Concepts and controversies of juvenile myoclonic epilepsy: still an enigmatic epilepsy.

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Review

Concepts and controversies of juvenile myoclonic epilepsy: still an enigmatic epilepsy Expert Rev. Neurother. Early online, 1–13 (2014)

Matthias J Koepp1, Rhys H Thomas2, Britta Wandschneider1, Samuel F Berkovic3 and Dieter Schmidt*4 1 Department of Clinical and Experimental Epilepsy, University College London – Institute of Neurology, 33 Queen Square, London WC1N 3BG, UK 2 MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Hadyn Ellis Building, Maindy Road, Cathays, Cardiff CF24 4HQ, UK 3 Epilepsy Research Centre, Melbourne Brain Centre, Austin Health, 245 Burgundy Street, Heidelberg, Victoria, 3084, Australia 4 Epilepsy Research Group, Goethestr. 5, D-14163 Berlin, Germany *Author for correspondence: Tel.: +49 308 017 679 Fax: +49 308 017 679 [email protected]

Juvenile myoclonic epilepsy (JME) is a clinically and genetically heterogenous, generalized epilepsy syndrome usually starting in adolescence. An age-related, predominantly frontocortical-subcortical network dysfunction is likely to be the substrate of bilateral myoclonic seizures occurring at full consciousness within hours after awakening, which are the clinical hallmark of JME. Although essential features of JME were recognized by Herpin more than 140 years ago, it is still an enigmatic epilepsy syndrome in many ways; advanced imaging techniques reveal multi-focal abnormalities in this paradigmatic generalized epilepsy syndrome; clinical studies reveal a major role of genetics in etiology, but the underlying molecular changes are likely to be highly heterogeneous; many JME patients have psycho-social issues, even though their intelligence is normal; antiepileptic drugs (AEDs), notably valproic acid, achieve seizure remission in two thirds of patients, but more patients seem to relapse after stopping AEDs than in any other epilepsy syndrome. This pessimistic outlook has been challenged in recent population-based studies and needs to be assessed in randomized AED withdrawal trials. This review summarizes recent focus neuroimaging, genetic, and behavioral aspects of JME and re-appraises the entrenched view that remission off AEDs is exceptionally rare in JME. KEYWORDS: behavioral problem • drug treatment • epileptogenesis • genetics • juvenile myoclonic epilepsy • neuroimaging • remission • valproic acid

Currently, juvenile myoclonic epilepsy (JME) is classified as a genetic generalized epilepsy (GGE) syndrome because of the bilateral aspect of seizures and EEG, with normal IQ, absence of structural imaging abnormalities and typically good response to treatment with valproic acid (VPA) [1]. JME, with its clinical hallmark of myoclonic jerks in full consciousness in the hours after awakening, has been recognized as early as 1867 by Herpin [2]. Ninety years later, the German neurologist Dieter Janz and the electroencephalographer Walter Christian outlined the essential features of JME, including its particular response to treatment [3]. A further 50 years have passed, and JME still remains an enigmatic epilepsy in several important ways. A recent panel of experts could not agree on uniform diagnostic criteria for JME [4]. It remains unclear: • How focal or multifocal clinical, EEG and imaging features occur in this paradigmatic GGE;

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• Whether JME is genetically one or several diseases; • Why psychosocial outcome is often unfavorable, which is surprising given the normal intelligence and good seizure control; • Why seizures are easy to control, but seem to relapse in most patients when antiepileptic drugs (AEDs) are stopped. We will address these controversies that make JME an enigmatic epilepsy, over 140 years after its initial description by Herpin [2]. Is JME generalized, frontal: neither or both? (MJ Koepp)

The characteristic feature of JME is myoclonic jerks of the proximal upper extremities, particularly after awakening. The age of onset for this syndrome is predominantly between 12 and 18 years. Usually, it starts with isolated jerks, followed by generalized tonic-clonic seizures (GTCS), and less often absence seizures.

2014 Informa UK Ltd

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Review

Koepp, Thomas, Wandschneider, Berkovic & Schmidt

Patients with JME are particularly susceptible to seizure facilitation through sleep deprivation, alcohol consumption or photic stimulation. JME is defined by electrophysiological features that show involvement of both cerebral hemispheres from the beginning of seizures with the typical EEG finding of 3–6 Hz generalized spike-wave (GSW) or polyspike-wave activity, with a frontocentral predominance. Common EEG abnormalities, however, are focal/asymmetric EEG changes, reported in up to 45% of JME patients [5]. According to the criteria of the International League Against Epilepsy (ILAE), structural brain abnormalities using MRI and computed tomography are not found, but the development of highly sensitive neuroimaging techniques has elucidated subtle structural and functional abnormalities in JME. These imaging findings in particular contributed to the current concept that JME involves thalamocortical networks [6]. Molecular imaging studies

PET demonstrated metabolic and neurotransmitter changes in the dorsolateral prefrontal cortex [7]; PET did not only show evidence of increased thalamic metabolic activity during GSW [8], and reduced metabolic activity in regional frontal networks, but also more specific alterations in the opioid [9], serotonin [10] and dopaminergic [11] systems in patients with GGE, including those with JME. Brainstem and basal ganglia involvement could be shown in addition to the commonly implicated thalamocortical systems. 1 H-magnetic resonance spectroscopy repeatedly showed prefrontal and thalamic neuronal loss or dysfunction [12,13], whereas no abnormalities were found in other GGE syndromes suggesting the frontal lobe findings were specific to JME [14]. Thalamic changes appeared to be progressive [15], which correlates with structural MRI evidence of progressive thalamic volume loss [16]. Volumetric imaging studies

