Objectives: To find out prescription patterns and seizure freedom with different mono-, duo- and poly-therapies used in various seizure disorders in Indian setting. Material and Methods: Subjects with seizures, not responding to first antiepileptic drug, were evaluated prospectively for a period of 6 months. Patients on various dual antiepileptic drugs (AEDs) prescriptions were prospectively analyzed for 1) the pattern and frequency of different duo-therapies; 2) etiological profile of patients in duo-therapy prescription; and 3) frequency of seizure freedom on various duo-therapy groups. Results: Among 2542 patients, 293 (11.5%) lost in follow-up and thus, 2249 (88.5%) were followed. 1324 (58.9%) had seizure freedom on mono-therapy, 532 (23.7%) required duo-therapy and only 45 (2%) were better controlled on poly-therapy. Among the subjects, who were on mono-therapy, Carbamazepine/Oxcarbazepine was the most commonly prescribed in 1285 (50.55%) patients as first drug followed by Valproate compound and Phenytoin. The most common duo-therapy used was combination of Valproate with Lamotregine, followed by Phenytoin and Phenobarbitone. Other mono-therapy and combinations are given in this paper. Conclusions: Duo-therapy was required and found to be effective in 23.7% of Indian patients with epilepsy. Selection of appropriate two drug combination is based on individual approach and overall clinical profile of patient.
Epilepsy is defined as a chronic, neurological condition whose cardinal feature is a predisposition to recurrent, unprovoked seizures. According to prevalence rate around 6 - 7 million persons in India are suffering from this disease [
Second issue for clinicians in treatment of patient with epilepsy in India is selection of conventional drugs versus newer drugs. Evidences suggest that there is no major difference in efficacy of conventional versus newer AEDs. However, newer drugs are better tolerated and have lesser interactions with other drugs but make the therapy costlier. We have been more commonly using conventional AEDs as the first line therapy for our patients over more than 10 years due to low-middle socio-economic status of our patients and no wide availability of new drugs in rural area. Here, we are presenting our experience regarding prescription pattern and response of various mono- and poly-therapies. This paper can be of help to the general physicians who are treating poor patients and will give them an idea regarding appropriate selection and mixing of AEDs.
Our data collection started in year 2001 up to 2010, after obtaining approval from institutional ethics committee. The rationale of the study was explained to the patients included in this study and informed consent was taken.
Consecutive patients of epilepsy presenting to the neurology clinic were diagnosed and classified according to ILAE classification 1989. Etiologically, cases were classified into two groups a) acute symptomatic with ring lesion (s), b) Epilepsies and Epileptic syndromes. The latter category, i.e., “epilepsies and epileptic syndromes” were further sub-classified according to ILAE classification 1989 and three categories were made; 1) idiopathic epilepsies (ILAE category 1.1 and 2.1); 2) symptomatic/cryptogenic partial epilepsies (category 1.2 and 1.3); and 3) cryptogenic/symptomatic generalized and undetermined epilepsies (ILAE categories 2.2, 2.3 and 3). However, cases of category 4.1 (situation related seizures) were not included. Thus, we had four groups of epilepsy: group I: acute symptomatic seizures; group II: idiopathic epilepsies; group III: symptomatic/ cryptogenic partial seizures and lastly, group IV: cryptogenic/symptomatic generalized and undetermined epilepsies. Patients in each of these groups were either new onset or follow-up case. We have developed a protocol at our center to prescribe various AEDs in a step wise pattern (vide infra). The aim of the treatment was to get complete freedom from disabling seizures. It was defined as no occurrence of seizures with regular usage of medicine and was documented on each monthly follow-up. Steps given below were followed for selection of antiepileptic drugs in various etiological groups.
Step 1 (first drug): Patients having acute symptomatic seizures (group I), symptomatic/cryptogenic partial (group III) were initially prescribed either phenytoin sodium (PHT) or Oxcarbazepine/carbamazipine (OXC/ CBZ) as a first AED. On the other hand, patients with idiopathic epilepsies (group II) were prescribed valproate compounds (VAL) or phenobarbitone (PB), lamotrigine (LTG) or Levetiracitam (LEV) as a first medicine depending on age, sex and affordability. In cryptogenic/symptomatic generalized and undetermined epilepsies (group IV) this is heterogeneous group and first drug selection was mainly based on seizure types and patient’s characteristics (can be CBZ/OXC, PB, PHT, VPA or newer AED). Patient with West syndrome was additionally given ACTH/steroids with antiepileptic medicine.
