Epilepsia, 51(1):3742, 2010 doi: 10.1111/j.1528-1167.2009.02141.

FULL-LENGTH ORIGINAL RESEARCH

Early versus late remission in a cohort of patients with newly diagnosed epilepsy
*Alessandra Del Felice, yEttore Beghi, zGiovanni Boero, xAngela La Neve, {Graziella Bogliun, xAlessia De Palo, and **Luigi M. Specchio
` degli Studi di Verona, Italy; *Clinica Neurologica, Dipartimento di Neurologia e Scienze della Visione, Universita yLaboratorio di Malattie Neurologiche, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy; ` degli zDivisione di Neurologia, Ospedale di Taranto, Italy; xCentro per lEpilessia, II Clinica Neurologica, Universita Studi di Bari, Italy; {Centro Epilessia, Ospedale San Gerardo, Monza, Italy; **Clinica delle Malattie del Sistema ` di Foggia, Italy Nervoso, Universita

SUMMARY
Purpose: To count patients with newly diagnosed epilepsy entering early and late remission and to identify prognostic predictors of late remission. Methods: Children and adults with previously untreated epilepsy from two Italian tertiary centers (Monza, Bari) were the study population. All patients received monotherapy at treatment start; drug choice and schedule were left to the physicians judgment. A retrospective audit was performed and the following prognostic predictors were identied: age, gender, putative etiology, rst electroencephalography (EEG) record, neurologic and psychiatric examination, disease duration at diagnosis, seizure type(s) and number prior to starting treatment, epilepsy syndrome, and rst antiepileptic drug. Early remission was dened by 2-year seizure control immediately after treatment start. Late remission was dened by 2-year seizure control achieved at least 24 months after treatment start. Prognostic pre-

dictors were assessed by logistic regression analysis, adjusting for age, gender, and center. Results: One hundred seventy-four women and 178 men (mean age 31.5 years) were included and followed for 2399.6 person-years. The cumulative time-dependent probability of 2-year remission was 56.3% at 2 years after treatment start, and 62.6, 69.4, and 79.5% at 3, 5, and 10 years. One hundred fteen patients (23.0%) achieved early remission and 38 patients (10.8%) achieved late remission. The interaction between partial seizures and number of seizures prior to treatment was the only independent predictor of late remission. Discussion: The course of epilepsy and the chance of remission are together a complex and dynamic process, possibly explained by the diversity of the mechanisms underlying drug response and the use of an increasing number of drugs. KEY WORDS: Prognosis, Epilepsy, Remission, Prognostic predictors.

The chance of seizure remission in epilepsy is an evolving concept. Epidemiologic studies indicate that 6080% of patients with newly diagnosed epilepsy achieve remission at some time after the onset of the disease (Annegers et al.,1979; Cockerell et al., 1997; Sillanp et al., 1998). Three different remission patterns have been recently identified: early remission (i.e., remission immediately
Accepted March 3, 2009; Early View publication June 1, 2009. Address correspondence to Dr. Ettore Beghi, Istituto di Ricerche Farmacologiche Mario Negri, Via G. la Masa 19, 20156 Milano, Italy. E-mail: beghi@marionegri.it Wiley Periodicals, Inc. 2009 International League Against Epilepsy

after or in the first year after diagnosis/start of drug treatment), late remission (i.e., remission starting even several years after diagnosis/start of drug treatment), and periods of remission alternating to relapse (identifying a relapsing-remitting course) (Sillanp & Schmidt, 2006). Early recognition of these patterns is helpful because of the differing medical and social consequences. Early remission has been intensively investigated and a number of negative predictors have been identified. These include a documented etiology of seizures (Annegers et al., 1979; Berg et al., 2001; Jallon, 2003), the presence of electroencephalography (EEG) abnormalities (Shafer et al., 1988; Berg et al., 2001), recurrence of seizures 37