Thalamic volume abnormalities were detected within 12 months of seizure onset, suggesting a clinically significant disruption of the thalamo-fronto-cortical circuitry early in the course of the condition, leading to both seizures and neurocognitive deficits, which seems to be unlikely the result of chronic seizures [17]. Frontal lobe structural changes are seen consistently in JME compared with controls, affecting orbitofrontal and superior mesial areas close to the supplementary motor area (SMA), and reduced structural and altered functional connectivity of the anterior SMA, motor cortex and frontoparietal cognitive networks [18–25]. These effects were stronger in patients still suffering from seizures, and normalized with increasing doses of VPA [25]. This may provide an explanatory framework for how cognitive effort can cause myoclonic jerks and account for several clinical observations, like ‘frontal’ cognitive and behavioral profiles in JME [26]. Increased functional coupling between the motor system and cognitive networks were also observed in siblings of JME patients [27], suggesting that this imaging finding is a heritable trait. doi: 10.1586/14737175.2014.928203

Combined EEG & functional MRI studies

Simultaneous EEG-functional MRI, primarily used to study GSW activity, identified thalamic activation and widespread deactivation of association cortex, the so-called ‘default mode’ networks, across several centers and different generalized syndromes [28–32]. These changes may represent downstream consequences of GSW, although mesial frontal and thalamic activations occurred up to several seconds before EEG spike-wave activity, followed by widespread ‘deactivations’ affecting frontal, parietal and cingulate areas [33]. Methodological limitations of imaging studies

Three methodological constraints of imaging studies need to be addressed in this context: • Most image analysis methods rely on setting arbitrary thresholds, which bias toward the detection of focal over generalized abnormalities; • Focal abnormalities resulting from correlations with either epilepsy-specific (duration of illness), or cognitive measures, provide evidence for involvement of certain anatomical structures, like the thalamus [17], but not necessarily for its causal role for epilepto- or ictogenesis; • The majority of imaging studies report findings in adult patients often with an ‘atypical’ cause of poor initial treatment response, matched in age and gender to healthy controls, which have no neurological or psychiatric comorbidities, nor take any medication. How do we reconcile multifocal imaging abnormalities with age-related, dynamic changes in the gross morphology and functional organization of the brain throughout adolescence?

The new classification of the epilepsies aims to reconcile available data on age, etiology, seizure type, EEG and imaging abnormalities, and ultimately, to assign causality through the identification of involved epilepto- and ictogenic mechanisms [34]. Most relevant for JME, the classification orders epileptic syndromes according to age of onset, emphasizing the importance of brain development during adolescence for this agerelated condition. Gray & white matter changes during brain maturation

The normally developing adolescent brain matures with thickening or thinning of the cortex at different rates and times depending on the region. Following sustained growth in early childhood, gray matter (GM) volume overall diminishes first over the primary sensorimotor areas, then following a back-to-front progression over the frontal cortex, with the last one to mature being the dorsolateral prefrontal cortex at the end of adolescence, while orbitofrontal regions continue to mature until old age [35]. These GM decreases may be related to pruning, apoptosis and myelination of intra-cortical axons, leading to functional refinement and Expert Rev. Neurother.


Concepts & controversies of JME

increased efficiency and resulting in cognitive and behavioral changes [36]. In addition to cortical changes, there are continued microstructural changes in the white matter (WM), with a regionand hemisphere-specific increase of WM volume and thalamocortical connectivity with increasing age [37]. These brain regions continue to re-organize during adolescence in relation to neurocognitive performance with maturation and refinement of complex attention, phonemic fluency, motor and sensorial skills and sensorimotor coordination. Assessment of the thalamocortical circuits at adolescence shows the strongest thalamic connection with the sensorimotor cortex [38]. Molecular & synaptic changes during brain maturation

GABA-ergic synapses, interneurons and other neurotransmitter systems follow the same general rule of initial generation of excessive synapses followed by massive pruning with maturation and refinement of connections during adolescence, showing differences according to the cortical area [39]. These processes are genetically determined. Indeed, a number of genes implicated in the etiology of JME (EHHC1, GABRA1, BRD2) have definite or putative roles in ion channel functioning, neuronal migration and apoptosis. Defective pruning with interrupted or delayed apoptosis resulting in unwanted (excitatory) synapses may lead to maintenance of excessive neuronal density and may be followed by abnormal hyperexcitable circuits and hyperconnectivity [25]. It remains elusive, how much ‘aberrant pruning’ and re-organization, in what region and at what critical time-point would be necessary for such seizures to occur. Conclusion from imaging studies

According to the new ILAE classification, ‘generalized seizures are conceptualized as originating at some point within, and rapidly engaging, bilaterally distributed networks’ [34]. Currently, we are not able to measure and quantify developmental abnormalities in the individual person within such networks that ‘ can include cortical and subcortical structures, but not necessarily include the entire cortex’ . Frontal, in particular dorsolateralprefrontal cortex, and SMA are important structures contributing to the development and persistence of the particular psychopathology, cognitive seizure triggers and myoclonic seizures. For JME patients with associated photo-sensitivity, other regions and related occipitofrontal connections may be also relevant. Based on the evidence from recent neuroimaging studies, JME can be considered both, a genetically determined, generalized epilepsy syndrome of brain maturation, resulting in age-related, predominantly frontocortical-subcortical network dysfunction.

