|Year : 2020 | Volume
| Issue : 3 | Page : 127-131
Etiological spectrum of drug-resistant epilepsy – A glimpse from North East India
Baiakmenlang Synmon, Shri Ram Sharma, Musharraf Hussain, Yasmeen Hyniewta
Department of Neurology, NEIGRIHMS, Shillong, Meghalaya, India
|Date of Submission||06-Jul-2020|
|Date of Decision||12-Aug-2020|
|Date of Acceptance||19-Aug-2020|
|Date of Web Publication||08-Sep-2020|
Dr. Baiakmenlang Synmon
Department of Neurology, NEIGRIHMS, Shillong, Meghalaya
Source of Support: None, Conflict of Interest: None
Introduction: Drug-resistant epilepsy (DRE) occurs in 20%–30% of all epilepsy patients. This group of patients is a clinical challenge and needs a multidisciplinary approach to achieve the etiological diagnosis and also guide their treatment protocol.Materials and Methods: A retrospective study was conducted at North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences (NEIGRIHMS) in the Northeastern region of India, where patients fulfilling the definition of DRE were followed up to establish an etiological diagnosis. Clinical and drug history was taken for these patients. Electroencephalogram and neuroimaging were done in all patients. An attempt to evaluate the various etiologies causing DRE was made.Results: Thirty-three patients were included in the study after the exclusion of pseudo-resistance. Seventeen males and 16 females were included with the age range of 2–57 years. The most common clinical semiology was focal seizure with dyscognitive features seen in 16 patients. The most common etiology documented was medial temporal lobe epilepsy seen in ten patients.Conclusion: DRE is a common entity seen in this part of the country where epilepsy surgery is still out of reach. Etiology needs to be established in these groups of patients as other modes of therapy can be offered which include surgical and other interventions other than optimal drug therapy.
Keywords: Drug-resistant epilepsy, etiology, neuroimaging
|How to cite this article:|
Synmon B, Sharma SR, Hussain M, Hyniewta Y. Etiological spectrum of drug-resistant epilepsy – A glimpse from North East India. Indian J Med Spec 2020;11:127-31
|How to cite this URL:|
Synmon B, Sharma SR, Hussain M, Hyniewta Y. Etiological spectrum of drug-resistant epilepsy – A glimpse from North East India. Indian J Med Spec [serial online] 2020 [cited 2021 Mar 4];11:127-31. Available from: http://www.ijms.in/text.asp?2020/11/3/127/294529
| Introduction|| |
Epilepsy is a common neurological condition sparing no age or sex group. Around 50 million people are said to suffer from epilepsy worldwide. The use of a single appropriate antiepileptic drug (AED) can control seizure in around 47%, further 13% of patients can be controlled on their 2nd AED added or changed but with a 3rd AED or with combination of multiple AED, only additional 4% undergo remission. Approximately 30%–35% of patients cannot sustain seizure freedom despite adequate medical therapy. The international league against epilepsy (ILAE) task force recently defined “Drug-resistant Epilepsy” as a failure of adequate trials of two tolerated, appropriately chosen, and used AED schedules as monotherapy or in combination to achieve sustained seizure freedom. It is estimated that between 6% and 69% of patients fail to respond to standard medical and surgical therapies and continue to experience debilitating refractory seizures.
Drug-resistant or pharmacoresistant epilepsy is a clinical challenge and usually requires a multidisciplinary approach. The first step is to achieve an etiological diagnosis to establish those candidates who will benefit more from other modalities of treatment like surgery. The second step is to rule out pseudoresistance due to poor compliance or wrong drug chosen or wrong diagnosis made for the patient. Precipitators and stressor which might add up to the drug-resistant state need to be highlighted.
With this in mind, we conducted a study to try to establish an etiological diagnosis in those patients defining drug-resistant epilepsy (DRE).
| Materials and Methods|| |
A retrospective study was carried out in the Department of Neurology in NEIGRIHMS hospital, a referral center in North East India from November 2018 to November 2019. Epilepsy patients who were drug resistant and fulfilling the definition of DRE as laid by the ILAE task force were enrolled.