38 A. Del Felice et al. during the first months of disease (Brorson & Wranne, 1987; Collaborative Group for the Study of Epilepsy, 1992; Sillanp, 1993; Arts et al., 1999; MacDonald et al., 2000; Lindsten et al., 2001), and lack of response to the first antiepileptic drug (AED) (Camfield et al., 1997; Kwan & Brodie, 2000; Dlugos et al., 2001). In contrast, the prognostic indicators of late remission are still unknown. Accordingly, the aim of our study was to assess the cumulative incidence of early and late remission in a retrospective cohort of newly diagnosed patients with epilepsy, and to identify predictors of late remission. Definitions Epileptic seizures and syndromes were defined according to the recommendations of the International League Against Epilepsy (ILAE) (Commission on Classification and Terminology of the International League Against Epilepsy, 1981, 1989). Etiology of seizures was documented by history, clinical examination, and/or neuroimaging findings and coded as present or absent. The EEG record was defined as normal, slow, or epileptiform (with or without slow waves). Neurologic and psychiatric examinations were coded as normal or abnormal according to clinical judgement. Disease duration was assessed as such and stratified into categories (<6 months; 612 months; >12 months). Seizure number at admission was counted and also indicated in categories (1; 25; 6+). The first AED was recorded as such, regardless of daily dose. For the purposes of this study only the most common active principles were assessed separately. A period of remission was defined as two or more years of complete seizure control after treatment start. Early remission was defined as a 2-year seizure control immediately after initial antiepileptic treatment. Late remission was defined as a 2-year seizure control achieved at least 24 months after treatment start. Patients who were not controlled immediately but achieved a 2-year seizure control within 2 years were excluded from further analysis. In patients with more than one period of remission, only the first ever episode was considered. All these variables were assessed by an independent abstractor who discussed any difficulty with the treating physician. Statistics The 2-year cumulative time-dependent probability of remission was calculated with the Kaplan-Meier method (actuarial analysis). Each prognostic predictor was assessed in patients with early versus late remission and tested with the chi-square for heterogeneity or for trend, as appropriate. Prognostic predictors with significantly different distribution on univariate analysis were also assessed by multiple logistic regression analysis with forward stepwise likelihood ratio, adjusting for age, gender, and center. Any p-value <0.05 was considered statistically significant. Statistical computations were done using SPSS for Windows, release 13.0 (SPSS Inc., Chicago, IL, U.S.A.).

Material and Methods

Setting and patients The study population was included from two tertiary epilepsy centers (Bari, Monza) between January 1, 1989 and December 1, 1999, and followed up until December 31, 2005. In these centers, patients were diagnosed by experienced epileptologists and regularly seen in an outpatient clinic every 612 months, or earlier if clinically indicated. History taking and general and neurological examination were performed by the attending neurologist. A standard awake EEG was performed in all cases, whereas a sleep EEG, a video-EEG, or an imaging test (generally magnetic resonance imaging, MRI) was performed only when clinically indicated. Monotherapy was the recommended starting treatment in all cases, but drug choice was left to the judgment of the caring physician. In patients relapsing with the first maintenance dose, further increases were attempted to achieve seizure control or up the highest tolerated dose, whichever came first. When a first monotherapy failed, another drug was given as alternative monotherapy (preferred) or adjunctive therapy based on the physicians choice. For each patient, baseline and follow-up clinical and demographic data were recorded on case-record forms. Treatment schedules and changes (with indications) were also reported and dated along with seizure recurrences. A patient was included at the time of treatment start, when a definite diagnosis of epilepsy (i.e., two or more unprovoked seizures) (Commission on Epidemiology and Prognosis, International League Against Epilepsy, 1993) was made or, if deemed necessary, at the time of the first unprovoked seizure. For each eligible patient, a number of variables were searched in the case-record forms by three trained abstractors (ADF, GV, and ADP) who completed a semistructured questionnaire. For each eligible case, the following prognostic predictors were identified and recorded: age at diagnosis, gender, disease duration at diagnosis, seizure type(s) and number prior to starting treatment, epilepsy syndrome, putative etiology, first EEG record, neurologic and psychiatric examinations, MRI findings, and first AED.
Epilepsia, 51(1):3742, 2010 doi: 10.1111/j.1528-1167.2009.02141.x

Results
Demographics and baseline features As shown in Table 1, the sample included 174 women and 178 men aged 384 years at diagnosis (mean 31.5 years). One hundred seventy-two patients were from Bari and 180 from Monza. Partial seizures and partial epilepsy syndromes were the predominant categories. Sixteen percent of cases had single seizures at entry. Mean

