Clinical, Neuropsychological and Neurophysiological correlates of Drug Resistant Juvenile Myoclonic Epilepsy

Transcription

1 Clinical, Neuropsychological and Neurophysiological correlates of Drug Resistant Juvenile Myoclonic Epilepsy Thesis submitted in fulfilment of the rules and regulations for DM Degree Examination of Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram By Dr. Davis Manuel A Resident in Neurology Month and Year of Submission: October 2011

2 CERTIFICATE I, Dr. Davis Manuel A hereby declare that I have actually carried out the project under report. Place: Thiruvananthapuram Signature: Date: Dr. Davis Manuel A Resident in Neurology Forwarded. He has carried out the project under report. Signature: Signature: Dr C. B. Rathore (Thesis Guide) Assistant Professor Department of Neurology, SCTIMST. Prof. M. D. Nair Professor & Head, Department of Neurology, SCTIMST. 2

3 Acknowledgement I take this opportunity to sincerely thank Prof. K. Radhakrishnan, Director, SCTIMST for providing me the opportunity to do this study. I am indebted to Prof. M. D. Nair, Senior Professor and Head, Department of Neurology for the constant support and encouragement during the period of this study. I sincerely thank Dr. C. B. Rathore, who was my guide for the study, for his expert guidance, review, kind help, and keen interest at each and every step during the completion of this study. I sincerely thank Mrs Alie Alexander, Clinical Psychologist, for carrying out the neuropsychological assessment of the patients. I sincerely thank Prof Sankara Sarma for carrying out the statistical analysis. I express my gratitude towards all the patients who took part in this study. Dr. Davis Manuel A 3

4 Contents 1. Abstract 5 2. Introduction 7 3. Review of Literature Aims and Objectives Material and Methods Results Discussion Conclusion References Appendix 44 4

5 ABSTRACT Purpose: To study the electro-clinical and neuropsychologic characteristics of patients with treatment resistant Juvenile myoclonic epilepsy (JME) Methods: All the patients with JME who attended the epilepsy clinics from April 2009 to June 2011 at our center were screened. JME was diagnosed as per the criteria defined by Classification and Terminology Commission of the International League Against Epilepsy. Treatment resistance was defined as two or more generalized tonic-clonic seizures (GTCS) or disabling myoclonus resulting in falls while on optimal dose of a first-line agent with proper compliance. All the patients underwent detailed clinical and EEG evaluation. Hospital Anxiety and Depression score (HADS) was used to screen for anxiety and depression. We used single and paired pulse Transcranial Magnetic Stimulation (TMS) parameters to measure cortical excitability. Clinical, EEG and neuropsychological characteristics of these patients were compared with equal number of randomly selected JME patients who were seizure free for last three years. Results: Of the 190 patients with JME identified during the study period, 30 (15.8%) were diagnosed as having treatment resistance JME. Twenty two patients participated in prospective evaluation. Patients with drug resistant JME had significantly later age of onset of myoclonic jerks, absence of typical early morning myoclonia, higher scores for depression and anxiety, low IQ scores and persistent EEG abnormalities while on treatment. 5

6 Frequency of GTCS inversely correlated with IQ scores and was proportional to the anxiety/depression scores. Doses of valproate were significantly higher for treatment resistant group. These patients also showed paradoxically decreased cortical excitability probably related to higher antiepileptic drug doses. Conclusions: Patients with treatment resistant JME form a distinct subtype with certain atypical neuropsychological and electrophysiological characteristics and are at higher risk of developing anxiety and depression. EEG can serve as a prognostic marker of drug resistance in JME. 6

7 Introduction 7

8 Introduction Epilepsy is the most prevalent chronic neurological disorder and a major public health concern, directly affecting an estimated 50 million people worldwide, and involving an additional 500 million people as family members and caregivers of patients. 1,2. Juvenile myoclonic epilepsy (JME) is one of the most common epilepsy syndromes, representing 26% of idiopathic generalized epilepsies 3. Under the proposal for revised classification of epilepsies and epileptic syndromes, in 1989, the Commission on Classification and Terminology of the International League Against Epilepsy defined JME (impulsive petit mal) as follows: "Impulsive petit mal appears around puberty and is characterized by seizures with bilateral, single or repetitive, arrhythmic, irregular myoclonic jerks, predominantly in the arms. Jerks may cause some patients to fall suddenly. No disturbance of consciousness is noticeable. Often, there are generalized tonic-clonic seizures (GTCS) and, less often infrequent absences. The seizures usually occur shortly after awakening and are often precipitated by sleep deprivation. Interictal and ictal EEG (electroencephalogram) have rapid, generalized, often irregular spikewaves (SW) and polyspike-waves (PSW); there is no close phase correlation between EEG spikes and jerks. Frequently the patients are photosensitive. The disorder may be inherited and sex distribution is equal. Response to appropriate drugs is good." 4 Seizures are in the form of 8

