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Keywords:

  • Discontinuation of antiepileptic drug;
  • Epileptic syndrome;
  • Seizure propensity;
  • Response to AEDs;
  • Symptomatic signs

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Summary: Purpose: To study factors associated with discontinuation of antiepileptic drugs (AEDs) in idiopathic generalized epilepsy (IGE) and symptomatic/cryptogenic localization-related epilepsy (S/CLRE)

Methods: For the IGE study, 71 patients who were able to discontinue their AED (discontinued-IGE group) were compared to 71 patients who continued AED therapy (continued-IGE group) and 20 patients with seizure relapse after discontinuing AED (relapsed-IGE group). For S/CLRE, 90 patients who were able to discontinue AED (discontinued-S/CLRE group) were compared to 90 patients who continued AED (continued-S/CLRE group) and 76 patients with benign childhood epilepsy with centrotemporal spikes who were able to discontinue AED (discontinued-BECTS group).

Results: Compared to the continued-IGE group, the discontinued-IGE group showed a weaker seizure propensity, better response to AEDs, more frequent epileptiform discharge suppression, and lower frequency of generalized tonic–clonic seizures (GTCs). Compared to the relapse-IGE group, the discontinued-IGE group had more frequent epileptiform discharge suppression. The discontinued-S/CLRE group showed a weaker seizure propensity, better response to AEDs, more frequent epileptiform discharge suppression, and less frequent symptomatic signs compared to the continued-S/C LRE group. Notably, the age at epilepsy onset was not a critical factor for discontinuing AEDs in both IGE and S/CLRE. Although the discontinued-S/CLRE group had more frequent symptomatic signs, older age at epilepsy onset and less frequent epileptiform discharge suppression than the discontinued-BECTS group, no difference was found in seizure propensity and response to AEDs between the two groups.

Conclusions: Seizure propensity, epileptiform discharge, and response to AEDs should be considered to predict the possibility of terminating AED therapy in IGE or S/CLRE. In addition, attention should be paid to seizure pattern in IGE and symptomatic signs in LRE.

Review of the clinical courses of epilepsies shows that intractable epilepsies are not as common as previously suspected (1–3), and the majority of patients with epilepsy achieve remission with antiepileptic drug (AED) therapy (4). Seizure remission is reported to occur early in 70–80% of patients in whom seizures develop for the first time (5). Several modes of epilepsy outcome are known; for example, spontaneous seizure remission, seizure remission followed by discontinuation of AED, seizure remission with AED therapy, and an intractable course despite AED therapy (5). During the early phase of AED therapy, predicting the outcome of epilepsy and the possibility of discontinuing the AED is important to plan a future career or to avoid the adverse effect of the AED (2, 6–8).

Many variables have been studied as predictors of favorable outcome after discontinuing AEDs, including age at epilepsy onset, seizure patterns, frequency of seizures, EEG findings, duration of seizure remission before discontinuing AEDs, neuroimaging findings, and the coexistence of cognitive and neurological deficits (9–13). Studies also have confirmed that benign childhood epilepsy with centrotemporal spikes (BECTS) remits before adulthood, and idiopathic epilepsy has a better prognosis than symptomatic epilepsy (14,15). However, the critical role of the epileptic syndrome in discontinuation of AEDs has not adequately been addressed. Previously identified favorable predictors for discontinuation of AEDs usually do not differentiate useful factors among different epileptic syndromes from those useful in predicting within a particular epileptic syndrome. We previously reported the clinical features of patients with idiopathic generalized epilepsy (IGE) and symptomatic/cryptogenic localization-related epilepsy (S/CLRE) who discontinued AEDs after seizure remission (14). The present study investigated intra-syndrome factors that influence discontinuation of AEDs for IGE and S/CLRE, compared to control groups.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

AEDs were discontinued, as of 1994, after seizure remission in 337 (4%) of 8,469 patients seen for the first time at the outpatient clinic of our epilepsy center from 1975 to 1985. The epilepsy classification of patients who discontinued AEDs were IGE in 71 (21%) patients, idiopathic localization related-epilepsy in 77 (23%), S/CLRE in 90 (27%), and unclassifiable epilepsy in 99 (29%). The term unclassifiableepilepsy designates a type of epilepsy with insufficient information to classify it as an epileptic syndrome. Five percent of patients with IGE, 76% of patients with idiopathic localization related-epilepsy, and 2% of patients with S/CLRE discontinued AEDs.