A detailed history regarding the seizure onset, duration, frequency, semiology, and any triggers or any other substance abuse was noted. A detailed drug history was taken regarding the dosage, side effect and compliance. An attempt to rule out pseudo-resistant due to noncompliance or wrong diagnosis, drug and dosage, and correctable triggers was also ensured.
Neuroimaging was done in all patients with both 1.5 and 3 tesla strength magnetic resonance imaging (MRI) of the brain according to the feasibility and affordability. MRI was carried out with epilepsy protocol (fluid-attenuated inversion recovery or inversion recovery sequences with coronal cross section) to improve sensitivity and specificity in identifying possible structural abnormalities that cause seizure disorders. Electroencephalogram (EEG) was done in all patients to correlate with the clinical semiology. Other investigation was tailored according to the patient clinical profile with an aim to achieve an etiological diagnosis. These include infective and autoimmune workup. Drug levels were done in few needful patients, which include serum eptoin and serum valproate level.
| Results|| |
After ruling out pseudoresistance among our epilepsy patients, a total of 33 patients were labeled as pharmacoresistant and included in the study. Seventeen males and 16 females were included. The age of presentation varied from 2 years to 57 years with the maximum number of patients in the age group of 11–40 years [Figure 1].
The most common seizure semiology was focal seizure with dyscognitive feature seen in 16 (48%) patients. Focal without dyscognitive feature was seen in 11 (33%) patients, generalized seizure in 4 (12%) patients, and multiple seizure type in 2 (6%) patients [Figure 2]. Out of five patients who had altered mentation, two had hypoxic ischemic encephalopathy (HIE), one patient had tuberous sclerosis, one patient had autoimmune encephalitis, and one had normal neuroimaging of the brain [Figure 3].
Six out of 33 patients presented with acute refractory status epilepticus which comprised of one patient with scar epilepsy, three with autoimmune etiology, and two with tuberculoma as etiology [Figure 4]. These patients were adequately treated for the primary cause before labeling as DRE. Other patients were long-term patients who were on follow-up for more than a year and were labeled as DRE.
Neuroimaging of 1.5 tesla was done in all patients and 3 tesla only in three patients. It was normal in six patients; the most common abnormality was medial temporal lobe sclerosis seen in ten patients [Figure 3]. Posttraumatic gliosis [Figure 5] was seen in three patients, tuberculoma was seen in three patients, and multiple neurocysticercosis in one patient [Figure 6]. Tuberous sclerosis was seen in two patients and patient of hypoxic ischemic injury in two patients. Other finding was focal cortical dysplasia and heterotropia [Figure 7], calcified lesion, arterio-venous (AV) malformation [Figure 8], glial tumor, and limbic encephalitis in one patient.
|Figure 5: Axial fluid-attenuated inversion recovery: Cystic lesion in the right parietal and frontal lobes with perilesional hyperintensities Suggestive of gliotic scar|
Click here to view
|Figure 6: Granuloma. (a) Axial T1-weighted image: Multiple small cystic lesions with eccentrically located small nodule at the wall which appear slightly hyperintense in T1-weighted image no perilesional edema seen (vesicular stage neurocysticercosis with scolex). (b) T1-weighted image postcontrast: Conglomerated ring-enhancing lesion in high parietal lobe with lipid lactate peak in magnetic resonance spectroscopy (MRS)|
Click here to view
|Figure 7: Cortical dysplasia. (a) Axial T1-weighted image: Hypointense area of focal cortical thickening with blurring of gray white matter. (b) Axial fluid-attenuated inversion recovery: Hyperintense area of focal cortical thickening in the left parietal lobe. (c) Sagittal T2-weighted image: Cortical thickening involving the cortex, underlying white matter, and indenting the superior surface of the lateral ventricle. (d) Coronal T2-weighted image: Focal cortical thickening in the left medial temporal lobe|
Click here to view
|Figure 8: Axial T2-weighted image: serpiginous flow void signal in the left parietal lobe with tortuous enlarge draining cortical veins. There are adjacent T2 hyperintensities of brain parenchyma suggestive of gliosis. No intralesional hemorrhage seen|
Click here to view
Cerebrospinal fluid analysis was done in seven patients out of thirty-three patients, three patients yield abnormal report suggestive of tubercular meningoencephalitis, and the rest were normal. Serum N-methyl-D-aspartate receptor antibody (NMDA) and antinuclear antibody (ANA) were done in three patients, out of which only one patient had NMDA positive and serum ANA was negative in all.