9 massive myoclonic jerks in 100% of the patients, generalised tonic-clonic seizures in 80%, and absence seizures in 25% 3. Photoparoxysmal response is seen in 40% of the patients 3. The seizures may be precipitated by various stimuli such as sleep deprivation, fatigue, alcohol intake, and stress. Sodium valproate is very effective in controlling seizures. Used alone, it leads to total control of seizures in about 80% of the patients 3. The main reason for treating patients with juvenile myoclonic epilepsy with drugs other than valproate is the occurrence of side effects such as tremors, weight gain, loss of hair, polycystic ovarian syndrome as well as high risk of teratogenecity. JME is thus usually considered as a relatively benign idiopathic generalized epilepsy syndrome. However, it is being increasingly recognized that JME is not a single disease entity by itself, but a broad group of various sub-syndromes with differences in the genetic background, clinical characteristics and prognosis 5. Though majority of patients with JME respond favorably to one of the primary drugs, there is a definite subgroup of patients who do not respond as favorably. Little is known about the electro-clinical and genetic characteristics of this group of treatment resistant JME patients. Only a few retrospective studies involving small number of patients have tried to identify the clinical characteristics of treatment resistant cases. Identifying such a subgroup of patients can help in better treatment planning, predicting the prognosis, and proper pretreatment counseling. If a homogenous group of such patients with identical electro-clinical features can be identified and further 9

10 studied, it can also help in better understanding of the pathophysiology and genetic characteristics of different JME sub-syndromes 6. 10

11 Review of Literature 11

12 Review of Literature JME was first described by Janz in 1985 and is hence also known as Janz syndrome 7. The diagnosis of JME is based on clinical findings and supplemented by characteristic EEG features. Symptoms usually begin in adolescence. Myoclonic jerks is the leading symptom which typically occur in the morning but might occur throughout the day. Patients do not lose consciousness during myoclonic jerks. The jerks are usually brief, bilateral, arrhythmic contractions that mainly involve the shoulders and arms. However some patients report jerking in the lower limbs, trunk, or head. Some jerks occur unilaterally. Myoclonic jerks occur as the only seizure type in approximately 17% of patients 5. GTCS occur in approximately 80% of patients with JME, typically shortly after awakening. GTCSs are sometimes preceded by a series of myoclonic jerks of increasing severity that evolve into an initial clonic phase of a GTCS. Janz reported that 28% of his patients with JME also had absence seizures 7. If present, they are often the first clinical manifestation of the syndrome, with myoclonic jerks typically following 1-9 years later. In JME, absence seizures are typically short, lasting a few seconds, and they usually are not accompanied by motor signs. Various combinations of seizures are possible in JME 5. Patients may have myoclonic jerks plus a combination of other seizure types. In about 60% of patients, JME begins with myoclonic jerks, which are followed by the onset of relatively uncommon GTCS a few years later. The finding of myoclonic jerks plus absence seizures and GTCS is the next 12

13 most common combination, occurring in approximately 30% of patients with JME. The combination of myoclonic jerks and absence seizures without GTCS is rare, occurring in only 2% of patients. Intelligence is normal. This observation is in contrast to findings with diseases such as progressive myoclonic epilepsies, in which progressive mental deterioration is the rule. Seizures of JME often are precipitated by lack of sleep, psychological stress, noncompliance of medication, and drinking alcohol. Patients with JME tend to be sensitive to photic stimulation. Approximately 30-40% of patients with JME are photosensitive; females typically are more sensitive than males 5. JME has a characteristic circadian pattern of clinical activity. Myoclonic jerks, GTCS, and absence seizures all tend to occur in the early morning after the patient awakens. To a lesser extent, these symptoms also occur in the evening when the patient is relaxing. When myoclonic jerks occur in the mornings, patients may have difficulty in eating breakfast or brushing their teeth. In some studies, nearly 90% of patients with JME had myoclonic jerks on awakening; the rest had either random jerks throughout the day or jerks at night 8. No abnormalities are usually identified on clinical examination in patients with JME. About 17-49% of patients have a family history of epilepsy 8. There have been only a few studies about the features associated with treatment resistant JME. Fernando-Dongas et. al studied 10 JME patients resistant to treatment with valproic acid (VPA) 9. In comparison to the VPA responsive patients they found that VPA resistant patients had higher frequency of EEG asymmetries (40% vs. 10%); atypical seizure 13