39 Early versus Late Remission in Epilepsy Table 1. General characteristics of the sample at admission (N = 352)
Variable No. cases % Drug 49.4 50.6 10.5 59.4 15.6 14.5 79.5 18.5 Carbamazepine Valproate Phenobarbital Phenytoin Vigabatrin Lamotrigine Primidone Oxcarbazepineb Clonazepam Topiramate
a b
a

Table 2. First antiepileptic drug: target daily dose (median and range)
Number of cases 166 100 47 14 9 9 3 2 1 1 % 47.2 28.4 13.4 4.0 2.6 2.6 0.8 0.6 0.2 0.2 Median dose (mg) 800 1,000 100 300 2,000 300 200 600 20 200 Range (mg) 2002,200 1002,800 50250 100400 2,0002,500 150600 50300

Gender Women 174 Men 178 Age (years) <15 37 1535 209 3564 55 >65 51 Family history of epilepsy/seizures No 280 Yes 65 NA 7 Documented etiologya No 234 Yes 60 NA 58 Disease duration at center diagnosis (months) <6 147 612 41 >12 161 NA 3 Number of seizures before treatment 1 55 25 161 >5 134 NA 2 Seizure type Partial 226 Generalized 123 Undetermined 3 Epilepsy syndrome Partial idiopathic 33 Partial symptomatic 46 Partial cryptogenic 115 Generalized idiopathic 70 Undetermined 21 Isolated seizure 58 NA 9 Neurologic examination Normal 294 Abnormal 58 Psychiatric examination Normal 320 Abnormal 32 First EEG record Normal or aspecic 123 Slow 43 Epileptiform 159 NA 27 MRIb Normal 191 Abnormal 91 NA 70

79.6 20.4

Target dose unknown in three cases. Target dose unknown in one case.

42.1 11.7 46.1

15.7 46.0 38.3

disease duration at diagnosis at the epilepsy centers was 35.5 months (range 066). The number of seizures before treatment start was mostly between 2 and 5 (45.7%). Neurologic and psychiatric examinations were abnormal in 16.5% and 9.1% of cases, respectively. EEG at entry was epileptiform in 159 cases (48.9%). The most common first AED was carbamazepine (47.2%), followed by valproate (28.4%) and phenobarbital (13.4%) (Table 2). Seizure outcome Patients were followed for 2399.6 person-years (mean 82.7 months; median 75.0 months). Two hundred twenty patients (62.5%) entered one or more 2-year periods of seizure freedom: 115 patients (32.7%) achieved an early remission and 38 patients (10.8%) achieved late remission. Of these, 101 (87.8%) and 34 (89.5%), respectively, were in remission at last follow-up. Using actuarial analysis, the cumulative time-dependent probability of 2-year remission was 56.3% at 2 years after treatment start, and 62.6%, 69.4%, and 79.5% at 3, 5, and 10 years (Fig. 1). The median period of time needed to achieve 2-year remission was 16 months (range 0138 months). Prognostic factors In univariate analysis (Table 3), significant predictors of late remission included partial seizures, six or more seizures prior to treatment, and abnormal (mostly epileptiform) EEG at diagnosis. In multivariate analysis, the only predictor of late remission was the interaction between seizure type and number prior to starting treatment. The odds ratio (OR) of late remission was 2.7 [95% confidence interval (CI) 1.06.8] in patients with 25 partial seizures and 6.7 (95% CI 2.319.3) in patients with more than five partial seizures. Gender, age, documented etiology, first EEG record, neurologic and psychiatric examinations, disease duration at diagnosis, epilepsy syndrome, and first

64.2 34.9 0.9 9.6 13.4 33.5 20.4 6.1 16.9

83.5 16.5 90.9 9.1 37.8 13.2 48.9

67.7 32.3 19.8

EEG, electroencephalography; MRI, magnetic resonance imaging; NA, not available. a Based on history, neurologic examination, and MRI ndings. b Not done in 54.