An etiological diagnosis was made only in 26 patients and was not possible in 7 patients. The most common etiology was medial temporal lobe sclerosis seen in ten patients, infective cause like tuberculoma and neurocysticercosis were also seen. Autoimmune etiology was suspected in three patients but confirmed only in one patient. In children, tuberous sclerosis and HIE were the most common etiology noted [Figure 4].
| Discussion|| |
The term “epilepsy” is labeled to a patient having two unprovoked seizures more than 24 h apart or having one single unprovoked (or reflex) seizure and a probability of further seizures of at least 60%. Among the newly diagnosed epilepsy, patient may respond to one or additional two antiepileptic but further increasing our dose and number of medications will not help.
Approximately one-third of the patients will fail to respond to medical therapy and will be requiring other modes of therapy. These medically resistant groups of patients have a high mortality and morbidity rate with a risk of sudden unexpected death in epilepsy (SUDEP); 0.5%–1% per year. DRE is a common challenge faced in our day to day practice. Based on a meta-analysis and systemic review, the pooled prevalence proportion of DRE among epilepsy patients was 0.30 (95% confidence interval [CI] 0.19–0.42), and the pooled incidence proportion was 0.15 (95% CI 0.11–0.19).
The diagnosis of DRE requires a multidisciplinary approach for its confirmative diagnosis and ruling out pseudoresistance. Improper drug choice and underdose, wrong diagnosis, noncompliance to medication due to many reasons, precipitant factors like job profile, and other comorbidities are the common factors leading to pseudo-resistant.
In our present study, after ruling out pseudoresistance, we labeled DRE in 33 epilepsy patients with near equal prevalence in both sexes. This is in contrast to other studies from India. Ramos et al. also found a male predominance among the DRE patients (59%). All recent studies on epilepsy and DRE from many parts of India showed male predominance including the study from North India having a 71% male predominance.,,, The absence of sex difference in our study is likely due to the small sample size.
Tripathi et al., in their intractable epilepsy group, found partial seizures in 83% patients, generalized seizure in 7% patients, myoclonic seizure in 6.5% patients, and multiple seizure types in 3.5% patients. In another study from Eastern India, most of their patients were suffering for single seizure type that is focal in 46.1%, GTCS in 38.7%, and multiple seizure in 15.2%. In the present study, most of the patient semiology were focal seizure seen in 27 patients (81%).
Once the diagnosis is confirmed, an etiological workup is required to confirm the surgical candidate and refer them to a comprehensive epilepsy care center for presurgical workup. Epilepsy surgery can offer better seizure remission rather than optimal medical therapy in few proper selected surgical candidates. In those candidates where surgery cannot be offered, other pillars of treatment are available such as neurostimulation, diet therapy, and other drugs like steroids and immunoglobulins that can be offered after establishing an etiological diagnosis.