Step 2: Those who had persistent seizures on first drug were given add-on drug and those who had not tolerated the drugs were given alternative mono-therapy. Add-on drug was clobazam, phenobarbitone, sodium valproate or newer drugs in groups I & III. Lamotrigine, clonazepam, levetiracetam were added in group II and any old or other newer antiepileptics were added in group IV depending on primary diagnosis, seizure type (s) and first drug given. The selection of first and additional AED was dependent on patients profile, affordability and local availability to patient’s home.
These patients were followed for maximum possible period and analysis was done in year 2014 to find out the 1) prescription pattern of various mono and poly therapies in various etiologies and 2) rate of complete seizure freedom on various mono- and poly-therapies in new onset and old cases of various epilepsy.
A total of 2542 patients were included in this study (
Etiologically, acute symptomatic seizures due to ring lesion(s) were found in 684 (26.9%) patients (569 new + 115 old), idiopathic epilepsies in 562 (22.1%) (219 new + 343 old), symptomatic/cryptogenic partial epilepsies in 722 (28.4%) (177 new + 545 old) and cryptogenic/symptomatic generalized or undetermined in 574 (22.6%) (158 new + 416 old) (
Patterns of various mono-therapy and poly-therapies: All 2542 patients were analyzed for the assessment of prescription patterns of antiepileptic medicines.
Group I: Total 684 (26.9%) patients were enrolled in this group. Total 60 patients lost in follow-up and 624 were further followed-up. Among these 475 (76.1%) were given CBZ/OXC and 209 (33.5%) given PHT as first drug. Total 61 (9.8%) patients were given alternative Mono-therapy (VPA/PB/CLOB/LEV) due to drug allergy and poor tolerance to first drug. Total 515 (82.5%) had freedom on first drug selected remaining 109 (17.5%) required add-on drugs for ongoing seizures. Further 81 (13%) patients had seizure freedom on duo-therapy and only 7 (1.1%) patients remitted on more than 2 drugs. Twenty one (3.4%) patients were poorly controlled even after poly-therapy. Most common combinations were PHT+PB (48 patients) and CBZ/OXC + CLOB (24 patients).
Group II: Total 562 (22.1%) patients were enrolled. Total 489 (87%) were given valproate compound and 73 (13%) other types of Monotherapy as first drug (PB, LTG, LEV or CZP). After first prescription 73 (13%) patients lost in follow-up and 489 (87%) were followed, among which 253 (51.7%) were seizure free on monotherapy, 164 (33.5%) on duo therapy and 19 (3.9%) on poly-therapy. Twenty one (4.3%) patients were given alternative mono-therapy due poor tolerance or side effects to first drug. Fifty three (10.8%) patients were having poor seizures control. Most common combination was VPA+LTG (146 patients) followed by VPA + CZP (58 patients) in this group.
Group III: Total 722 (28.4%) patients in this group were either given CBZ/OXC (in 544 (75.3%) patients) or PHT (in 178 (24.7%) patients). Then 83 (11.5%) were lost in follow-up and finally 639 (88.5%) patients were followed. During follow-up 342 (53.5%) had freedom on single drug, 160 (25%) on duo-therapy and 6 (0.9%) on poly-therapy, rest 131 (20.5%) used to have break-through seizures even on poly-therapy. Total 66 (10.3%) patients were given alternative mono-therapy due to side effects by first drug.
Group IV: This was the most heterogeneous group of 574 (22.6%) patients and CBZ/OXC was most commonly used (in 266 (46.3%) patients) then VPA (in 242 (42.1%) patients) and PHT (in 66 (11.5%) patients). After losing 77 (13.4%) patients in follow-up, 214 (43%) had seizure freedom on single drug, 127 (25.6%) on duo-therapy and 12 (2.4%) on poly therapy. Total 144 (29%) continued to have poor controlled. VAL + LTG (in 63 patients), CBZ/OXC + CLOB (in 52 patients), OXC/CBZ + PB or VPA (in 38 patients each) and PHT + PB (in 30 patients) were most common duo-therapies.