Epilepsia, 51(1):3742, 2010 doi: 10.1111/j.1528-1167.2009.02141.x

40 A. Del Felice et al. Table 3. Patients with early remission (N = 115) versus late remission (N = 38) by prognostic factor (univariate analysis)
Early remission, N (%) Gender Women 47 (40.9) Men 68 (59.1) Age (years) <15 10 (8.7) 1534 69 (60.0) 3564 17 (14.8) >64 19 (16.5) Family history of epilepsy/seizures No 90 (79.6) Yes 23 (20.4) NA 2 Documented etiologyb No 64 (78.0) Yes 18 (22.0) NA 33 Disease duration at diagnosis (months) <6 51 (44.3) 612 17 (14.8) >12 47 (40.9) Number of seizures before treatment 1 24 (21.1) 25 65 (57.0) >5 25 (21.9) NA 1 Seizure type Partialc 63 (54.8) Generalized 51 (44.3) Undetermined 1 (0.9) Epilepsy syndrome Partial idiopathic 7 (8.4) Partial symptomatic 11 (13.3) Partial cryptogenic 32 (28.9) Generalized idiopathic 27 (22.9) Undetermined 10 (6.0) Isolated seizure 25 (20.5) NA 3 Neurologic examination Normal 99 (86.1) Abnormal 16 (13.9) Psychiatric examination Normal 107 (93.0) Abnormal 8 (7.0) First EEG record Normal or aspecic 48 (43.2) Slow 11 (9.9) Epileptiform 52 (46.9) NA 4 MRI at entryd Normal 65 (71.4) Abnormal 26 (28.6) NA 24 Late remission, N (%) 19 (50.0) 19 (50.0) 6 (15.8) 23 (60.5) 6 (15.8) 3 (7.9) 30 (78.9) 8 (21.1) 28 (87.5) 4 (12.5) 6 15 (39.5) 3 (7.9) 20 (52.6) 6 (15.8) 16 (42.1) 16 (42.1) 30 (78.9) 7 (18.4) 1 (2.6) 3 (7.5) 4 (10.0) 21 (52.5) 5 (12.5) 2 (5.0) 3 (12.5) 30 (79.9) 8 (21.1) 35 (92.1) 3 (7.9) 8 (22.2) 6 (16.7) 22 (61.1) 2 23 (74.2) 8 (25.8) 7

p-value NS

NSa

NS

Figure 1. Cumulative time-dependent probability of 2-year remission in the study cohort. Epilepsia ILAE AED were nonsignificant in the logistic regression analysis model. The results were fairly similar when a subanalysis was performed for adults only (i.e., patients aged 18 years or older) (data not shown).

NS

NS

0.046a

Discussion
In our study, late remission was documented in about 10% of patients with newly diagnosed epilepsy followed for a prolonged period. Other reports from population or referral cohorts of patients with apparently drug-resistant epilepsy provide consistent findings on the chance of late remission, even if with different results. Camfield et al., (1997) found that 42% of 72 children failing to respond to the first AED later achieved remission. In a prospective cohort of 613 children followed for a median of 9.7 years, 83 met a stringent definition of intractable epilepsy, defined as failure of two drugs and 1 seizure/ month (average) for 18 months (Berg et al., 2006). Of these, 20.5% subsequently entered remission and 13.3% were seizure free at last contact. Late remission (with a mean delay of 9 years) was achieved in 50% of adults with childhood-onset epilepsy (Sillanp & Schmidt, 2006). In a cohort of patients with uncontrolled chronic epilepsy, 28% of cases had been rendered seizure-free (i.e., complete seizure control for 12 months or longer) during follow-up (Luciano & Shorvon, 2007). The observation of patients entering remission after prolonged periods of active epilepsy indicates that initial failure to enter remission is not always a reliable indicator of longterm failure. Our results have several implications. First of all, patients experiencing true drug resistance can be identified
Epilepsia, 51(1):3742, 2010 doi: 10.1111/j.1528-1167.2009.02141.x

0.014

0.050

NS

NS 0.049a

NS

EEG, electroencephalography; MRI, magnetic resonance imaging; NA, not available; NS, nonsignicant a p-values obtained from chi-squares for trend. b Based on history, neurological examination and MRI ndings. c Includes secondary generalized seizures. d Not done in 27 cases.