In the present study, most of our patients had an abnormal MRI with structural abnormality as the most common cause seen in 17 patients (66%), where temporal lobe epilepsy was the most common (38%). Infective cause was seen with three tuberculoma (11%) and one neurocysticercosis patient (4%). Hypoxic etiology was seen in two patients (8%) and autoimmune was suspected in three patients but confirmed in one patient (4%). Vascular etiology and tumor were seen in one each. In a meta-analysis, symptomatic seizure was seen in 3.42 (95% CI 2.21–5.27), which is more common in comparison to cryptogenic (1.28 95% CI 0.48–3.45) and idiopathic (0.33 95% CI 0.19–0.59). Tripathi et al., while searching for predictors of DRE in North India in a case–control study, found that abnormal brain imaging was seen in 79% of the patients in the intractable group. However, in another study from Eastern India, most of the patients were suffering from primary/idiopathic resistant epilepsy (n = 168), followed by HIE (n = 13), granuloma (n = 13), and hippocampal sclerosis (n = 11).
Neuroimaging of 1.5 tesla and preferably 3 tesla MRI of the brain has to be done with the epileptogenic focus in mind, after correlating the clinical seizure profile and the electroencephalogram. In case of new-onset refractory epilepsy, other workup needs to be done to rule out infective and autoimmune etiology.
This present study has a few limitations such as lack of 3 tesla MRI for most patients and functional neuroimaging for all of them. Serum drug level could not be done for certain antiepileptic drugs in all our patients. The prevalence and incidence cannot be addressed in the present study. EEG correlation among various etiologies was not done. These limitations need to be overcome in future studies.
| Conclusion|| |
Etiological evaluation of DRE patients is important to assign proper treatment and assess the outcome in these patients. Neuroimaging is one of the most important investigations in identifying the epileptic focus. These patients can be offered other modes of treatment available and also to identify those who will benefit more from a surgical approach.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. N
Engl J Med 2011;365:919-26.
Kwan P, Brodie MJ. Early identification of refractory epilepsy. N
Eng J Med 2000;342:314-9.
Téllez-Zenteno JF, Hernández-Ronquillo L, Buckley S, Zahagun R, Rizvi S. A validation of the new definition of drug-resistant epilepsy by the international league against epilepsy. Epilepsia 2014;55:829-34.
Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al
. ILAE official report: A practical clinical definition of epilepsy. Epilepsia 2014;55:475-82.
Hesdorffer DC, Tomson T, Benn E, Sander JW, Nilsson L, Langan Y, et al
. Combined analysis of risk factors for SUDEP. Epilepsia 2011;52:1150-9.
Kalilani L, Sun X, Pelgrims B, Noack-Rink M, Villanueva V. The epidemiology of drug-resistant epilepsy: A systematic review and meta-analysis. Epilepsia 2018;59:2179-93.
Ramos-Lizana J, Rodriguez-Lucenilla MI, Aguilera-López P, Aguirre-Rodríguez J, Cassinello-García E, A study of drug-resistant epilepsy testing the new ILAE criteria. Seizure 2012;21:266-72.
Tripathi M, Padhy UP, Vibha D, Bhatia R, Srivastava MV, Singh MB,et al
. Predictors of refractory epilepsy in north India: A case-control study. Seizure 2011;20:779-83.
Pandey S, Singhi P, Bharti B. Prevalence and treatment gap in childhood epilepsy in a north Indian city: A community-based study. J Trop Pediatr2014;60:118-23.
Das SK, Biswas A, Roy T, Banerjee TK, Mukherjee CS, Raut DK, et al
. A random sample survey for prevalence of major neurological disorders in Kolkata. Indian J Med Res 2006;124:163-72.
] [Full text]
Radhakrishnan K, Pandian JD, Santhoshkumar T, Thomas SV, Deetha TD, Sarma PS, et al
. Prevalence, knowledge, attitude, and practice of epilepsy in Kerala, South India. Epilepsia 2000;41:1027-35.
Mukherjee J, Chakraborty DP, Guha G, Bose B, Saha SP. Recent DRE spectrum in eastern India. J Epilepsy Res 2017;7:39-44.
Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N
Engl J Med 2001;345:311-8.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]