14 characteristics including auras and post-ictal confusion (30% vs. 4%); and intellectual deficiency (20% vs. 0%). However in this retrospective study, the diagnostic definition for JME and the exact criteria used to define treatment resistance were not documented. Gelisse P et. al studied 155 JME patients and found 24 (15.5%) patients resistant to treatment 10. It was a retrospective study. The diagnosis of juvenile myoclonic epilepsy was based on the criteria of the International Classification of Epilepsies. Only patients who had a minimum follow up of 1 year since seizure onset were evaluated for this study. The population was divided into three groups: (1) fully controlled, (2) truly resistant defined as persisting seizures (myoclonic jerks and/or absence seizures and/or generalised tonic-clonic seizures) despite adequate lifestyle and treatment that included adequate doses of valproate, (3) pseudoresistant due to inadequate lifestyle, to low compliance, or to inadequate choice of drugs. Clinical features associated with drug resistance were (1) the presence of psychiatric problems (58.3% vs 19%; χ 2, p<0.001) and (2) independently, the combination of seizure types (Fischer s exact 2 by 4, p=0.0026). Three types of seizures were present in 62.5% of resistant patients and 23.3% of non-resistant patients (χ 2, p=0.0001). None of the resistant patients had myoclonic jerks as the only seizure type or a combination of absences and myoclonic jerks. Six patients with serious psychiatric disorders including psychosis (two), severe mental retardation (one), and anorexia nervosa (two) were classified as non-resistant whereas two with a pervasive mental disorder were classified as resistant. Personality disorders were the most frequent finding and were 14

15 detected in 25% of resistant cases as compared to and 10.3% of nonresistant cases (Fisher s exact test, p=0.09). Among them, a borderline personality responsible for social maladjustment was the most frequent personality disorder. It was found more often in patients with drug resistance but the difference was not significant; 12.5% v 2.6% (Fisher s exact test, p=0.06). Family history of epilepsy, age at onset of seizures, sex, presence of photoparoxysmal response, results of conventional neuroimaging (CT and MRI), and delayed diagnosis were not significantly associated with drug resistance. In another study, Dasheiff and Ritaccio reported a retrospective series of 12 patients with intractable juvenile myoclonic epilepsy and found a long duration of epilepsy in these patients (mean 21 years) during which the diagnosis and appropriate treatment were delayed and a high percentage of asymmetric or focal discharges on scalp EEG (six of nine patients) 11. They emphasised that juvenile myoclonic epilepsy is not necessarily a benign epilepsy and alternative therapies, such as surgery, may be considered. However in their study, almost all patients (9/12) were on inappropriate drugs such as carbamazepine and/or phenytoin in monotherapy or in association with valproate, phenobarbital, and a benzodiazepine which precluded the definite diagnosis of treatment resistant. Baykan B et al assessed the long-term follow-up of JME, with an emphasis on the course of the myoclonic seizures 12. They noted a resistant course to treatment in 16.7% of patients and it was significantly associated with psychiatric disorders and the presence of thyroid diseases. 15

16 To summarize, the available studies are few in number and are retrospective in nature. Most of them studied very small number of patients with variable follow-up periods. Diagnostic criteria for JME and treatment resistant varied considerably among the studies. These factors preclude any uniform conclusions regarding the frequency of treatment resistant in JME and different clinical, and neuropsychological characteristics of patients with treatment resistant JME. None of the studies reported about the EEG features and presence of reflex component in the seizures. There are no available Indian studies on this topic. 16

17 Aims & Objectives 17

18 Aims & Objectives 1. To study the prevalence of treatment resistance in patients with JME 2. To study the electro-clinical and neuropsychologic characteristics of patients with treatment resistant JME 18

19 Materials and Methods 19

20 Materials & Methods Study site and Subjects This study was carried out from April 2009 to June 2011 at R. Madhavan Nayar Center for Comprehensive Epilepsy care and the Department of Neurology at Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India. It is a tertiary referral center for epilepsy care in India and receives patients from all parts of the country. Epilepsy clinics are run twice in a week and the average patient attendance per clinic is approximately 60. After the initial diagnostic workup, all patients with primary generalized epilepsy are regularly followed in these clinics under the care of experienced epileptologists. For the purpose of this study, all the patients above 12 years of age attending the epilepsy clinics during this period with a provisional diagnosis of JME, primary generalized epilepsy or generalized epilepsy were screened. Case definition of JME was based on the published criteria of the Commission on Classification and Terminology of the international league against epilepsy (ILAE). For inclusion in the study, diagnosis of JME was based upon the presence of myoclonic jerks with or without GTCS and absences. As majority of the patients were already on antiepileptic drugs (AED), we included patients with normal EEG if they fulfilled the clinical criteria. Myoclonic jerks were defined as bilateral, single or repetitive, arrhythmic, irregular jerks, predominantly in the arms. Patients with evidence of structural, metabolic 20