Review

not rigidly defined. An admirable recent attempt illuminated the variation in definition used by international experts, and proved that a single classification could not fully describe the recognized clinical features of JME [4]. This heterogeneity can be explained partially, if JME is: • part of a GGE spectrum sharing features with related subsyndromes such as juvenile absence epilepsy and epilepsy with generalized tonic-clonic seizures alone; • not one, but many similar syndromes. This argument has been extrapolated by authors who describe subsyndromes within JME based on clinical evolution and prognosis [40–42]. Furthermore, the genetic determinants of JME are largely unknown, but we argue that evidence from clinical evolution, epidemiology and genetic studies argue toward a complex polygenic etiology, each with likely differing suites of variants in each case. Clinical genetics of JME

Despite challenges in tightly defining JME, clues to its genetic architecture and the question as to whether JME is genetically homogeneous come from clinical genetic studies and genetic epidemiology. First-degree relatives of JME probands have an elevated risk of epilepsy (~6% [43]), and especially of generalized epilepsy, but not to the extent that would be expected in a Mendelian dominant or recessive trait. The risk of a first-degree relative having seizures may be dependent on the JME phenotype; in one series studying multiplex families, when JME was associated with absence seizures, the risk to first-degree relatives was doubled [44]. These data are consistent with complex inheritance with oligogenic or polygenic architecture. Twin studies confirm the importance of genetics in GGE in general and JME in particular. Historic and contemporary twin studies strongly support a major heritable component with very high monozygous concordances [45]. Importantly, within concordant monozygous pairs, the syndrome is nearly always identical, whereas concordant dizygous pairs may have heterogeneous syndromes. This parallels the situation in multiplex families with GGE, where heterogeneous syndromes are usually observed, although JME probands are more likely to have relatives with JME than relatives with absence epilepsies [46–49]. Other puzzling observations underscoring the likely complex inheritance is the observation by some authors of greater maternal than paternal inheritance of epilepsy [50] and that there may be a greater proportion of females with JME than males [44]. The latter finding is controversial due to competing claims of ascertainment bias when selecting cases.

Is JME genetically one or many diseases? (RH Thomas & S Berkovic)

Molecular genetics of JME

To accurately describe the genetics of a disorder or trait, its diagnostic boundaries should be known. For JME, these are

Finding genes for JME, which began in the 1980s [50], has proven more challenging than initially expected, probably


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because of the complex genetic architecture of JME. A recent review lists 29 loci or genes that have been implicated [51]. Unfortunately, for the most part, they have not assisted in identifying common genes for JME and many of these findings may be false positives. Here, we briefly critique the field in rough chronological order of the development of genetic technologies.


Linkage analysis

Linkage analyses were first used to attempt to look for loci of chromosomal sharing, generally within families, with the aim of then finding mutated genes. Many loci have been reported [50,51], but few were validated. Linkage is most robust in analyzing large families with Mendelian traits and we suspect that the generally disappointing results of linkage studies reflect the fact that JME is rarely a Mendelian trait. Of loci and genes discovered using linkage, GABRA1 at 5q34-q35 [52] and EFHC1 at 6p12 [53] and SLC2A1 at 1p35–p31 [54,55] are the most notable. A GABRA1 mutation in autosomal dominant JME was identified in a large French-Canadian family [52]. The mutation was shown to disrupt GABA-evoked currents, but mutations in GABRA1 are very rare even within apparently dominant JME families [56]. EFHC1 (‘myoclonin 1’) is a controversial ‘JME gene’. It may be that in the rare situation of autosomal dominant JME, the EFHC1 mutations are causative. This is yet to be proven beyond doubt. The original report of seven families included asymptomatic carriers and clinically asymptomatic carriers with an EEG phenotype [53]; the penetrance was approximately 40%. Further studies of autosomal dominant JME families identified EFHC1 variants in: 1/54 [56], 0/18 [57] and 4/27 families [58]. There appears to be an excess of missense variants in people of Hispanic ethnicity compared with Caucasians [59,60]. It is also worth noting that EFHC1 is in the top 10% of genes that are particularly tolerant of variation without producing a phenotype [61]. The glucose transporter, GLUT1, encoded by SLC2A1 is well known as a cause of GLUT1 encephalopathy [62]. Its role in milder epilepsies was shown in a large family with seizures and paroxysmal exercise-induced dystonia [54]. Subsequently, it was shown to be important in small families and sporadic cases of early onset-childhood absence epilepsy (CAE) or epilepsy with myoclonic-atonic seizures. However, families with segregating pathogenic SLC2A1 mutations are notable for their genetic heterogeneity and there are many individuals with JME within these families with a GLUT1 deficiency [55,63]. Identification of this is important, because there is the opportunity for seizure control with the ketogenic diet. CASR, a calcium sensing gene has been reported as a dominant JME gene in India [64]. This was identified by linkage to 3q13.3-q21 in a three-generation family, but has not yet been replicated. doi: 10.1586/14737175.2014.928203

Candidate gene studies

Candidate gene screening is the hypothesis-based system of identifying an excess of variation within a gene compared with the unaffected control population. Despite 20 years of studying ion channels and receptors, there are few convincing high frequency findings in JME [65]. Mutations were identified in GABA genes 10 years ago [52,66], but these are neither necessary nor sufficient to cause most cases of JME. It is possible that reported genes associated with JME either do not have the directly causative effect reported or are one of many contributory genes. Connexin-36 variants are common in unaffected controls, but some variants have been reported to be more frequently expressed in people with JME [67]. BRD2 was initially implicated by linkage analysis [68], but the association of the candidate causal single nucleotide polymorphism could not be confirmed in a sample of 531 people with JME [69] or 154 French [70] cases. Similarly, malic enzyme 2 identified by single nucleotide polymorphism association was not supported by a German study of 660 patients [71,72]. The calcium channel gene CACNB4 is a possible rare contributor to JME [73]. Copy number variation