Idiopathic generalized epilepsy

Three groups of patients with IGE were studied (Table 1). Seventy-one patients (33 men and 38 women) who were able to discontinue AEDs (discontinued-IGE group) were compared to 71 patients (34 men and 37 women) who continued AED therapy (continued-IGE group) and 20 patients (seven men and 13 women) with seizure relapsed after discontinuing AEDs (relapse-IGE group). The continued-IGE group was composed of consecutive patients in chronologic order of first presentation at our epilepsy center from 1975. The relapse-IGE group was identified from patients who visited our center for the first time from 1975 to 1985.

Table 1. Summary of idiopathic generalized epilepsy
 Discontinued-IGE groupRelapse-IGE groupContinued-IGE group
  1. IGE, idiopathic generalized epilepsy; AED, antiepileptic drug.Statistically difference was studied between the discontinued-IGE group and the relapsed-IGE group or the continued-IGE group. ap < 0.01, bp < 0.05.

  2. cThe duration of epilepsy in the continued-IGE group was compared with duration from epilepsy onset to AED discontinuation in the discontinued-IGE group.

Male/femaleM 33/ F 38M 7/F13M 34/F 37
Age at epilepsy onset (yr)10.17 ± 5.51 (n = 71)12.76 ± 6.66 (n = 20)11.6 ± 4.81 (n = 71)
Duration from epilepsy onset to the last seizure (yr) 5.38 ± 4.46 (n = 71) 7.27 ± 6.73 (n = 19)20.67 ± 11.37 (n = 71)a
Age at the last seizure (yr)15.55 ± 6.74 (n = 71)19.45 ± 11.55 (n = 20)32.27 ± 13.01 (n = 71)a
Age at AED discontinuation (yr)24.51 ± 7.08 (n = 71)26.00 ± 11.73 (n = 20) 
Duration from epilepsy onset to AED discontinuation (yr)14.34 ± 5.21 (n = 71)13.23 ± 7.74 (n = 20) 
Duration of epilepsy (yr) 34.41 ± 9.67 (n = 71)b,c
Length of seizure-free period before AED discontinuation (yr) 9.16 ± 4.30 (n = 71) 8.07 ± 4.23 (n = 20) 
Length of AED reduction period (yr) 4.29 ± 2.83 (n = 50) 2.78 ± 2.20 (n = 15) 
Epilepsy syndrome (subdivision of IGE)
 Childhood absence epilepsy16/71 (22.54%)1/20 (5%)6/71 (8.45%)a
 Juvenile absence epilepsy2/71 (2.82%)00
 Juvenile myoclonic epilepsy10/71 (14.08%)4/20 (20%)6/71 (8.45%)
 Epilepsy with grand mal seizures on awakening3/71 (4.23%)2/20 (10%)7/71 (9.86%)
 Other generalized idiopathic epilepsies not defined above40/71 (56.34%)13/20 (65%)52/71 (73.24%)b
No. of patients with generalized tonic clonic seizure64/71 (90.14%)20/20 (100%)71/71 (100%)a
Frequency of seizures except for absence
 More than once a day001/71 (1.41%)
 Once or more than once a week but less than once a day01/20 (5%)6/71 (8.45%)b
 Once or more than once a month but less than once a week1/71 (1.41%)3/20 (15%)17/71 (23.94%)a
 Less than once a month53/71 (74.65%)15/20 (75%)35/71 (49.30%)a
No. of patients with epileptic discharge suppression at discontinuing AED60/71 (85.91%)12/20 (60%)b36/71 (50.70%)a
Period of epileptic discharge suppression before discontinuing AED (yr) 5.20 ± 3.81 (n = 60) 3.32 ± 3.42 (n = 11) 
Age at epileptic discharge suppression (yr)18.68 ± 7.42 (n = 60) 21.5 ± 7.95 (n = 15)35.77 ± 10.84 (n = 35)a
No. of AED at the last seizure (no. of patients with monotherapy) 2.27 ± 0.99 (16/71 = 22.53%) 2.56 ± 0.98 (3/18 = 16.67%) 
No. of AEDs at discontinuation (no. of patients with monotherapy)1.04 ± 0.20 (3/71 = 95.77%)1.15 ± 0.49 (18/20 = 90%) 
No. of AEDs at present (no. of patients with monotherapy)  1.42 ± 0.65 (66.20%)a
No. of patients with febrile convulsions23/71 (32.39%)4/20 (20%)23/71 (32.39%)
No. of patients with convulsion in third-degree relatives19/71 (26.76%)9/20 (45%)33/71 (46.48%)
Follow-up period (yr) 2.58 ± 2.04 (n = 70) 21.9 ± 4.41 (n = 16) 
Duration from AED discontinuation to seizure relapse (yr) 2.08 ± 2.91 