Parameters | Frequency | ||
---|---|---|---|
Total Patients | 2542 (100%) | ||
New Onset Cases | 1123 (44.5%) | ||
Known Cases | 1419 (55.5%) | ||
Age Range Median Age | 3m-76y 19 y | ||
Sex ratio 1. Male 2. Female 3. Ratio | 1733 809 2.14:1 | ||
Etiology | New | Old | Total |
1. Acute symptomatic seizures with ring lesion(s) 2. idiopathic epilepsies (ILAE CLASS 1.1 & 2.1) 3. symptomatic/cryptogenic partial epilepsies (ILAE CLASS 1.2, 1.3) 4. cryptogenic and undetermined epilepsies (ILAE CLASS 2.2, 2.3, 3.1 & 3.2) | 569 219 177 158 | 115 343 545 416 | 684 562 722 574 |
Seizure Freedom in New versus Old Cases
New onset seizures (
Follow up cases (
Second sub group of 1131 (79.7%) patients presented with poorly controlled seizures on drugs prescribed outside. On adequate doses of appropriate drug 362 (32%) patients could achieve seizure freedom on mono- therapy. Moreover, 308 (27.2%) on two drugs and 34 (3%) on more than 2 drugs were controlled, while 285 (25.2%) still had poor control.
Frequency of various mono-therapy and duo-therapy (
Overall freedom (
Etiology | New onset (n = 1123) | Seizure freedom on single drug | Seizure freedom on two drugs | Seizure freedom on more than two drugs | Poor control even after poly-therapy | Lost in follow-up |
---|---|---|---|---|---|---|
Acute symptomatic Seizures with ring lesions | 569 (50.7%) | 461 (41%) | 50 (4.5%) | 3 (0.3%) | 7 (0.6%) | 48 (4.3%) |
Symptomatic/cryptogenic Partial epilepsies | 219 (19.5%) | 131 (11.7%) | 51 (4.6%) | 4 (0.4%) | 7 (0.6%) | 26 (2.3%) |
Idiopathic epilepsies | 177 (15.8%) | 117 (10.4%) | 29 (2.6%) | 0 (0%) | 13 (1.2%) | 18 (1.6%) |
Cryptogenic/symptomatic generalized or Undetermined epilepsy | 158 (14%) | 90 (8%) | 24 (2.2%) | 1 (0.1%) | 21 (1.9%) | 22 (2%) |
Total | 1123 | 799 (71.1%) | 154 (13.7%) | 8 (0.8%) | 48 (4.3%) | 114 (10.2%) |
Etiology | Old cases (n = 1419) | Seizure freedom on single drug | Seizure freedom on two drugs | Seizure freedom on more than two drugs | Poor control even after poly-therapy | Lost in follow-up |
---|---|---|---|---|---|---|
Acute symptomatic seizures with ring lesion (s) | 115 (8.1%) | 54 (3.8%) | 31 (2.2%) | 4 (0.3%) | 14 (1%) | 12 (0.9%) |
Symptomatic/cryptogenic partial epilepsies | 343 (24.2%) | 122 (8.6%) | 113 (8%) | 15 (1.05%) | 46 (3.2%) | 47 (3.3%) |
Idiopathic epilepsies | 545 (38.4%) | 225 (15.9%) | 131 (9.2%) | 6 (0.4%) | 118 (8.3%) | 65 (4.6%) |
Cryptogenic/symptomatic generalized and undetermined epilepsies | 416 (29.3%) | 124 (8.7%) | 103 (7.3%) | 11 (0.8%) | 123 (8.7%) | 55 (4%) |
Total | 1419 | 525 (37%) | 378 (26.6%) | 36 (2.5%) | 301 (21.2%) | 179 (12.6%) |
Group | CBZ/OXC | PHT | VPA | CBZ/OXC + CLOB | CBZ/OXC + PB | CBZ/OXC + VPA | PHT + PB | VPA + LTG | VPA + CZP |
---|---|---|---|---|---|---|---|---|---|
I | 475 | 209 | 0 | 24 | 13 | 4 | 48 | 0 | 0 |
II | 0 | 0 | 489 | 0 | 0 | 9 | 13 | 146 | 58 |
III | 544 | 178 | 0 | 74 | 79 | 29 | 73 | 10 | 0 |
IV | 266 | 66 | 242 | 52 | 38 | 38 | 30 | 63 | 7 |
Total | 1285 | 453 | 731 | 150 | 130 | 80 | 164 | 219 | 65 |
Group | Total patients | Lost in follow up | Patients followed | Seizure freedom on 1st AED | Seizure freedom on 2nd AED | Seizure freedom on 3rd AED | Combined |
---|---|---|---|---|---|---|---|
I | 684 | 60 | 624 | 515 | 81 | 8 | 604 |
II | 562 | 73 | 489 | 253 | 164 | 19 | 436 |
III | 722 | 83 | 639 | 342 | 160 | 6 | 508 |
IV | 574 | 77 | 497 | 214 | 127 | 12 | 353 |
Total | 2542 | 293 (11.5%) | 2249 (88.5%) | 1324 (58.9%) | 532 (23.7%) | 45 (2%) | 1901 (84.5%) |
Findings of our study suggest that around 83% patients achieved seizure freedom on treatment and 59% had got the seizure freedom on mono-therapy. New onset epilepsy had better response to therapy as compared to follow- up cases. Significant numbers (23.7%) required duo-therapy for seizure freedom. Carbamazepine or oxcarbazepine were the most common mono-therapy while valproate with lamotrigine was the most common duo-therapy used in our experience.