Copy number variation is a form of genomic structural variation that results from usually having one extra, or one too few copies of a portion of DNA often many kilobases in length; these can be inherited from either an affected or an unaffected parent or occur de novo. A recent review [74] identified that the recurrent microdeletion at 15q13.3 occurs in 19/1762 (1.1%) of patients with GGE compared with 0.02% of controls (an estimated odds ratio of 68). Of the 19 cases, 10 had JME, and of those 2 had a mild intellectual disability. Recurrent microdeletions at 15q11.2 and 16p13.11 have also repeatedly been shown in patients with JME, but at a lower frequency: together these three ‘hot spot’ CNVs are seen in an estimated 3% of patients with JME [74,75]. Surprisingly, despite resulting in the loss of a number of genes, these microdeletions clearly act to raise risk as part of complex genetic architecture, rather than acting as Mendelian mutations [66]. Unbiased genome-wide approaches

Technological advances in the late 2000s enabled a switch from individual gene studies to genome-wide approaches. Genome-wide association studies, when sufficiently powered, are far superior to the old candidate gene studies. A large (1527 patients) genome-wide association study of people with GGE (586 with JME) identified and replicated a significant association at 1q43 for JME (and 2p16.1, 17q21.32 for GGE). The nearest gene to the 1q43 locus was CHRM3, the muscarinic cholinergic receptor [76]. Whole exome sequencing, as opposed to sequencing individual genes, became practical in the last 5 years. One hundred and eighteen individuals (93 with JME) underwent exome sequencing and 3897 variants of interest were identified; these were subsequently genotyped in a large follow-up cohort [77]. Expert Rev. Neurother.



No variant reached a level of significance that could overcome correction for multiple comparisons, despite the study being powered (80%) to identify variants with a frequency of 0.5% and a relative risk of 5.4. There were a number of variants enriched in patients compared with controls: the strongest of these were in GREM1, OR10S1, PPEF2 and CHD1. Furthermore, 1289 variants identified in patients with GGE were absent in over 5400 control samples including a variant in PSME2, which was seen five-times in unrelated cases. They estimated that if the PSME2 mutation was causal, it would account for only 0.6% of the studied cases with JME. Of interest, 115 genes contained unique variation that was not seen among extensive control cohorts. Genetic heterogeneity in JME

JME is a complex disorder, as shown by clinical genetic and molecular genetic studies. Unlike Dravet syndrome, where a single gene (SCN1A) is causal in the majority of cases, most individuals with JME are likely to have multiple genetic determinants. The evidence above argues against there being an unnamed gene of large or moderate effect yet to be identified in a substantial proportion of JME cases. Heinzen et al. [77] may have identified unique variants in genes, which only occur in JME. The more likely scenario is that an unknown number, perhaps dozens or hundreds, could combine, in various ways, to create the JME phenotype. This would help explain the clinical heterogeneity and the varying presentation within the GGE spectrum. ‘Complex inheritance’ is sometimes used euphemistically, but in JME the pattern is certainly complex. It is possible to speculate about genomic imprinting, non-exomic regulation of genes and genes overlooked by massively parallel sequencing. Many of the variants that comprise the JME phenotype may be ‘tolerated’; present at a moderate or low frequency in the unaffected population. If there are truly hundreds of gene variants combining to a phenotype, then each JME case, aside from identical twins, would be almost as unique as a snowflake. Yet, paradoxically this potential myriad of variation produces a phenotype that is easily recognizable on electroclinical criteria. Personality & social/psychiatric comorbidities: are JME patients different from other epilepsies? (B Wandschneider)

There is a considerable heterogeneity in terms of social and psychiatric outcome. In their initial syndrome description, Janz and Christian [3] anecdotally reported immature and impulsive behavior in JME patients, contributing to poor seizure control and social adaption. Seizure control & psychosocial outcome

Camfield and Camfield [78] corroborated this anecdotal evidence by population-based and long-term follow-up studies. The authors interviewed 24 patients with ‘classic’ JME 25 years after seizure onset. Although 87% achieved high informahealthcare.com