Symptomatic/cryptogenic localization-related epilepsy

First, 90 patients (55 men and 35 women) with S/CRLE who were able to discontinue AEDs (discontinued-S/CLRE group) were compared to 90 patients (49 men and 41 women) with S/CRLE who continued AEDs (continued-S/C LRE group) and 76 patients (39 men and 37 women) with BECTS who were able to discontinue AEDs (discontinued-BECTS group). Patients with idiopathic localization-related epilepsy designated by the International Classification of Epilepsies and Epileptic Syndromes published in 1989 (16) were excluded from the discontinued-S/CLRE and continued-S/CLRE groups. All patients in the discontinued-S/CLRE and continued-S/CLRE groups were confirmed to have focal epileptiform discharges in our EEG examinations.

The continued-S/CLRE group was composed of consecutive patients in chronologic order of first presentation at our epilepsy center from 1975. The discontinued-BECTS group was selected from patients with idiopathic localization-related epilepsy including a patient with childhood epilepsy with occipital paroxysms and 76 patients with BECTS. AEDs were discontinued after seizure remission during the same period as the discontinued-S/CLRE group.

Investigated variables

Medical records were reviewed retrospectively. The variables analyzed included etiologic and hereditary factors, neurological and mental status, age and duration related to epilepsy and AED therapy, seizure types and epileptic syndromes, EEG findings, and AED therapy, as shown in Tables 1 and 2.

Table 2. Summary of localization-related epilepsy
 Discontinued-S/CLREContinued-S/CLREDiscontinued-BECT
  1. AED, antiepileptic drug; S/C, symptomatic/cryptogenic; LRE, localization-related epilepsy; BECTS, benign childhood epilepsy with centrotempral spikes; CT, computed tomography; MRI, magnetic resonance imaging.

  2. Statistically difference was studied between the discontinued-S/CLRE group and the continued-S/CLRE group or the discontinued-BECTS group. ap < 0.01, bp < 0.05.

  3. cDuration of epilepsy in the continued-S/C LRE was compared with duration from epilepsy onset to AED discontinuation in the discontinued-S/C LRE.

