|Year : 2012 | Volume
| Issue : 1 | Page : 106-110
Use of anti-epileptic drugs in a tertiary care hospital of Eastern India with emphasis on epilepsy due to neurocysticercosis
Amrita Sil1, Kamalesh Das2, Nilay K Das3, Dibyendu Chakraborty1, Goutameswar Mazumdar1, Santanu K Tripathi4
1 Department of Pharmacology, Burdwan Medical College, Burdwan, India
2 Department of Neuromedicine, Burdwan Medical College, Burdwan, India
3 Department of Dermatology, Venereology and Leprology, Medical College, Kolkata, India
4 Department of Clinical and Experimental Pharmacology, School of Tropical Medicine, Kolkata, West Bengal, India
|Date of Submission||13-May-2011|
|Date of Decision||06-Sep-2011|
|Date of Acceptance||18-Oct-2011|
|Date of Web Publication||14-Jan-2012|
Department of Pharmacology, Burdwan Medical College, Burdwan
Source of Support: None, Conflict of Interest: None
Introduction: Epilepsy is a chronic disease and neurocysticercosis is an important cause of secondary seizures. Its therapy is modified by a number of parameters and thus the pattern of anti-epileptic drugs used varies in different clinical settings. It was our objective to evaluate clinico-demographic and treatment profile of epilepsy patients attending neurology outpatient department, efficacy and side-effect profile of anti-epileptic drugs with special emphasis on epilepsy resulting from neurocysticercosis.
Materials and Methods: This was a cross-sectional descriptive study of epilepsy patients over four months in neurology outpatient department. Clinico-biological data were obtained by interrogating patients and from recorded data using standard case-report form.
Results: 79 patients were studied with 54.43% having primary etiology, 40.51% having seizures secondary to neurocysticercosis. 81% had generalized tonic-clonic seizure, 17.7% partial and 1.3% myoclonic seizures. Phenytoin (86.08%), valproate (30.38%), clobazam (26.58%) and carbamazepine (10.13%) were used either alone or in combination, with no use of anthelmintics even in cases of neurocysticercosis. Control of seizure was obtained in 79.7% with significant decrease in seizure frequency from 2.92 to 0.51 (P < 0.0001). Weight loss, nausea, decreased appetite, increased sleep, drowsiness, tremors were found to be significantly associated (P < 0.05) with phenytoin use.
Conclusion: Phenytoin is the primary antiepileptic in spite of its side effects; though addition of other anti-epileptic drugs (valproate, clobazam) was required for better seizure control. Cases of neurocysticercosis respond to anti-epileptic drugs without addition of anthelmintics. Side effects observed were mostly neurological in nature.
Keywords: Anti-epileptic drugs, neurocysticercosis, usage pattern
|How to cite this article:|
Sil A, Das K, Das NK, Chakraborty D, Mazumdar G, Tripathi SK. Use of anti-epileptic drugs in a tertiary care hospital of Eastern India with emphasis on epilepsy due to neurocysticercosis. Indian J Pharmacol 2012;44:106-10
|How to cite this URL:|
Sil A, Das K, Das NK, Chakraborty D, Mazumdar G, Tripathi SK. Use of anti-epileptic drugs in a tertiary care hospital of Eastern India with emphasis on epilepsy due to neurocysticercosis. Indian J Pharmacol [serial online] 2012 [cited 2019 Jun 20];44:106-10. Available from: http://www.ijp-online.com/text.asp?2012/44/1/106/91882
| » Introduction|| |
Epilepsy is a long-term disease which requires chronic therapy. The prevalence of epilepsy in India varies from 4.15 to 7.03 per 1000 population.  Neurocysticersosis is one the important reasons for secondary seizures and it is known that in 50-80% of neurocysticercosis, seizures are the most common presenting symptom.  Amongst the various factors affecting anti-epileptic drug (AED) usage, the major determinants are type of epilepsy, age and gender of patient, side effect profile and availability of medicines, affordability of the patient, and preference of the treating physician as well as the practice setting. Attempt to control epilepsy is done using mono and polytherapy.  Due to the long duration of treatment, various adverse reactions (ADRs) are seen, which require change of medication and monitoring. This outpatient department (OPD) based cross-sectional study aimed at providing a snapshot of the AED usage pattern in a tertiary care hospital of eastern India.