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school graduation, at least one major unfavorable social outcome was noted in 74% patients, including unemployment (31% of patients), depression and social isolation. Notably, at least 80% of pregnancies occurred either unplanned or outside of a stable relationship. Despite these objective markers of social dysfunction, up to 77% of patients were ‘very satisfied’ regarding their personal and professional life. Interestingly, there was no relationship between seizure and social outcome, and 8 of the 17 patients with unfavorable social outcomes were seizure-free and no longer on antiepileptic treatment. Syvertsen and colleagues [79] reported favorable psychosocial outcome in one-third of 42 interviewed patients at 20 years follow-up, whereas 35% of patients had received treatment for psychiatric comorbidities, 17% had a history of substance abuse and 10% had a criminal record. Similar to the study by Camfield and Camfield [78], no correlation was found between unfavorable social outcome and long-term seizure control. However, other studies report a clear relationship between seizure control and social outcome. A recent study, using the QOLIE-31-P questionnaire (QoL In Epilepsy) and Beck Depression Inventory, reported at least one unfavorable psychosocial outcome in 87.9% of patients after a mean follow-up time of 38 years [80]; unplanned pregnancies occurred in 36.2%; living single in 27.3%; unemployment in 26.3%, which was higher than both the average unemployment rate nationally (6.6%) and in epilepsy patients (12.8%). Unlike in previous studies, poor seizure control correlated with social outcome measures. There was an improvement of social and occupational adjustment, as well as quality of life in those with early and long-term seizure freedom. To formally assess psychosocial outcome, Moschetta and Valente [81] employed the self-report social adjustment scale and evaluated impulsivity with the Temperament and Character Inventory in 42 JME patients with disease duration of 18 years compared with 42 healthy controls, who were matched to patients for age, gender, educational level and socioeconomic status. In addition, psychiatric disorders had been excluded in controls through assessment by an experienced psychiatrist. Patients showed worse adjustment scales than controls in overall social adjustment, work and family relationship. Social adjustment scale factors were not correlated with measures of executive functions, attention or memory functions on neuropsychological assessment. However, poorer social adjustment at work was correlated with higher frequencies of myoclonic jerks and GTCS. Though this JME cohort was not directly compared with an epilepsy control group, in a previous study in patients with temporal lobe epilepsy by the same authors [82], impairment of social adaption did not correlate with seizure control. Interestingly, higher novelty seeking scores as a measure of impulsivity correlated with poor social adjustment in several domains (global, work, social/leisure) in JME patients. Impulsive behavior and decision-making has also been described in two recent doi: 10.1586/14737175.2014.928203

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Table 1. Early studies of relapse rates in juvenile myoclonic epilepsy following antiepileptic drugs discontinuation in remission. Rate of relapse

Comments

Ref.

34 of 37 (91%)

Patients with 2-year remission of myoclonic and tonic-clonic seizures on medication (mostly valproate and primidone). No data on seizure provocation

[91]

4 of 16 (25%)

As above but only patients with myoclonic or absence seizures no tonic-clonic seizures

[91]

4 of 4 (100%)

Remission of 2.9 years and follow-up of 6.8 years. No data on seizure provocation

[119]

9 of 11 (90%)

One-year follow-up precipitation factors in 93% of patients

[120]

6 of 6 (100%)

Two year remission, No data on seizure provocation

[92]

Modified with permission from [94].

case–control studies [83,84], employing the Iowa Gambling Task. In both studies, dysfunction of experience-related learning leading to impulsive decision-making was more prominent in patients with poor seizure control. Since working memory function is involved in decision-making, one study [84] correlated functional activation patterns during a functional MRI working memory task with Iowa Gambling Task performance. Impulsive decision-making was associated with activation in the dorsolateral-prefrontal cortex, bilateral medial prefrontal cortex and SMA, regions previously identified as part of underlying disease mechanisms in JME. Hence, inter-ictal dysfunction within these networks may implicate impulse control leading to maladaptive social behavior, especially in patients with ongoing seizures. How much social outcome in JME actually differs from other epilepsy syndromes is difficult to substantiate since comparison studies are rare. One cross-sectional study [85] in children with recent-onset epilepsies of different sub-syndromes and healthy controls reported similar behavioral and competence complications in both focal epilepsy syndromes and GGEs (including JME).

criteria for personality disorders and reduction of N-acetylaspartate/creatinine and an increase in the glutamate-glutamine/creatinine ratio was found in the primary motor areas. Thalamo-fronto-cortical dysfunction has been previously described as potential underlying disease mechanism of JME. Hyperconnectivity of motor areas with prefrontal cognitive networks has been associated with both reflex traits, that is, seizure precipitation by cognitive tasks, such as reading, decision-making or planned movement and cognitive dysfunction in JME [25]. Guaranha and colleagues [41] identified an association of comorbid cluster B personality disorders, moderate-to-severe degrees of anxiety traits and prevalence of seizures triggered by praxis-induction or speech with poor seizure control. Hence, the imaging findings associated with these clinical markers may indicate a more severe form of thalamo-fronto-cortical dysfunction in JME. In summary, psychosocial comorbidities seen in the early phase of the disease seem to prevail into later stages of the disease. We hypothesize that the particular disease onset during a crucial phase in brain development and education may interfere with identity formation, education and socializing.

Psychiatric comorbidities in JME

Within the last decades, several studies have investigated psychiatric comorbidities in JME compared with the normal population and epilepsy control groups. Psychiatric disorders have been reported in up to 47% of patients, particularly mood, anxiety and cluster B personality disorders (for overview see [86]). Though psychiatric comorbidities may not be specific for JME and are similarly described in temporal lobe epilepsy [87], studies investigating their biological underpinnings point toward more syndrome-specific findings. De Arau´jo Filho and colleagues performed several imaging studies comparing JME patients with and without cluster B personality disorder, that is, histrionic, borderline and passive–aggressive personalities, and healthy controls [88–90]. The orbitofrontal cortex has been described as a key structure in decision-making and learning from previous experience by integrating emotions and higher cognitive functions such as working memory in healthy subjects. In a proton magnetic resonance spectroscopy study [88], the strongest association of positive diagnostic doi: 10.1586/14737175.2014.928203

Are seizures easy to treat but rarely remain in remission off AEDs in JME? (D Schmidt)

Early anecdotal observations in JME reported exceptional rates of complete seizure control on suitable AEDs for more than 2 years in 80–96% of patients [1,3,91,92]. Yet, a very high relapse rate off AEDs in the 90% range seemed to suggest that JME is a chronic epilepsy requiring life-long treatment (TABLE 1). A number of subsequent observations with a follow-up of 5 years or less, and anecdotal reports confirmed the initial findings [93]. A possible exception is patients with JME having only myoclonic seizures (without a history of GTCS) who seem to have a better chance of remission on AEDs and off AEDs [94]. For those, JME is not necessarily a life-long epilepsy. Taken together, our knowledge of the prognosis of JME on and off medication was largely based on anecdotal evidence for many years. Furthermore, a recent critical review suggested that the available literature on the effect of AEDs in new-onset JME was based on observations of a poor Expert Rev. Neurother.



evidence class [95]. Given this uncertainty, this chapter has three goals:

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Table 2. Long-term follow-up and outcome of juvenile myoclonic epilepsy sub-syndromes in 222 patients.

