; associated treatment was1–3 AEDs (mean: 1.91 per patient): CBZ in six,OXC in four, LTG and CLB in three, PB andVPA in two, PHT, TPM and FLB in one. Pa-tients are considered reponders if the frequency ofseizures decreased, in a follow-up period at leastof 1 year, more than 50% of baseline, withoutintolerable adverse effects (AEs).3. Results3.1. GTs groupSeven patients (63.6%) are responders, withthree (27.2%) seizure-free (SF), without differenceby seizure type. Tolerability of TGB was good inall but two patients; referred AEs were nausea inone case, not leading to drop-out, and tiredness inanother, not-responder, patient.Patient 8 shifted her CPS in very frequent SPS,with disagreeable epigastric aura, so leading todrop-out. No relevant changes in plasma concen-tration of concomitant AEDs was noticed duringadd-on of TGB.3.2. Matching groupTwo patients (16.6%) are responders, withoutSF cases. One patient, with FLE, and anotherwith CD, dropped-out during titration phase, dueto worsening of seizure frequency and severity;another patient dropped-out, because of appear-ance of myoclonus. Furthermore, minor AEs (as-thenia, dizziness) were reported in twonon-responders patients.4. DiscussionValue of this clinical observation is limited andit should be interpreted with criticism. The sampleof patients is small, and possible confusion can berelated to the natural evolution of disease. Inaddition, this open-label add-on treatment canS. Striano et al. / Epilepsy Research 49 (2002) 81–85 83Table1ClinicaldataofGTsgroupKindoftumorSex,Radio-therapySeizuretypeFrequencyAdd-onAEDsPatientTGBmaxdoseSurgicalOutcomeandlocalizationyears(mgperdie)resection(year)Yes1CPS,SPSLefttemporal10per[GVG,PB]60ResponderaM,20Partial(1995)astrocytoma(lowmonthCBZgrade)2Partial(1991)YesCPS1perday[PHT]Leftfrontal45ResponderM,33CBZ+LTGoligodendroglioma(relapse)YesSPS2permonthPB+PHTRightfrontal303ResponderM,36Partial(1998)oligodendroglioma(lowgrade)RightfrontalPartial(1999)YesSPS,GTCS10perPB+PHT30NotresponderM,494monthmultiformglioblastomaSPS51perdayRightparietalCBZ30ResponderM,29Partial(1997)YesoligodendrogliomaYesCPS1perdayCBZ+PB45Partial(1989)SF6F,20LefttemporalpilocitycastrocytomaCPS1perday[PB]M,33307NotresponderaLeftoccipitalTotal(1981)NoCBZ+GVGoligodendrogliomaCPS10perNoCBZ+LTGPartial(1996)308NotresponderbLefttemporalF,45montholigodendrogliomaSPS91perdayRightrolandic[CNP]M,5230SFNoNoastrocytomaPHT+PBCPS2permonth[PB,GPT]CBZ30Total(1989)SFRighttemporalF,31No10oligodendrogliomaYes11CPSLeftfrontal15perF,10PB+CBZ20NotresponderPartial(1999)monthastrocytoma(relapse)[],previous,discontinuedAEDs;SPS,simplepartialseizure;CPS,complexpartialseizures;GTCS,secondarilygeneralizedtonicclonicseizures;SF,seizure-free.aAdverseeffects.bAppearanceofSPS.S. Striano et al. / Epilepsy Research 49 (2002) 81–8584not be reasonably compared with double blind,randomized, placebo-controlled, fixed drug regu-latory trials.In the attempt to evidence a possible aetiology-specific efficacy, we matched the GTs group witha group of very severe epilepsy related to a varietyof lesional aetiologies. However, also this com-parison must be interpreted cautiously. Age ofpatients, type and frequency of seizures, numberand type of associated AEDs are similar in bothgroups, but duration of epilepsy is much longer inthe control than in GTs group (21.5 vs. 7.36years). Therefore, the long duration of epilepsycould justify the very low rate of responders in thematching group.However, despite these limitations, TGB seemsto be very effective in DRPE related to cerebralGTs: about 2/3 of our patients are responders,with higher rate of efficacy compared with Litera-ture data (Loiseau, 1999; Crawford et al., 2001);in addition, tolerability is generally good.However, the hypothesis of a relatively specific,aetiology-related, efficacy of TGB in DRPE dueto GTs should be confirmed in larger, policentric,double blind trials.Possible role of TGB in GTs could be related tointeraction of underlying pathology with its spe-cific mechanism