The primary objective was to compare the efficacy of the anti-epileptic drugs used in mono/poly-therapy regime for control of seizures and also to evaluate their ADR profile. It was also intended to get an insight into the frequency of the type and etiology of epileptic seizures to describe the drug utilization pattern of AEDs for the treatment of various types of epileptic seizures with special emphasis on the epilepsy resulting from neurocysticercosis.
| » Materials and Methods|| |
This cross-sectional observational study was conducted in the Neurology OPD of a tertiary care hospital in eastern India over four months between August and November, 2009. The patients attending the OPD with complaints of seizures and receiving treatment were evaluated. The study population included all consecutive patients with epilepsy, either idiopathic or with seizures due to granuloma, of any age and of either gender who were receiving treatment for at least two months in the Neurology OPD. Secondary epilepsy due to head injury, stroke, cerebral palsy, metabolic imbalance, very sick and hospitalized patients or those in whom proper history could not be elicited were excluded from the study.
Patients fulfilling the above criteria were interviewed, assessed and information of their biological data, socio economic status, epilepsy, presence of co-morbidity , relevant investigations, treatment received, response to treatment, and ADRs to AEDs were recorded in case report form. Clinical examination was done to find the ADRs to AEDs.
Details of complaint, duration, hospitalization due to seizure (if required), and frequency of seizures initially and after treatment were recorded. Diagnosis of epilepsy was based on history, clinical examination, CT scan, EEG and biochemical tests. Primary etiology comprised of those cases in which cause was unknown, secondary etiology were those in which a cause of seizure was ascertained and those which could not be ascribed to either group were clubbed in unclassified group. CT scan findings were used to differentiate tuberculoma from neurocysticercosis (granuloma - 5 to 20 mm diameter with perilesional edema) , in cases of granulomatous etiology. AEDs prescribed to achieve seizure free status, doses of individual drugs, concomitant medication, duration of monotherapy / polytherapy and compliance were noted. ADRs were recorded using a check list.
Effectiveness of AEDs was determined by using 50% responder rate, which indicates the fraction per hundred patients who had a 50% or greater reduction in seizure frequency compared to baseline. Frequency of seizure was graded before and after treatment as a parameter of efficacy as follows: 0 = no seizure, 1 = single episode, 2 = 1-3 times a month, 3 = 1-6 times a week, 4 = 1-5 times a day, 5 = > 5times a day. Validation of the grading system was done by determining its correlation with the actual frequency of seizure. Parametric data was analyzed using Students' T-test or ANOVA and categorical data was analysed using Chi-square test. The statistical software SPSS v 10.0 was used for analysis.Approval of the Institutional Ethics Committee was obtained before commencing the study. Informed consent from the patients was obtained in their vernacular language.
| » Results|| |
The study screened 87 patients and evaluated 79 patients (men: women ratio 1: 0.39) with mean age of onset of seizure 16.8 ± 10.4 years (range 0.2 to 40, median 16 years), for final analysis. Among the 79 patients, 43 (54.43%) had primary etiology whereas 32 (40.51%) had seizures secondary to granulomatous disease and in four (2.53%) etiology could not be determined [Table 1]. All the 32 cases of granulomatous etiology were diagnosed to be of neurocysticercosis (NCC) in origin as per the CT scan finding [Figure 1].
The mean age of onset of epilepsy due to primary etiology (13.93±9.45 years) was significantly lower (P < 0.025) as compared to NCC (20.06±9.02 years). The study population were mostly residents of rural India. Most of the study population were students (32.90%). Majority of the patients (57%) were economically dependent.
The mean duration of epilepsy prior to attending the OPD was 52.18±57.31 months with the primary etiology (54±54.06 months) having longer duration of disease than those having seizures arising secondary to NCC (37.25±25.88 months). The most common seizure type was generalized tonic-clonic (81%), followed by partial epilepsy (17.7%) and 1.3% myoclonic epilepsy.
Grading score of frequency of seizure was validated with the frequency of seizure per week by Spearman's rank correlation at initial presentation (rho =0.944, P < 0.0001) and at evaluation (rho = 0.998, P < 0.0001). Thus, the grading system developed correlated strongly with the seizure frequency and was subsequently used as efficacy parameter. The mean grading of seizure was found to be significantly lower in NCC than due to primary, both at presentation and at final analysis [Table 1].