21 or degenerative diseases of the brain as well as those with atonic/astatic or tonic seizures or partial seizures of any form, stimulus-induced myoclonic jerks alone or with a family history of progressive myoclonus epilepsy were excluded. Similarly patients with a proven or probable diagnosis of progressive myoclonus epilepsy based upon the clinical and EEG criteria were excluded from this study. After the initial identification, all the patients with JME were evaluated for the presence of treatment resistance. Treatment resistance for the purpose of the study was defined as two or more GTCS or disabling myoclonus resulting in falls while on an optimal dose of a first-line agent with proper compliance. Anti-epileptic drugs and doses considered as first-line agents were Sodium valproate 1200 mg/day; Lamotrigine 200 mg/day; Topiramate 200 mg/day; and Phenobarbitone 90 mg/ day. Levetiracetam was introduced late in the management of patients with JME in our clinics and those patients only on Levetiracetam were not considered as treatment resistant cases. Similarly, the presence of nondisabling myoclonus alone was also not considered as treatment resistance. Patients with isolated seizures clearly related to certain precipitating factors like sleep deprivation and alcohol intake were not included in the treatment resistant group. Patients with no GTCS or disabling myoclonus while on medication during the previous three years were considered to have good response to AED. 21

22 Methods Medical records of all the JME patients attending the epilepsy clinics from 1995 onwards, at SCTIMST were scrutinized. All the patients defined as treatment resistance cases were identified and formed the study group. An equal number of randomly selected patients with treatment responsive JME were identified and formed the control group. Both sets of these patients were prospectively evaluated using a detailed clinical interview and examination. We obtained a detailed history including birth and perinatal history, developmental milestones, history of febrile seizures, CNS infection and trauma, and history of psychiatric problems from the patients and first degree relatives. Details of academic performance, a detailed family history and a history of any comorbidity were also obtained. Age at seizure onset was recorded for each type of seizures namely myoclonic seizures, absences and generalized tonic clonic seizures. Frequency of each seizure type was also noted. We noted the details regarding myoclonic jerks like presence of any aura, the body parts involved, whether single or multiple, and the time of the day in which the jerks occurred. Similarly for GTCS the time of the day, history of any preceding myoclonic jerks, presence of aura, any focal features in the semiology, the duration, and any post-ictal deficits were noted. For absence seizures also the time of the day, presence of aura, semiology and duration were noted. We specifically inquired about the precipitating factors for seizures like sleep deprivation, psychological stress, alcohol 22

23 use, photic stimulation, and menses for each patient. The time to therapy was defined as the number of years from seizure onset to appropriate therapy. Details of AEDs tried and their maximum dose, response to treatment, and side effects were noted. Family history of seizures was determined. As most patients were unfamiliar with the type and etiology of seizures in the family members, all relatives with any type of seizure disorder were included. Mental functioning was assessed based on examiner s mental status examination, school performance (whether patient required special education) and intelligence quotient (IQ) scores. Verbal IQ and Performance IQ were assessed and Full scale IQ was calculated by using Wechsler Adult Intelligence Scale-III. For each of the patient, all the previous EEG records were reviewed. All patients underwent one hour EEG recording including both asleep and awake record including the testing for any reflex components. This included photic stimulation, testing for pattern sensitivity and cognitive tasks. The background activity, the frequency and duration of generalized spike, polyspike and slow-wave discharges were noted. Asymmetry was defined as consistently unilateral epileptiform discharges, focal slowing, or a persistent unilateral predominance of the synchronous polyspike and wave discharges. All patients also underwent detailed neuropsychological and psychiatric evaluation. We used the Hospital Anxiety and Depression score (HADS) to assess anxiety and depression. All patients with treatment resistant epilepsy had at least one 1.5 T MRI scan done as per our epilepsy protocol defined previously 13. The clinical, electrophysiological and 23

24 neuropsychological features were compared between the two groups. In a subgroup of patients, Transcranial Magnetic Stimulation (TMS) study, as a noninvasive clinical measurement of neuronal excitability, was also conducted as a pilot study. The parameters measured by TMS included motor threshold, motor evoked potential (MEP) amplitude, and cortical silent period (CSP). Additional parameters measured with paired-pulse stimulation techniques included intracortical inhibition (ICI) and intracortical facilitation (ICF). Statistical methods We summarized the demographic data as mean and median. We compared the various clinical, electrophysiological and neuropsychological parameters between treatment resistant and treatment responsive JME groups. Student s t test was used for parametric variables, and Mann- Whitney test and Chi-Square test used for non-parametric variables. Spearman s correlation coefficient was used to assess the correlation between the number of seizures and various continuous variables. A p value of <0.05 was considered significant. All the analyses were done with SPSS Statistics version 17 (Chicago, Illinois). 24