41 Early versus Late Remission in Epilepsy only after prolonged periods of follow-up. Studies done in population-based cohorts showed that the percentage of patients achieving complete seizure remission was 21% at 4 years (Ecuador), 62% at 5 years (France), 55% at 7 years (Canada), and 68% at 10 years or longer (Switzerland, Finland) (Jallon, 2003). Second, the possibility to enter late remission is against the interpretation of drug resistance as a predetermined, perhaps genetically based, clinical condition. This theory claims that in most cases pharmacoresistance, which is intended as a failure of several drugs to reach the receptor sites to exert their action (Schmidt & Loscher, 2005), has been fully developed before the start of the first AED and even before the first seizure. Third, population-based cohorts followed for several years from the time of the diagnosis of epilepsy present a continuous increase in the number of patients entering remission, albeit at a slower rate, even after five or more years of seizure recurrence (Annegers et al., 1979; Cockerell et al., 1997). Fourth, late remissions may be explained at least in part by the increasing number of new pharmaceutical compounds, each showing remission rates in some patients with chronic active epilepsy recruited in regulatory trials. The second most important finding in our study was the interaction between seizure type and number in predicting late remission. Compared to generalized seizures, partial seizures have been found to be associated with lower remission rates (Annegers et al., 1979; Cockerell et al., 1997; Arts et al., 1999; MacDonald et al., 2000). However, as shown in this study and confirmed by others (Berg et al., 2006), delayed remission can be observed in patients with focal epilepsies. This finding may be part of a relapsingremitting pattern (Sillanp & Schmidt, 2006), which suggests that early remission or intractability may not be enduring outcomes. The number of seizures experienced by the patient before intake or the onset of treatment or during the first months after treatment start has been consistently found to predict seizure outcome (Brorson & Wranne, 1987; Collaborative Group for the Study of Epilepsy, 1992; Sillanp, 1993; Arts et al., 1999; MacDonald et al., 2000; Lindsten et al., 2001). A failure to achieve early seizure control has been thought to render epilepsy more resistant to treatment, perhaps because of structural changes in the brain (Reynolds, 1987; Reynolds, 1995). Another explanation is that epilepsy has an inherent severity and response to treatment (Sander, 1993; Chadwick, 1995; Shinnar & Berg, 1996). However, in our study a higher number of partial seizures prior to treatment predicted late remission rather than early remission. This encouraging finding can be explained at least in part by the increasing number of different AEDs for partial seizures now available. Other factors were not found to influence the outcome in our population, despite past evidence of a prognostic role of age, epilepsy syndromes, or etiology (Jallon, 2003). The study population and design may explain the differing results. Our study has some limitations. First, ours is a study done in referral patients: eligible patients were referred to tertiary centers either by their general practitioners or by first/second level hospitals. Therefore, selection bias may affect our population, as previously indicated. Second, data were collected retrospectively. Therefore, a predefined standard classification of our putative prognostic factors was impossible. Third, this is mostly an adult sample, and these results may not be applied to a pediatric population. Fourth, a large proportion of our cases had cryptogenic partial epilepsies. Although the syndromic diagnosis was directed by the EEG findings and in several of them with uncontrolled seizures neuroimaging studies were repeated, we cannot exclude that a symptomatic etiology would go undetected in some cases. Fifth, assignment of first AED was not randomized, which prevents us from driving conclusions on the comparative efficacy of drugs assigned at the time of diagnosis. Last, at the time of the opening of the study many new AEDs were not available. This precludes their role on the chance of seizure remission (whether early or late) in newly diagnosed patients with epilepsy. In conclusion, compared to the rest of our study population, patients with 25 partial seizures before starting treatment had a 2.7 chance of late remission. The risk increased to 6.7 in those with 6+ partial seizures. These findings suggest that the outcome of epilepsy and the chance of seizure remission is a fairly complex and dynamic process. This may be explained by the diversity of the mechanisms underlying the response to AEDs. However, the possibility that some drugs used later in the course of the disease play a role cannot be excluded. Because the study was retrospective, we have been unable to investigate more deeply treatment changes and patients compliance. This will be the object of future studies.

Acknowledgments
We confirm that we have read the Journals position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. None of the authors has any conflict of interest to disclose.

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Epilepsia, 51(1):3742, 2010 doi: 10.1111/j.1528-1167.2009.02141.x