Monotherapy was started in 92.4% participants and continued in 54.4% (though 10.13% required titration of dose). Phenytoin (86.08%), valproate (30.38%), clobazam (26.58%) and carbamazepine (10.13%) were used either alone or in combination with no use of anthelmintics even in secondary cases arising because of NCC [Table 2]. Phenytoin was the most common first line drug used in 100% (n=32) primary generalized tonic-clonic epilepsy while either carbamazepine (in two out of 10 patients, i.e., 20%) or phenytoin (in eight out of 10 patients i.e., 80%) was preferred as first line therapy in primary cases of partial seizures. Valproic acid was used as the initial drug in the single case of myoclonic epilepsy. Epilepsy secondary to NCC, irrespective of generalized or partial, was treated initially with phenytoin in most cases (30 out of 32 patients, i.e., 87.5%) followed by valproate (two out of 32 patients, i.e., 6.25%). Six of 79 patients (7.59%) were started with polytherapy from the very beginning (two primary, four secondary) among whom phenytoin was used in combination with valproate in two and with clobazam in four patients. All these six patients had generalized tonic-clonic epilepsy and were found to have significantly higher (ANOVA test, P = 0.049) grading of seizure (4.0±1.55) than those who were started with mono-therapy (2.84±1.35).
|Table 2: Drug utilization in epilepsy patients at the initiation of therapy and at the time of final assessment|
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The therapy was modified in 57 out of 79 patients (72.15%), among whom eight needed a reduction of the dose, 22 needed increase in dose(alone or in combination) and in 34 patients new drug(s) was/were introduced [Table 2]. Phenytoin was the most frequently used drug, either alone (50.6%) or in combination with valproate (17.7%), clobazam (7.6%) or carbamazepine (2.5%) [Table 2]. The modification was done after a mean period of 11.07 ± 8.12 months (range 1 to 38) mostly for the purpose of control of seizure (in 59.5% patients) and only in 2.5% patients it was changed because of ADRs. Control of seizure was obtained in 63 (79.7%) at the time of evaluation and there was significant decrease in the mean grade of seizure frequency from 2.92 to 0.51 (paired t test, P <0.0001). 50% responder rate was achieved in 41 out of 43 (54.4% of total) patients with seizures due to primary etiology and 30 out of 32 (40.5% of total) patients with secondary etiology. The 50% responder rate showed no significant association with the etiology of seizure (P= 0.8512), initial therapy (P = 0.7039) or final therapy (P = 0.084).
Duration of monotherapy for primary etiology was 9.54±7.81 months (range 2 to 38, median 7 months), for secondary etiology due to NCC was 12.18±8.30 months (range 1 to 26,) with significance level reaching P = 0.053. Duration of monotherapy did not significantly differ with the type of seizure (P = 0.955) or initial grading of frequency of seizure (P = 0.1135). It was found that 69 out of 79 patients (87.34%) were compliant to therapy and the compliance was significantly more in those on monotherapy (54.4%) than polytherapy (45.6%) (Chi-square test, P = 0.0456) [Table 3]. There was significant decrease (paired t-test, P < 0.0001) in the grading of seizure frequency from the initial visit to the time of evaluation for all the groups, including primary, secondary to NCC or unclassified etiology.
|Table 3: Clinico-therapeutic profile of monotherapy compared to polytherapy at the time of final assessment|
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Increased sleep (41.8%), gum hyperplasia (38%), decreased appetite (38%), fatigue (35.4%), headache (32.9%), irritability (30.4%), nausea (27.8%) were among the common ADRs. Weight loss, nausea, decreased appetite, increased sleep, drowsiness, tremors were found to be significantly associated (Chi-square, P < 0.05) with phenytoin. Cutaneous side effects, viz.gum hyperplasia, acneiform eruption, alopecia were found in those patients who were taking phenytoin.
| » Discussion|| |
In a hospital setting which caters to mostly the rural population, the patient population is of the lower socio-economic strata with meagre per-capita income and poor education. The main aim of epilepsy therapy is to make the patient totally seizure-free or to reduce the duration, frequency and severity, if the seizures cannot be totally suppressed. The choice of an AED depends on the type of seizure, drug's efficacy, availability, accessibility, ADR profile and patient factors.
Most patients were without any own source of income (57%) and an appreciable 26.60% of patients were illiterate and another 53.2% educated below/up to primary level. Thus availability and accessibility was guided by the free availability of medicines from the hospital pharmacy. Potential AED ADRs affect not only the choice of the physician but also acceptance of the drug by the patient. However not all patients develop ADRs and not all of them are unacceptable; e.g., coarsening of facial features, gum hyperplasia, alopecia, hirsutism etc. which are less acceptable to women patients than men. It is of less concern in the present study population because of men predominance (men:women 1:0.38). We found that most patients were continued on phenytoin though it had more ADRs. The poor economic status of the study population played the major role, since phenytoin was supplied free from the hospital pharmacy.