25 Results 25

26 Results Demographic characteristics During the study period, 190 patients with JME attended the epilepsy clinics. After reviewing the records, 30 (15.8%) patients were considered to have treatment resistant JME. Out of these, six patients refused to participate in the study and two patients did not return for the scheduled follow-up. Thus study group included 22 patients who fulfilled the criteria for treatment resistant JME. We randomly selected identical number of 22 patients with treatment responsive JME as control group. Mean age of the patients was 27.6 ± 8.1 years (range, 15-48); 24.5 ± 8.2 years (range, 15-48) for the treatment responsive group, and 30.7 ± 6.9 years (range, 19-44) for the treatment resistant group (p<0.01) (Figure 1). More number of female patients were represented in the treatment responsive group (16, 63%) as compared to treatment resistant group (11, 50%; p=0.2). Mean age at onset of epilepsy for the treatment resistant group was 13.4 ± 2.8 years and for the treatment responsive group was 12.7 ± 2.8 years (p=0.4). Sixteen patients in the treatment resistant group had GTCS as the initial seizure type as compared to 10 patients in the treatment responsive group (p=0.2). Rest all the patients had myoclonic jerks as the initial manifestation. Patients in the treatment resistant group tended to have later onset of myoclonic jerks than those with treatment responsive JME (15.1 ±4.3 vs ± 2.8 years, p=0.05) (Table 1). However age of onset of 26

27 GTCS and absences were similar between the two groups. The treatment of JME after the onset of seizures was delayed by an average of 1.83 years. Although the delay was more in the treatment resistant subgroup, the difference was not statistically significant (Table 1). Twelve (27.3%) JME patients had family history of seizures, six in each group. Comparison of different variables between two groups is presented in Table-2. Seizure characteristics History of typical early morning myoclonic jerks was noted in 18 patients of treatment responsive group and in nine patients of treatment resistant group (p=0.005; OR: 6.5, CI: ) (Table-2 and Table 5). There was no difference in the other characteristics of myoclonic jerks and GTCS between two groups. Absence seizures were present in four (9%) patients, two in each group. Emotional stress acting as a precipitating factor was reported to be more common in the treatment resistant group than the treatment responsive group (72.7% vs 27.3%; p=0.003; OR: 7.1, CI: ). Association with other precipitating factors like sleep deprivation, alcohol use, or menstrual cycle associations was not different between the two groups. History of light or pattern sensitive seizures was present in 3 patients with treatment resistant seizures and none in the treatment responsive group. However this finding did not attain statistical significance. 27

28 One patient with treatment resistant JME reported focal semiology. History of aura was given by one patient in each group. None of the patients in either group had any history of postictal deficits. Intellectual functioning Patients in the treatment responsive group had higher IQ scores as compared to those in treatment resistant group (Table-3). Mean scores for full-scale IQ (p=0.026), verbal IQ (p=0.038), and the performance IQ (p=0.04) were significantly higher in the treatment responsive group. Spearman s correlation analysis comparing the IQ scores with the total number of GTCS in each patient showed an inverse correlation which was statistically significant for VIQ and FSIQ (Table-4). The correlation coefficients were and respectively. Poor scholastic performance was present in 4 patients in treatment responsive group and 6 in treatment resistant group. Similarly, both the mean anxiety scores and mean depression scores were higher in the treatment resistant group (p=0.03) (Table-3). Spearman s correlation analysis comparing the anxiety and depression scores with the total number of GTCS in each patient showed a direct correlation which was statistically significant. The correlation coefficients were and respectively (Table-4). Self reported psychiatric problems were 28

29 present in 2 patients in treatment resistant group and none in treatment responsive group. EEG findings Total numbers of EEG available were 51 for the resistant group and 40 for the responsive group. Being a referral center, all the patients were already on AED by the time they visited our institute. Initial EEG was normal in eight of the 15 patients with treatment responsive JME and two of the 16 patients with resistant JME (p<0.02). At the time of final evaluation, EEG was normal in 12/22 (55%) patients with treatment responsive JME and 4/22 (18%) patients with resistant JME (p<0.01). Thus the patients with treatment resistant JME are more likely to have abnormal EEG during the treatment than those with drug responsive JME. (p<0.01; OR, 5.4, 95% CI, ). There was no statistically significant difference between the two groups regarding the background activity frequency, or the frequency of the spike and wave discharges. A total of six (13.6%) patients had focal abnormalities on EEG, three in each group. Scotosensitivity was seen in two patients with treatment resistant seizures and none in treatment responsive group. Photoparoxysmal response was noted in three patients of treatment responsive group and two patients of treatment resistant group. No patients in either group showed pattern sensitivity. There was no 29