The goal of antiepileptic therapy is to achieve a seizure-free state and to improve the quality of life (QOL) [
In order of frequency carbamazepine or oxcarbazepine, valproate compound and phenytoin sodium were the most commonly prescribed mono-therapy at our center and similarly reported by others [
Nearly one quarter of our patients were prescribed duo-therapy to achieve seizure freedom. In Finland study also ultimately 15% patients required duo-therapy to control their seizures. Selection of appropriate combination of AED is as important as the selection of most appropriate mono-therapy. Rationale drug combinations are available in anti-cancer and anti-infection chemotherapy, to produce greater therapeutic benefits. However, combining two AEDs to get better therapeutic efficacy for patients having difficult to treat epilepsy, is still debatable. Long discussion is continued about the good and bad aspects of various combinations of antiepileptic medication. Few questions were discussed in literature like: is there a rationale for this practice? Is there any evidence that two drugs in combination may do better than one in selected individuals? Are some drug combinations preferable to other? [
The antiepileptic drug combination can be labeled as acceptable when the two agents interact to produce superior efficacy without a parallel rise in side effects. In principle, antiepileptic drugs with similar mode of action should not be combined together because the effect of combination could be achieved simply by increasing the dose of one of these drugs. Though our knowledge is grossly incomplete but available evidence suggests that phenobarbitone, benzodiazapines and valproate act through prolongation of inhibitory post-synaptic potentials (IPSP) by increasing the mean chloride channel opening time and duration of GABA induced burst of neuronal activity. Sodium valproate additionally acts by limiting sustained, repetitive neuronal firing through voltage dependent sodium channel. Phenytoin sodium, carbamazepine, oxcarbazepine and Lamotrigine primarily act through inhibiting voltage gated sodium channel. Thus we can presume that AED acting on sodium channel (PHT, CBZ, OXC & LTG) can be effectively combined with either PB, CZP or VPA. In our study combinations of duo-therapies were selected on the same principle. In animal models it was also found that combining two drugs with different mode of action can produce better anticonvulsant effects than those produced by individual agent when given alone [
Various drug combinations used as duo-therapy in our study were selected on the basis of underlying etiology and predominant seizure type. In generalized epilepsy VPA + LTG, in partial epilepsy CBZ/OXC+PB, in unclassified epilepsy VPA + CBZ/OXC and for acute symptomatic seizures CBZ/OXC + CLB were the most frequent combinations. The study from Singapore has shown that the most common combination in their study was VAL+CBZ [
Clobazam, as suggested, was mainly used as add-on antiepileptic for short duration in acute symptomatic seizures cases like neurocysticercosis [
A fixed dose formulation combination of phenobarbitone with phenytoin is available in Indian market for many years. This combination is found to be associated with good potency with no increment in neuron-toxicity [
Antiepileptic with shorter half life requires 2 - 3 daily doses and frequently results in breakthrough seizures even when single day dose is missed by patients [
Apparent disadvantage of combining drugs with same mode of action is additive neurotoxic side effects of antiepileptics. The combinations used in our study had not shown any such effects in short term follow-up. Phe- nobarbitone is a poor add-on drug with valproate due to more neurotoxic effect through GABAergic neurons [
Our study is important as scanty data is available on the impact of duo-therapy in epilepsy management of Indian patients. Since a significant proportion of epileptic patients in hospital setting need duo-therapy, this study can help in selection of appropriate combination.
Deepak Goel,Manish Mittal, (2015) Mono-Therapy versus Poly-Therapy: Ten Years Indian Experience on Various Seizure Disorders. World Journal of Neuroscience,05,350-357. doi: 10.4236/wjns.2015.55034