• to critically re-examine the evidence for Response to treatment Classic JME CAE/JME JME/Abs JME with the efficacy of AEDs to achieve seizure astatic seizures control in JME; (n = 161) (n = 35) (n = 18) (n = 8) • to reassess the notion that seizures in 93 (58%) 3 (7%) 10 (56%) 5 (63%) JME are easy to treat but tend to Remission on AEDs relapse off AEDs, based on more recent Remission off AEDs 4 (2.5%) – – – evidence from several long-term studies; In remission from all seizure types (remission). Remission off AEDs (>5 years without medication). • to re-appraise the traditional view that CAE: Childhood absence epilepsy; JME/aPA: JME with adolescent onset pyknoleptic absence. JME is necessarily requiring life-long Modified with permission from [104]. treatment with AEDs, even in those seizure-free on medication. Finally, current recommendations absence and 62% with JME plus astatic seizures. In eight to stop AEDs in seizure-free JME patients will be reassessed patients (9%) JME may not be lifelong. These eight patients have been seizure-free without medication for 1–11 years, in light of the new evidence. four of them from 5 to 11 years. It is not clear, however, in how many patients AED withdrawal had been attempted. Efficacy of AEDs to achieve seizure control in JME: the The study authors concluded that long-term follow-up indievidence A recent critical review concluded that there is an absence of cated that all JME sub-syndromes are chronic and, in the well-controlled trials of AEDs in patients with JME [95]. The words of the authors, perhaps lifelong [104]. choice of current drugs is based on clinical observation and anecdotal evidence. The best seizure control is probably achieved by VPA, but only a few studies have examined new AEDs, such as levetiracatam, lamotrigine, topiramate and zonisamide as alternative treatment options for JME [96–99]. Only one short randomized controlled trial examined monotherapy with VPA or topiramate in children with new-onset and chronic JME [100]. The low number of previously untreated patients prevents to draw meaningful conclusions from this study. Observational studies and anecdotal evidence suggest that some drugs used for treatment of partial seizures such as carbamazepine, gabapentin, oxcarbazepine, phenytoin, tiagbaine and vigabatrin may precipitate, or even aggravate myoclonic seizures, and in some cases GTCS [95]. Finally, there have been reports that lamotrigine may exacerbate seizures in JME [101,102]. Long-term observational evidence

Several long-term observational studies of JME patients with a follow-up of at least 20 years have been published since the year 2000. For this review, and in accordance with the literature, the term ‘remission’ is to imply an abeyance of epilepsy on AEDs and the term ‘cure’ is to imply its disappearance, that is, a chance of recurrence off AEDs no greater than for the general population [103]. Los Angeles series (2006)

A hospital-based observational study of 257 prospectively ascertained JME patients with mostly classic JME analyzed remission on and off AEDs (TABLE 2). The average follow-up was 11 years and as long as 52 years. The main finding was that only 7% of those with CAE evolving to JME were seizure free compared with 58% of those with classic JME (p < 0.001), 56% with JME plus adolescent pyknoleptic informahealthcare.com

Istanbul series (2008)

In a retrospective hospital-based study, the authors identified 48 patients with JME (29 female, aged 39.9 years (standard deviation [SD] ± 9.5 years) who were followed-up for a mean of 20 years [105]. The remission rate for 5 years followup and relapses were evaluated for all seizure types and the changes in severity/frequency of myoclonic seizures were systematically assessed in interviews. The study authors reported remission on AEDs in 67%, whereas 17% had pseudoresistance due to problems with treatment or lifestyle. In the remaining 17%, the truly drug-resistant course was significantly associated with psychiatric disorders and the presence of thyroid diseases. In 54% of the patients, myoclonic seizures had stopped for a mean duration of 8 years (SD ± 7.7 years). Of those 48 patients, 6 were on a lower dose of AED in comparison to the dosage needed to control the seizures in the beginning, and 5 patients had stopped AED treatment. None of these 11 patients relapsed during follow-up, except for one [105]. Halifax series (2009)

A cohort study ascertained cases with JME through hospital EEG records from a defined population base in Nova Scotia, Canada. All patients developing JME by age 16 years between 1977 and 1985 were identified [106]. The patients were contacted in 2006–2008. Twenty-four patients (17 female) had JME, and 23 of 24 were contacted (96%) at a mean age of 36 years (SD ± 4.8 years). All patients were initially treated with AEDs. At the end of a mean 25.8-year (SD ± 2.4 years) follow-up, 11 (48%) had discontinued treatment. Of those 11 patients, 6 were seizure-free for 5–23 years, 3 had myoclonic seizures only for >18 years and 2 continued with rare seizures. Convulsive status epilepticus occurred in eight (36%) doi: 10.1586/14737175.2014.928203

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and three had intractable epilepsy. All seizure types in JME resolved in 17%, and only myoclonus persisted in 13%. Therefore, the authors noted that in one-third of people with JME troublesome seizures vanish, and AED treatment is no longer needed.