30 statistically significant difference between the two groups regarding the occurrence of IEDs in sleep and wakefulness. Neuroimaging findings All the patients in the treatment resistant group had MRI brain done as described. Plain CT brain films were available with four patients in the treatment responsive group and one patient had MRI brain. None of the patients in either of the two groups had any abnormal findings in the CT or MR images. Other variables There was no statistically significant difference between the two groups in the incidence of cesarean section delivery, motor or language developmental delay, and history of febrile seizures. None of the patients in either group had preterm delivery, birth asphyxia, central nervous system infection, significant head trauma, precipitation of seizures with cognitive tasks, or status epilepticus. 30

31 AED therapy All the patients in the treatment responsive group were on single AED; 16 patients were on Valproate (VPA), five were taking Levetiracetam while one patient was on Lamotrigine. Twelve patients in the treatment resistant group were taking more than one AED (p<0.0002). VPA was the most commonly used AED (n=15) in this group followed by phenobarbitone (n=11). Mean dose of VPA was significantly higher in the treatment resistant group as compared to treatment responsive group (500 ± 210 mg vs 1290 ± 440 mg; p<0.001). TMS parameters TMS parameters of cortical excitability were studied in a subgroup of seven patients with resistant JME and five patients with treatment responsive JME (Table 6). Patients with treatment resistant JME had significantly increased mean values for motor threshold, CSP and ICI, suggesting a paradoxically decreased cortical excitability. MEP was unelicitable even with maximal stimulation in two of these patients. 31

32 Discussion 32

33 Discussion Our results show that approximately 15% of patients with JME have drug resistant epilepsy. We found that drug resistant JME is associated with later age at onset of myoclonic jerks, relative absence of early morning myoclonia, persistence of EEG abnormalities during treatment, lower IQ, and higher rates of depression and anxiety. Moreover, depression and anxiety in these patients is partly related to uncontrolled epilepsy and higher seizure frequency. We tried to assemble a relatively uniform group of patients with drug resistant JME who were chosen as per the predefined criteria. Secondly, all the patients with drug resistant epilepsy were then prospectively evaluated. As JME patients usually have an excellent response to first-line AEDs at appropriate dosages, presence of two or more GTCS despite good compliance was regarded as treatment resistance. Previous studies have used various definitions of drug resistance and included heterogeneous group of patients such as those with uncontrolled myoclonic seizures or GTCS. However, in our opinion persisting minor nondisabling myoclonic jerks may not need any additional therapy and may not warrant a diagnosis of drug resistant JME. Hence we included only those patients with GTCS or those with disabling myoclonic jerks impairing activities of daily living in the drug resistant group. Similarly, as an occasional seizure may be precipitated by various factors which patients may not recall, we included 33

34 the criteria of two or more seizures to classify drug resistant. JME is considered as easily treatable epilepsy and drug resistance is not very common. Presence of drug resistance in JME should raise the suspicion of pseudo-resistance related to improper diagnosis, compliance or improper treatment. We tried to exclude all the possible causes of such pseudoresistance in our cases. However, in the absence of definite genetic testing, we cannot exclude the possibility that some patients in this group had milder variant of PME syndrome. A further study of such groups including genetic testing may clarify these issues. It is being increasingly recognized that JME is not a uniform disease and there are distinct subtypes within this syndrome. In a large study of 257 patients with JME, Martinez-Juarez and colleagues identified four distinct subsyndromes and the syndrome of JME evolving from childhood absence epilepsy (CAE) was associated with highest risk of drug resistance 14. We did not find any patient with CAE evolving into JME in our cohort. Different selection criteria and study settings might have contributed to this difference. Majority of our patients belong to the classical JME phenotype as described by Martinez-Juarez et al. and we tried to identify the predictors of drug resistant within this subgroup. We found that younger age at the onset of myoclonic jerks and presence of early myoclonic jerks is associated with good response to treatment. It has been previously been documented that patients with early morning myoclonic jerks have relatively benign course 15. Patients with drug resistant JME were also more likely to 34