Male/femaleM 55/ F 35M 49/ F41M 39/ F 37
Age at onset of epilepsy (yr)8.82 ± 7.57 (n = 90)10.75 ± 8.06 (n = 90)6.26 ± 2.72 (n = 76)
Duration from epilepsy onset to the last seizure (yr)5.18 ± 4.97 (n = 90)31.85 ± 9.46 (n = 90)a3.57 ± 2.30 (n = 76)
Age at the last seizure (yr)14.00 ± 10.41 (n = 90)42.61 ± 10.67 (n = 90)a9.71 ± 2.63 (n = 76)
Age at AED discontinuation (yr)22.27 ± 10.75 (n = 90)16.76 ± 2.88 (n = 76)
Duration from epilepsy onset to AED discontinuation (yr)13.41 ± 5.48 (n = 90)10.37 ± 3.60 (n = 76)
 Duration of epilepsy (yr) 35.72 ± 7.78a,c 
Length of seizure-free period before AED discontinuation (yr)8.45 ± 3.78 (n = 90)6.93 ± 2.96 (n = 76)
Length of AED reduction period (yr)3.85 ± 2.15 (n = 70)3.53 ± 2.28 (n = 67)
No. of patients with generalized tonic-clonic seizure61/89 (68.54%)68/90 (75.56%)36/76 (47.37%)a
Frequency of seizures
 More than once a day1/87 (1.15%)12/90 (13.33%)a1/75 (1.33%)
 Once or more than once a week but less than once a day019/90 (21.11%)a0
 Once or more than once a month but less than once a week9/87 (10.35%)42/90 (46.67%)a11/75 (14.67%)
 Less than once a month77/87 (88.51%)17/90 (18.89%)a63/75 (84.00%)
No. of patients with epileptic discharge suppression at discontinuing AED74/88 (84.09%)14/90 (15.56%)a69/74 (93.24%)a
Period of epileptic discharge suppression before discontinuing AED (yr)3.72 ± 3.01 (n = 76)3.62 ± 2.24 (n = 69)
Age at epileptic discharge suppression (yr)19.00 ± 10.55 (n = 84)42.36 ± 11.33 (n = 14)a13.57 ± 3.35 (n = 74)a
No. of AEDs at the last seizure (no. of patients with monotherapy) 2.36 ± 1.07 (21/88 = 23.86%)2.25 ± 1.05 (21/76 = 27.63%)
No. of AEDs at discontinuation (no. of patients with monotherapy) 1.07 ± 0.29 (85/90 = 94.44%)1.04 ± 0.20 (73/76 = 96.05%)
No. of AEDs at present (no. of patients with monotherapy)  2.79 ± 1.23 (14.44%)a 
No. of patients with convulsion in third-degree relatives29/90 = 32.22%20/90 (22.22%)24/76 (31.58%)
No. of patients with etiology27/89 (30.33%)49/89 (55.06%)a0a
No. of patients with neurological deficit3/90 (3.33%)14/89 (15.73%)a
No. of patients with mental retardation7/90 (7.78%)27/90 (30.00%)a0b
No. of patients with lesions in MRI or CT19/75 (25.33%)70/88 (79.55%)a0 (n = 68)a
Follow-up period (yr) 2.61 ± 3.1124.69 ± 2.202.01 ± 2.15

Statistical analysis

Data were analyzed by the χ2 test for independence, the Fisher's exact probability test, and the Mann–Whitney U test.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Idiopathic generalized epilepsy

Discontinued-IGE group and continued-IGE group

Comparison between the discontinued-IGE and continued-IGE groups is shown in Table 1. Age at epilepsy onset did not differ for the two groups. Compared to the continued-IGE group, the discontinued-IGE group showed shorter duration from epilepsy onset to the last seizure (p < 0.01), younger age at the last seizure (p < 0.01), higher incidence of childhood absence and juvenile absence epilepsy (p < 0.01), fewer patients with generalized tonic–clonic seizures (GTCs) (p < 0.01), fewer patients with convulsive seizure frequency of more than once a week (p < 0.05) and more than once a month (p < 0.01), and more patients with seizure frequency less than once a month (p < 0.05). The discontinued-IGE group also had significantly shorter duration of AED therapy (p < 0.01), more patients receiving AED monotherapy (p < 0.01), and more patients with epileptiform discharge suppression at the time of discontinuation of AEDs (p < 0.01), when compared to the continued-IGE group at the time of study.

The age at the last seizure was younger than 20 years in ∼80% of patients in the discontinued-IGE group, and older than 20 years in almost all patients in the continued-IGE group (Fig. 1A). The duration from epilepsy onset to the last seizure was <10 years in 80% of patients of the discontinued-IGE group; in contrast, the duration was ≥10 years in almost all patients of the continued-IGE group (Fig. 1B). The duration from epilepsy onset to discontinuation of AED was <20 years in 80% of patients of the discontinued-IGE group, but duration of AED therapy was at least 20 years in the continued-IGE group. The age at epileptiform discharge suppression was younger than 30 years in 80% of patients in the discontinued-IGE group, whereas it was 30 years or older in more than half of patients in the continued-IGE group (Fig. 1C).

image

Figure 1. Age at the last seizure (A), duration from epilepsy onset to the last seizure (B), and age at epileptiform discharge suppression (C) in the discontinued-idiopathic generalized epilepsy (IGE) group and the discontinued-IGE group. Ordinates show the percentage of patients of each group in three figures. Abscissas show the age of patients (A and C), and years (B). See explanation in the text.