of action. TBG acts through theinhibition of GABA reuptake, thus increasing itsconcentration in brain (Fink-Jensen et al., 1992;During et al., 1992). GABA reuptake is realizedby at least four different transporters (Borden,1996; Roettger and Amara, 1999); TGB blocksmostly GAT-1, and, in a lesser extent, GAT-3(Borden et al., 1994). In the rat, GAT-1 is pre-dominantly localized to GABAergic neural termi-nals, but, at least in some cerebral regions, it isfound additionally or exclusively in glia (Minelliet al., 1995); therefore, higher efficacy in GTscould simply be related to particular plenty ofGAT-1 in neoplastic tissue derived from cells ofglial line. However, the specific mechanism lead-ing to epileptic seizures in patients with GTs isstill debated. In particular, is not clear whetherthe tumor transforms the normal surroundingbrain tissue into an epileptic structure, thus induc-ing the seizures, or if neoplastic tissue itself con-tains epileptogenic cells. Recent in vitro studiesshowed that brain slices obtained from humansurgical material from oligodendroglioma cangenerate action potentials, so making as electri-cally excitable cells, at least in first days of itsgrowth.In other words, cells derived from glial linecould transitorily acquire neuronal properties,and serving as epileptogenic substrate (Ketten-mann, 1999). Obviously, data from a clinical trialare not enough to give sufficient answers in favorof an ipothesis or the other one; in vitro studieson neoplastic tissue, e.g. with patch-clamp tech-nique, could probably offer more precise informa-tions about TGB mechanism of action in thesecell population.ReferencesBorden, L.A., 1996. GABA transporter heterogeneity: phar-macology and cellular localization. Neurochem. Int. 4,335–356.Borden, L.A., Murali-Dhar, T.G., Smith, K.E., Weinsshank,R.L., Branchek, T.A., Gluchowski, C., 1994. Tiagabine,SK&F 89976A, CI-966 and NNC-711 are selective for thecloned GABA transporter GAT-1. Eur. J. Pharmacol.Mol. Pharmacol. 269, 219–224.Crawford, P., Meinardi, H., Brown, S., et al., 2001. Tiagabine:efficacy and safety in adjunctive treatment of partialseizures. Epilepsia 42 (4), 531–538.Dean, A.C., Godsey, C., Matsuo, F., 1998. Utility ofTiagabine (TGB) in epilepsy patients with glial tumors[abstract]. Epilepsia 39 (Suppl 6), 57.During, M., Mattson, R.H., Scheyer, R., et al., 1992. Theeffect of tiagabine HCL on extracellular GABA levels inthe human hippocampus [abstract]. Epilepsia 33, 83.Fink-Jensen, A., Suzdak, P.D., Sweberg, M.D.B., Judge,M.E., Hansen, L., Nielsen, P.G., 1992. The GABA uptakeinhibitor, tiagabine, increases extracellular levels of GABAin awake rats. Eur. J. Pharmacol. Mol. Pharmacol. 220,197–201.Kettenmann, H., 1999. Physiology of glial cells. In: Delgado-Escueta, A.V., Wilson, W.A., Olsen, R.W., Porter, R.J.(Eds.), Jasper’s Mechanism of the Epilepsies, Advances inNeurology, vol. 79, third ed. Lippincott Williams&Wilkins, Philadelphia, PA, pp. 565–571.Kleihues, P.C., Burger, P.C., Scheithauer, B.W., 1993. WorldHealth Organization international histological classifica-tion of tumors. Histological typing of tumor of centralnervous system. Springer, Geneve.Loiseau, P., 1999. Review of controlled trials of Gabitril(Tiagabine): a clinician’s viewpoint. Epilepsia 40 (Suppl. 9),S14–S19.S. Striano et al. / Epilepsy Research 49 (2002) 81–85 85Minelli, A., Brecha, N.C., Karschin, C., DeBiasi, S., Conti, F.,1995. GAT-1, a high-affinity GABA plasma membranetransporter, is localized to neurons and astroglia in thecerebral cortex. J. Neurosci. 15, 7734–7746.Roettger, V.R., Amara, S.G., 1999. GABA and glutamatetransporters: therapeutic an etiologic implications forepilepsy. In: Delgado-Escueta, A.V., Wilson, W.A., Olsen,R.W., Porter, R.J. (Eds.), Jasper’s Mechanism of theEpilepsies. Advances in Neurology, vol. 79, third ed. Lip-pincott Williams & Wilkins, Philadelphia, PA, pp. 551–560.

Tiagabine in glial tumors.

Tiagabine in glial tumors.

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