Greifswald series (2012)

A retrospective hospital-based study reported long-term seizure outcome in 31 patients with JME after median follow-up of 39 years with a range from 25 to 63 years [107]. Patients were reevaluated with a review of their medical records and direct telephone or face-to-face interview. Twenty-one of 31 patients (67.7%) became seizure-free on AEDs; in only six of them (28.6%), AED treatment was discontinued. The presence or history of GTCS, preceded by bilateral myoclonic seizures (p = 0.03), a long duration of epilepsy with unsuccessful treatment (p = 0.022), and AED polytherapy (p = 0.023) were predictors for poor long-term seizure outcome. Complete remission of GTCS on AED significantly increased the chance for complete seizure freedom (p = 0.012). Photo-paroxysmal responses were significantly associated with the risk of seizure recurrence after AED discontinuation (p = 0.05). This study also showed that life-long AED treatment is not necessarily required to maintain seizure freedom, and emphasized that JME is a heterogeneous epilepsy syndrome. Recognition of outcome predictors may help to identify candidates for successful removal of all anti-seizure drugs [107]. Heidelberg/Berlin series (2013)

In the latest follow-up of this retrospective, hospital-based cohort study, seizure outcome was analyzed in 66 patients with JME initially diagnosed by the same physician [108]. The patients were seen by the senior authors originally in Heidelberg and later in Berlin (see earlier publications by Janz and Christian). The two most frequently used AEDs in mono- or polytherapy were primidone (48%) and VPA (52%). After a mean follow-up time of 45 years (20–69 years), 59% of 66 patients remained free of seizures for at least 5 years before the last follow-up. Twenty-eight of 39 seizure-free patients (71.8%) were still taking AEDs, and only 11 patients (28.2%) were off AEDs for at least the last 5 years of follow-up [108]. Absence seizures at onset of JME were an independent predictor for persisting seizures, confirming an earlier report by Martıńez-Jua´rez and colleagues [104]. A reappraisal of seizure treatment outcome on & off AEDs in JME

Based on recent large cohorts and a population-based study with long-term follow-up of 20 years, the two major findings of this review on remission on and off AEDs in JME are: • Remission on AEDs occurs in only two-thirds of patients with new-onset JME [104–108], in contrast to earlier reports on remission rates on AEDs of 90% and above, which were based of small hospital-based observations with a shorter

doi: 10.1586/14737175.2014.928203

follow-up with substantial methodological problems [1,3]. This is within the range of longitudinal cohort studies of prognosis in epilepsy, which have shown that epilepsy has an often good prognosis with 65–85% of cases eventually entering long-term remission, and an even higher proportion of cases entering a short-term remission [109]; • Up to 30% of patients are in long-term remission off AEDs. The study by Senf et al. [108], for example, reported remission off AEDs in 28% of patients. However, 72% of patients in remission had not stopped their medication in that study. Of 21 patients seizure-free on AEDs in the Greifswald series, only 6 (29%) discontinued AED treatment [107]. The high number of patients in remission remaining on medication introduces a substantial ascertainment bias to detect the maximum rate of remission without medication. This is a major methodological concern, which limits the ability to determine the true cure rate of JME. Assessing the true extent of remission off AEDs in JME requires randomized withdrawal studies in remission. In that respect, it is of interest to note that the only large AED withdrawal study in epilepsy found a higher relapse rate for patients with myoclonic seizures [110]. By 2 years after randomization, seizure-freedom was observed in 78% of patients in whom treatment was continued, compared with 59% of those in whom it had been withdrawn, but thereafter the differences between the two groups diminished. The most important factors determining outcome were longer seizure-free periods (reducing the risk), and more than one AED and a history of GTCS (increasing the risk) [110]. A history of myoclonic seizures increased the risk of recurrence in the first 2 years following withdrawal versus no withdrawal by 1.85 (95% CI: 1.09–3.12). By 10 years off AEDs, the annual risk for seizures probably is very low and not different from that of patients on medication [111]. Few data are available on seizure recurrence risk after being seizure-free and off medication for extended periods of time. The long-term study by Sillanpaä¨ and Schmidt [109] reported seizure relapse after AED discontinuation in 33 of 90 patients (37%) at an average follow-up of 32 years. Only one patient had JME. The results suggest that the relapse rate reported in some of the long-term studies of JME is broadly similar to results seen with other epilepsies. This remains to be confirmed in randomized studies of AED withdrawal in remission comparing patients with JME versus those with other genetic generalized epilepsies, such as CAE. Expert commentary

JME is a complex disorder, as shown by clinical genetic and molecular genetic studies. Most individuals with JME are likely to have multiple genetic determinants. The evidence reviewed above argues against the existence of a yet unidentified gene of large or moderate effect in a substantial proportion of JME cases. Heinzen et al. [77] may have identified unique variants in genes, which only occur in JME. The more likely scenario is that an unknown number, perhaps dozens or hundreds of

Expert Rev. Neurother.