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Discontinued-IGE group and relapse-IGE group

The number of patients with epileptiform discharge suppression before discontinuing AEDs was the only variable showing a significant difference between the two groups (Table 1); the number was larger in the discontinued-IGE than in the relapse-IGE group (p < 0.05).

Symptomatic/cryptogenic localization-related epilepsy

Discontinued-S/CLRE group and continued-S/CLRE group

Compared to the continued-S/CLRE group, the discontinued-S/CLRE group had significantly shorter duration from epilepsy onset to the last seizure (p < 0.01), younger age at the last seizure (p < 0.01), fewer patients with seizure once or more than once a month (p < 0.01), more patients with seizures less than once a month (p < 0.01), and more patients with epileptiform discharge suppression at discontinuation of AEDs (p < 0.01). The discontinued-S/CLRE group also showed significantly fewer patients with specific etiological factors (p < 0.01), neurological deficits (p < 0.01), developmental delay (p < 0.01), and cerebral damage on computed tomography (CT) or magnetic resonance imaging (MRI) of the brain (p < 0.01), and more patients utilizing AED monotherapy (p < 0.01).

The age at the last seizure was younger than 20 years in 80% of patient in the discontinued-S/CLRE group; in contrast, the age was older than 20 years in ∼90% of the patients in the continued-S/CLRE (Fig. 2A). The duration from epilepsy onset to the last seizure was <10 years in >80% of the patients of the discontinued-S/CLRE group, but was at least 10 years in almost all patients of the continued-S/CLRE group (Fig. 2B). The duration from epilepsy onset to discontinuation of AEDs was <20 years in almost all patients of the discontinued-S/CLRE group, whereas the duration of epilepsy was at least 20 years in almost all patients of the continued-S/CLRE group. The age at epileptiform discharge suppression was younger than 30 years in 80% of patients in the discontinued-S/CLRE group, compared to 30 years or older in almost all patients of the continued-S/C LRE group (Fig. 2C).

image

Figure 2. Age at the last seizure (A), duration from epilepsy onset to the last seizure (B), and age at epileptiform discharge suppression (C) in the discontinued-symptomatic/cryptogenic localization-related epilepsy (S/CLRE) group and the continued-S/CLRE. Ordinates show the percentage of patients of each group in three figures. Abscissas show the age of patients (A and C) and years (B). See explanation in the text.

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Discontinued-S/CLRE group and discontinued-BECTS group

Compared to the discontinued-BECTS, the discontinued-S/CLRE group had significantly greater proportions of patients with etiologic factors (p < 0.01), mental retardation (p < 0.05) and brain damage on CT or MRI (p < 0.01), GTCs (p < 0.01), and epileptiform discharges at discontinuation of AEDs (p < 0.01). All patients in the discontinued-BECTS group had epilepsy onset at younger than 12 years. Conversely, the age at epilepsy onset in the discontinued-S/CLRE group ranged between 1 and 39 years and was older than 13 years in 29% of patients. The age at the last seizure in the discontinued-BECTS group was younger than 17 years. Conversely, the age at the last seizure in the discontinued-S/CLRE group ranged between 4 and 50 years and was 17 years or older in 22% of patients. The age at epileptiform discharge suppression was significantly older in the discontinued-S/CLRE group than in the discontinued-BECTS group (p < 0.01).

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Previous reports identified diverse risk factors for seizure relapse after discontinuation of AEDs or intractable seizures, including adult- and adolescent-onset epilepsy, occurrence of GTCs and myoclonic seizures with more than one AED, continuation of seizures and epileptiform discharges after initiation of AED therapy, short seizure-free period before discontinuing AEDs, and symptomatic signs in miscellaneous epileptic syndromes (1,3,5,6,10–13,17,18). However, it is necessary to confirm the factors predicting discontinuation of AEDs and seizure relapse after discontinuation of AED by comparing two groups within the same epileptic syndrome; one group that was able to discontinue AEDs and another group that was unable to discontinue AEDs or had seizure relapse after discontinuation of AEDs.