The exact type of seizure was determined by clinical history, examination, neuro-imaging studies and EEG at concessional rates. Monotherapy with first line drugs, which has shown the best combination of high efficacy and low toxicity, was primarily instituted (in 73 patients, 92.4%), like phenytoin (91.1%), valproate (6.3%) or carbamazepine and clobazam in 5.1% each. In 22 patients (27.8%), where seizures were controlled with this average dose and no serious ADRs appeared, the drug was continued in the same dose for a period of two to three attack-free years. In other cases (57 patients i.e., 72.1%), the dose was increased to the maximum tolerable dosage (22 of 79 i.e., 27.85%), seizures were not controlled (47 of 79 i.e., 59.49%) or ADRs developed (2 of 79 i.e., 2.53%), mandating a second/third anti-epileptic to be added. Others have recorded similar anti-epileptic drug usage in a tertiary care set-up in India.  Reassessment of diagnosis was done in cases of uncontrolled seizures. Other studies also document the preference of single-drug approach for initial therapy in 60-90% of patients  since polytherapy exposes the patients to unnecessary hazards like drug allergy, drug interactions, non-compliance, cost. The present study reveals that patients were more compliant to monotherapy (41 of 43 i.e., 95.3%) than polytherapy (28 of 36 i.e., 77.8%).
Secondary cases of epilepsy due to neurocysticercosis (in 40.5%) were diagnosed in CT scan. Central nervous system (CNS) infections have been documented as the main cause of seizures and acquired epilepsy in the developing world. We found that neurocysticercosis is more prevalent in Hindu population than the Muslims (P= 0.01) and showed a higher age of onset of seizure than the primary ones (P = 0.025). This difference can be explained by the differential exposure to ova of the parasite due to religious and social customs influencing the dietary habit. The etiology (primary or secondary to neurocysticercosis) was not found to influence the types of seizure (GTS or partial) (P = 0.1) neither there was any sexual difference (P = 0.34). Neurocysticercosis was found to be having significantly lower seizure grade (P = 0.01) and higher hospital admission (P = 0.001) as the cases tend to present with status epilepticus.
Although cysticidal drugs have been found to be well tolerated and effective against the parasite in a study,  there has been controversy regarding their beneficial role. After anti-parasitic therapy, there may be an immediate risk of exacerbated seizures and encephalopathy because of acute inflammation of the brain due to release of toxic material from cysts. An inflammatory reaction and edema invariably occurs 5-7 days after the commencement of anthelmintics medication.  Also the long-term prognosis concerning seizures may worsen because of an increased incidence of scarring due to local inflammation of the brain  and most parasites die naturally within a short period.  Antiparasitic agents have no role in calcified lesions as the cysts are already dead and those with single enhancing lesion are likely to do well with AEDs independent of whether anti-parasitic therapy is added. In case of massive infections (cysticerci encephalitis), antiparasitic agents are best avoided as they may exacerbate the inflammatory reaction in brain parenchyma and the present hospital setting refrains from adding an antiparasitic agent in such cases.  Another study found no significant difference in improvement between albendazole and non-albendazole treated group of neurocysticercosis and highlighted the fact that single parenchymal cyst is the most common manifestation and they improve without antiparasitic therapy.  The present study documented that patients of neurocysticercosis had equally significant improvement (P < 0.0001) in seizure grade as that of patients with primary etiology. Thus AEDs are the mainstay for control of seizures in neurocysticercosis and as aforesaid can be used as a single agent therapy.
Efficacy of an AED refers to the effectiveness in reducing seizure frequency which was objectively shown in this study by the 50% responder rate and by the decrease in the grade of seizure frequency in all patients treated with monotherapy and 88.89% of those treated with polytherapy. Association between the mean initial grade of seizure and final prescription of polytherapy (P = 0.001) was seen by us highlighting fact that control of seizure needs to be achieved by polytherapy in those having higher grade of seizure at the time of presentation. The finding opens a new door of research for exploring the utility of the grades of seizure developed for the purpose of this study, to be used as a marker for deciding the need for polytherapy.
In the study, two women patients experiencing acne and alopecia from phenytoin were prescribed valproate. In other cases, most of the AEDs were continued ignoring mild side effects, probably because of adequate control of seizure and also the side effects were acceptable to the patients. Clobazam, the newly introduced AED, though effective was not found to be devoid of side effects, and had high incidence of appetite disturbance, drowsiness, headache, vomiting, agitation /irritability associated with it.
Phenytoin, a government supplied AED, is quite acceptable to patients, effective and can be used in combination with other drugs safely. Also, restricting the use of anthelmintics can lead to safer prescribing in cases of seizures due to neurocysticercosis.
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[Table 1], [Table 2], [Table 3]
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