35 have GTCS as the initial seizure type rather than myoclonic jerks. Although this variable did not reach statistical significance probably related to small number of patients, these factors does indicate that those patients with classical JME phenotype who start with early morning myoclonic jerks and later develop GTCS are more likely to respond to AED therapy. Other important finding of our study is the higher rates of self reported depression and anxiety among our patients with treatment resistant JME. In a similar previous study, psychiatric problems especially the personality problems were found to be more frequent in patients with treatment resistant JME 10. Mild but characteristic personality problems were initially described in patients with juvenile myoclonic epilepsy by Janz 3. Our study further shows that mood disorders are quite frequent in these patients and it is partly related to the seizure frequency. Also, emotional stress precipitating the seizures was much more likely in patients with poor seizure control. Our results indicate that mood disorders partly result from the poor seizure control in JME and do not necessarily represent a separate phenotype. This indicate the need for regular screening of treatment resistant JME patients for anxiety and depression and appropriate treatment should be instituted once diagnosed. We also found that patients with poor seizure control had lower verbal as well as performance IQ scores. Withstanding a direct cause effect relationship, it indicates that patients of JME with relatively lower IQ scores are at a higher risk of poor seizure control. 35

36 Both the initial EEG and last EEG were more likely to show interictal epileptiform discharges in patients with treatment resistant JME. Majority of the patients were on AED therapy during the time of EEG indicating that persistence of IED in spite of adequate treatment portends poor response to AED therapy. We found focal EEG abnormalities in 13.6% of patients, distributed equally in both the treatment responsive and treatment resistant subgroups. Focal EEG abnormalities have been reported in 15-20% of patients with JME 16,17,18. While one study showed that focal abnormalities are more common in patients with drug resistant JME 11, others have not found such association. Different study populations and patient selections are likely to be the causes for these heterogeneous results. We found a relatively lower prevalence of photoparoxysmal response in 11.4% of patients, probably related to AED use. Our results indicate that majority of patients will require lower doses, typically between mg of sodium valproate for seizure control. We also found paradoxical decrease in cortical excitability, on TMS studies, in patients with drug resistant epilepsy again probably related to higher doses of AED in these patients. Whether TMS parameters before the initiation of drug therapy can predict drug resistance needs to be studied further. Progress in identifying genetic mutations in patients and families with JME has been considerable. The syndrome of JME likely consists of many genetic diseases that result in a similar electro-clinical syndrome. It is possible that some of these mutations cause subtypes of JME which are 36

37 relatively resistant to treatment. Identification of a uniform group of such patients and further genetic studies linking them may be helpful for delineating the underlying basis of drug resistant in JME. 37

38 Conclusion 38

39 Conclusion We conclude that approximately 15% of patients with JME have drug resistant epilepsy. These patients have GTCS as earliest seizure type, later age of onset of myoclonic jerks, absence of typical early morning myoclous, lower IQ scores and more likelihood of developing depression and anxiety. These patients have persistent abnormalities on EEG in spite of adequate treatment which can be used as a useful marker of treatment resistance. The clinical characteristics of the treatment sensitive group resemble the typical JME syndrome described by Janz. Further studies involving larger number of patients aiming at genetic categorization of these patients may be helpful in better understanding of underlying pathophysiology. 39

40 References 40

41 References 1. Kale R. Global campaign against epilepsy: the treatment gap. Epilepsia. 2002;43: World Health Organization. Epilepsy in the WHO Africa Region, Bridging the Gap: the Global Campaign Against Epilepsy Out of the Shadows. WHO Press, Geneva, Janz D and Durner M. Juvenile myoclonic epilepsy. In: Epilepsy, A Comprehensive Textbook (Eds J. Engel and T. A. Pedley). Philadelphia, Lippincott-Raven, 1998: pp Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30: Genton P, Gélisse P, Thomas P. Juvenile myoclonic epilepsy today. In: Schmitz B, Sander T, eds. Juvenile myoclonic epilepsy: the Janz syndrome. Petersfield, UK: Wrightson Biomedical, 2000: Regesta G, Tanganelli P. Clinical aspects and biological bases of drug-resistant epilepsies. Epilepsy Res. 1999;34: Janz D. Epilepsy with impulsive petit mal (JME). Acta Neurologica Scandinavica 1985;72: Genton P, Salas-Puig X, Tunon A, Lahoz C, Sanches M. JME and related syndromes: Clinical and neurophysiologic aspects. In: Idiopathic Generalized Epilepsies (Eds A. Malafosse, P. Genton, E. 41