In the IGE study, high seizure frequency, long period until seizure remission, long duration of epilepsy, and persistent epileptiform seizure discharges were factors against discontinuation of AEDs. These indicators seem to show that a strong tendency toward spontaneously recurring seizures (2), and persistent epileptiform discharge are critical factors for the inability of patients with IGE to discontinue AEDs. Patients with infrequent or no GTCs tend to belong to the discontinued-IGE group. Thus, high frequency of GTCs is associated with intractability of IGE. Our results also showed that patients in the discontinued-IGE group achieved seizure remission soon after the beginning of AED therapy. Previous reports have indicated (17) that a long seizure-free state with AED therapy and remission achieved while receiving monotherapy were important factors for successful discontinuation of AEDs, supporting our results that good seizure response to AEDs is favorable for discontinuing AEDs in IGE. Our results for IGE showed no significant difference in the age at epilepsy onset between the discontinued-IGE group and the continued-IGE group. Contrary to previous findings in miscellaneous epilepsies, the age at epilepsy onset did not play an important role as a predictive factor for discontinuation of AEDs in IGE. In summary, strong seizure propensity, persistent epileptiform discharges, poor response to AEDs, and presence of a GTC seizure pattern are seen to be unfavorable factors for discontinuation of AEDs in IGE.

Comparison of the discontinued-IGE group with the relapse-IGE group reveals that the presence of epileptiform discharges at discontinuation of AEDs is a risk factor for seizure relapse, even if other factors are favorable for discontinuing AEDs. Therefore, whether epileptiform discharges persist is a very important index to judge discontinuation of AEDs in patients with IGE. As reported in our previous article (14), only a few of our patients had seizure relapses after AEDs were discontinued. The low incidence of seizure relapse in this series might be due to a very gradual reduction of AEDs, taking sufficient time to observe whether seizures or epileptiform discharges are aggravated (14). Our experience suggests that slow reduction of AEDs, in conjunction with EEG monitoring, is a reasonable method for avoiding seizure relapse after discontinuation of AEDs.

The favorable indices for discontinuation of AEDs identified in S/CLRE cases were low level of seizure tendency and a good response to AEDs, almost the same as those in the discontinued-IGE group. In addition, the discontinued-S/CLRE group had less frequent symptomatic signs compared to the continued-S/CLRE group. Less frequent symptomatic signs in the discontinued-S/CLRE group are reflected by a smaller proportion of patients with etiologic factors, neurological deficits, developmental delay, and brain damage signs on CT or MRI. Thus, symptomatic signs seem to be important factors reflecting difficulty in discontinuing AEDs in S/CLRE. This result is consistent with previous articles reporting that patients with symptomatic factors are associated with difficulty in discontinuing AEDs (3,5,7,9,14). According to previous reports, earlier onset of epilepsy before age 12 years and no history of GTCs are favorable factors in the localization-related epilepsy group (1,3,16,17). In contrast, our results showed no significant difference in the age at epilepsy onset and GTC frequency between the discontinued-S/CLRE group and the continued-S/CLRE group. The present study was conducted by excluding idiopathic location-related epilepsy that started before age 10 years in most patients and was cured before adulthood. The different results between our findings and previous reports on the discontinuation of AEDs in LRE may be due to the criteria for patient selection. Our results also suggest that seizure tendency has an important connection with the discontinuation of AEDs in S/CLRE, but generalization of focal seizures shown by secondarily GTCs has no connection.

Compared to the discontinued-BECTS group, the discontinued-S/CLRE group had more frequent symptomatic signs and a lower rate of epileptiform discharge suppression at time of discontinuation of AEDs, but indices of seizure propensity and response to AEDs were not different between the two groups. The discontinued-S/CLRE group also had widespread distribution of age at epilepsy onset, including patients older than 20 years. These results suggest that, of the factors, low seizure propensity and a good response to AEDs are important for discontinuation of AEDs in S/CLRE.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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