genes, could combine, in various ways, to create the JME phenotype. This would help explain the clinical heterogeneity and the varying presentation within the GGE spectrum. Imaging studies have shown dynamic changes in the gross morphology and functional organization of normally developing adolescent brain structures maturing at strikingly different rates and times. An age-related, predominantly frontocorticalsubcortical network dysfunction is likely to be the substrate of both, the specific type of bilateral myoclonic seizures with its particular, cognitive triggers and the cognitive, psychosocial profile suggestive of frontal lobe dysfunction. Existing imaging studies are limited by sample size and methodological constraints. Future studies need to tackle issues of a priori sample size and the statistical power of neuroimaging methods, as well as pursue underlying mechanisms for phenotypic variation in this heterogenous disorder. Genetic status, drug responsiveness, seizure severity and frequency and predominant seizure types are all factors that can and need to be correlated in larger studies to address the biological variability, underlying genetic heterogeneity and signal-to-noise ratio of imaging measures to better understand disease pathophysiology [112]. Early studies, measuring the effects of certain genes on cortical development in both new-onset and drug-naı¨ve JME patients will help to disentangle the effects of genes, drugs and seizures in this population. Longitudinal studies in both, relapsing and remitting patients will help to explain, why seizures and behavioral changes persist over time, most likely caused by maturation defects, which are not corrected by currently available AEDs. Inhibition of histone deacetylases, which are involved in modulation of gene expression, by VPA and resultant increases in gene expression could explain why this drug works particularly well by acting on cell growth, differentiation and apoptosis through epigenetic mechanisms, if given at a critical time for a prolonged time [113]. Regarding treatment of JME, and when to end it in those in remission, clinicians will have to individualize the risk and benefit of stopping AEDs in a seizure-free patient with JME. The results of this review suggest that a subgroup of patients with long-term remission on AEDs lasting 10 years or more may be suitable candidates to consider AED discontinuation. The better seizure prognosis off AEDs than previously thought, may offer AED discontinuation for patients in remission in those showing features predictive of good outcome off AEDs. This recommendation is in line with a recent consensus report, recommending AED withdrawal in JME in certain clinical conditions, such as longterm seizure freedom [114,115]. However, patients with JME with shorter periods of remission may have a high risk of relapse. This is in broad accordance with a recent report of the ILAE Task Force to define epilepsy as being no longer present for individuals who had an age-dependent epilepsy syndrome, but are now past the applicable age, or those


Review

who have remained seizure-free for at least 10 years off antiseizure medicines, provided that there are no known risk factors associated with a high probability (‡60%) of future seizures. Examples given for high-risk conditions included JME and cortical dysplasia [103]. This assessment reflects the earlier, more pessimistic reports of relapse rates close to 90–100% when AEDs are withdrawn in patients in remission [1]. From a research perspective, the difficulties to remain in remission following AED withdrawal reflects the failure of current AEDs to exert disease-modifying effects [116,117]. To address this unmet need of current drug treatment, we need to develop anti-epileptogenic treatments for epilepsy [117]. Finally, the reason for the high relapse rate following AED withdrawal in remission for JME will not be fully understood, unless and until we understand the aberrant development of functional and structural of neuronal connections and brain networks during brain maturation in ictogenesis and epileptogenesis in JME [118]. Five-year view

Once we have robust seizure outcome data from randomized trials of AEDs and AED withdrawal in remission for patients with JME, we can reliably determine in whom we can safely withdraw AEDs. Technological advances will allow more genome-wide approaches to explore the genetic heterogeneity of JME. Genome-wide association studies, when sufficiently powered, are far superior to the old candidate gene studies. If resistance to AEDs can be explained by impaired mechanism of brain maturation, and hyperconnected motor-circuits can be detected reliably as a specific heritable trait [25,27], we could expect that it will be possible to influence and reverse aberrant synaptogenesis, pruning and apoptosis as a therapeutic strategy, and influencing early the modeling of hyperexcitable circuits as a preventative strategy for JME. Financial & competing interests disclosure

MJ Koepp served on scientific advisory boards and has received honoraria for lectures from of GE Healthcare, UCB Pharma, Novartis, Eisai and Desitin. SF Berkovic served on scientific advisory boards and has received honoraria for lectures from UCB Pharma, Novartis and Eisai. B Wandschneider and RH Thomas report no financial disclosures. D Schmidt served on scientific advisory boards and has received honoraria for lectures from Abbott, Eisai, Novartis, UCB Pharma, Sun Pharma and Viropharm. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.

doi: 10.1586/14737175.2014.928203

Review


Key issues • Juvenile myoclonic epilepsy (JME) is a clinically heterogenous generalized epilepsy syndrome. Even experts cannot agree on a single syndrome definition of this syndrome. • JME is a genetically heterogenous generalized epilepsy syndrome. Unbiased whole genome studies will be better suited than single candidate gene studies to explore the genetic basis of JME. • JME patients present with aberrant functional and structural connectivity in networks that normally mature before and during adolescence. Early studies with longitudinal follow-up in newly diagnosed, drug-naı¨ve JME patients, and in those at a genetic risk of Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by National University of Singapore on 06/15/14 For personal use only.

developing JME, will help to disentangle the effects of genetic effects, delayed or altered brain maturation, drugs and seizures. • Many patients with JME face psychosocial issues even though they have normal intelligence, and present in later life with behavioral and psychosocial characteristics, usually seen only during adolescence. • Perhaps the most baffling conundrum of JME in older hospital-based observations is that unlike patients with other epilepsies, JME patients enter seizure remission early on antiepileptic drugs (AEDs), but fail to remain seizure-free following discontinuation of AEDs in remission. The speculative explanation for this is that the underlying mechanism of JME differs from that of other epilepsies. However, newer population-based studies have shown a much better prognosis to remain seizure-free off AEDs. This more positive outcome in JME needs to be confirmed in randomized controlled trials of AED withdrawal in JME patients in remission.

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