42 Hirsch, C. Marescaux, Broglin and R. Bemasconi). London, R. John Libbey, 1994: pp Fernando-Dongas MC, Radtke RA, Vanlandingham KE et al. Characteristics of valproic acid resistant juvenile myoclonic epilepsy. Seizure 2000;9: Gelisse P, Genton P, Thomas P, Rey M, Samuelian JC, Dravet C. Clinical factors of drug resistance in juvenile myoclonic epilepsy. J Neurol Neurosurg Psychiatry 2001;70: Dasheiff RM, Ritaccio AL. Characterization of intractable JME: new perspectives on primarily generalized seizures. Seizure 1993;2: Baykan B, Altindag EA, Bebek N et al. Myoclonic seizures subside in the fourth decade in juvenile myoclonic epilepsy. Neurology 2008; 70: Sylaja PN, Radhakrishnan K, Kesavadas C, Sarma PS. Seizure outcome after anterior temporal lobectomy and its predictors in patients with apparent temporal lobe epilepsy and normal MRI. Epilepsia 2004;45: Martínez-Juárez IE, Alonso ME, Medina MT et al. Juvenile myoclonic epilepsy subsyndromes: family studies and long-term follow-up. Brain 2006;129: Jain S, Padma MV, Maheshwari MC. Occurrence of only myoclonic jerks in juvenile myoclonic epilepsy. Acta Neurol Scand 1997;95:

43 16. Aliberti V, Grunewald RA., Panayiotopoulos CP, Chroni E. Focal EEG abnormalities in JME. Epilepsia 1994;35: Lancman ME, Asconape JJ, Penry JK. Clinical and EEG asymmetries in JME. Epilepsia 1994;35: Vijai J, Cherian PJ, Sylaja PN, Anand A, Radhakrishnan K. Clinical characteristics of a South Indian cohort of juvenile myoclonic epilepsy probands. Seizure 2003;12:

44 Appendix 44

45 Figure 1: Age distribution of patients with Treatment responsive and Treatment resistant JME 45

46 Table 1: Comparison of age of onset of different types of seizures and the time to treatment (in years) between the two groups Treatment responsive JME Treatment resistant JME Mean (SD) Mean (SD) P value Age of onset 12.7 (2.76) 13.4 (2.81) MJ age of onset 12.8 (2.8) 15.1 (4.3) 0.05 GTCS age of onset 13.8 (1.9) 14.4 (3.8) Absence age of onset 10.3 (3.2) 9.5 (3.5) Time to treatment 2.1 (3.9) 1.6 (2.5) MJ: Myoclonic jerks; GTCS: Generalized tonic-clonic seizures; SD: standard deviation 46

47 Table 2: Comparison between the 2 groups regarding various clinical and EEG characteristics Treatment responsive JME (n) Treatment resistant JME (n) P value Consanguinity Motor delay Language delay Febrile seizures Psychiatric problems Family history of seizures Poor academic performance Frequent MJ Axial MJ Multiple MJ Early morning MJ Early morning GTCS Sleep GTCS MJ preceding GTCS Aura Focal semiology Absence seizures Other semiology Sleep deprivation Stress precipitating seizure Alcohol precipitating seizure Light/pattern precipitating seizure Menses precipitating seizure Normal initial EEG Normal EEG at time of study Asymmetric IEDs Sleep IEDs Photoparoxysmal response Scotosensitivity Monotherapy

48 Table 3: Comparison of IQ scores and anxiety/ depression scores between the two groups Treatment responsive JME Mean (SD) Treatment resistant JME Mean (SD) P value Verbal IQ 94.4 (12.2) 86.5 (11.5) Performance IQ 90.8 (15.7) 81.2 (15.5) Full Scale IQ 92.8 (13.0) 84.0 (12.8) Anxiety score 5.3 (4.8) 7.8 (3.7) Depression score 3.4 (3.7) 5.9 (4.3) IQ: Intelligence quotient; SD: standard deviation 48

49 Table 4: Spearman's correlation analysis between the total number of GTCS and other variables Correlation coefficient P value Verbal IQ Performance IQ Full Scale IQ Anxiety score Depression score Age of onset of MJ Age of onset of GTCS GTCS: Generalized tonic-clonic seizures; IQ: Intelligence quotient 49

50 Table 5: Odd s ratio for Treatment responsive JME for the variables which showed statistical significance Odd's ratio 95% confidence interval Early morning MJ Stress precipitating seizures Normal initial EEG Normal EEG at time of study

51 Table 6: Statistical analysis of TMS parameters in the 2 groups Parameter Treatment responsive JME Mean (SD) Treatment resistant JME Mean (SD) P value RMT % 37 (3.2) 70.6 (13.2) CSP 110% (ms) 97.7 (6.2) (6.3) CSP 120% (ms) (12.8) 139 (9.8) 0.04 CSP 130% (ms) (15.5) (7.3) 0.13 CSP 140% (ms) (13.7) (10.3) 0.08 ICI % 33 (5.3) 22 (3.5) ICF % (14.7) (14.4) 0.01 RMT Resting Motor Threshold, CSP Cortical Silent Period, ICI Intracortical Inhibition, ICF Intracortical facilitation 51