2014 Round-up

Epilepsy: redefining the boundaries

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An important advance in the specialty of epilepsy in 2014 was the introduction of new diagnostic criteria to establish the beginning and end of epilepsy. Of equal importance was the discovery of abnormal brain network properties in unaffected first-degree relatives of patients with epilepsy, which has virtually eliminated the long-held idiopathic category of generalised epilepsy. Fisher and colleagues1 recently changed the criteria for the definition of epilepsy by including people with a single seizure and a 60% chance of having more seizures over the next 10 years. The 60% boundary was chosen because it is similar to the risk of further seizures when someone has a history of two unprovoked seizures, as in the classic definition of epilepsy, which is still valid and in common use.1 The Achilles’ heel of the new definition is that it does not offer evidence-based criteria for how to anticipate a 60% risk after one seizure. However, many neurologists would suspect a risk of 60% after a single seizure in a person who has a neurological deficit, a congruent lesion on MRI, or familial epilepsy in firstdegree relatives. The new single-seizure definition of epilepsy is welcome: it might lead to earlier diagnosis and treatment and thus protect patients from further seizures. It might also lead to a better understanding of why some people stop having further seizures. We need to learn how to better establish and forecast seizure recurrence in patients presenting with a first seizure. The ultimate goal of epilepsy treatment is the complete remission of seizures without any treatment.

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But how can the achievement of this goal be clinically defined? In research terms, this goal is achieved when a person who no longer takes anti-epileptic drugs has a risk of seizure recurrence that is similar to that of the general population. To clarify the criteria for the end of epilepsy, Fisher and colleagues1 stated that “epilepsy is considered to be resolved for individuals who either had an age-dependent epilepsy syndrome but are now past the applicable age or who have remained seizure-free for the last 10 years and off anti-seizure medicines for at least the last 5 years”. Again, this new definition is welcome because it tries to clarify how the brain ends epilepsy and how often this happens after stopping medication during seizure remission. Fisher and colleagues are to be commended for trying to tackle this important and difficult clinical problem. However, their definition has been criticised as being arbitrary, and evidence that epilepsy has stopped might be better defined as when the risk of seizure is similar to that of the general population (ie, yearly risk of 1%).2 Factoring in variables such as age, seizure type, and persistence or resolution of electroencephalography abnormalities would allow for individualised determination of the time at which an annual relapse rate of 1% or less is reached.2 In a study with a median follow up of 17 years by Anne Berg and colleagues,3 the relapse rate for the first 5 years of follow up was 10·7 in 1000 person-years; for the subsequent 5 year follow-up period, the relapse rate was 6·7 in 1000 person-years. These findings are broadly in line with data from our earlier study4 with respect to remission and seizure recurrence rates. Irrespective of the definition, virtually any study of epilepsy resolution is biased: even when medical indications for drug discontinuation exist, other reasons for continuation might remain, including a patient’s or the physician’s anxiety about a relapse upon anti-epileptic drug withdrawal or concerns about the patient’s job or driving licence. Idiopathic generalised epilepsy (IGE) has long been held to have a genetic basis; the mechanism of seizure expression is not fully known, but it is assumed to involve large-scale brain networks. One elegant way to show that IGE has a genetic cause is to detect familial endophenotypes in patients and their unaffected first– degree relatives. Endophenotypes are characterised by www.thelancet.com/neurology Vol 14 January 2015

2014 Round-up

measurable biomarkers that correlate with an illness, at least in part because of shared underlying genetic factors. One study5 detected abnormal brain network properties in the 6–9 Hz band of scalp electroencephalography in patients with IGE and in their unaffected first–degree relatives. The authors propose that abnormal brain network topology might be an endophenotype of IGE, although not sufficient to cause epilepsy.5 Juvenile myoclonic epilepsy is a heritable IGE syndrome with myoclonic jerks that can be provoked by cognitive activity, and functional MRI showed that increases in cognitive load in patients and unaffected siblings caused abnormal activation of primary motor cortex and the supplementary motor area.6 This study provides evidence for familial endophenotypes in patients with IGE and unaffected relatives and suggests that their epilepsy should no longer be classified as idiopathic. 7 What are the implications of the changing criteria and categories of epilepsy? As with all good research, they reveal new horizons and prompt new questions. The

next steps will be to define better when epilepsy begins and when it ends, at least for most patients. Dieter Schmidt Epilepsy Research Group, Berlin D-14163, Germany [email protected] I declare no competing interests. 1 2 3

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Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014; 55: 475–82. Hauser A. Commentary: ILAE Definition of Epilepsy. Epilepsia. 2014; 55: 488–90. Berg AT, Rychlik K, Levy SR, Testa FM. Complete remission of childhoodonset epilepsy: stability and prediction over two decades. Brain 2014; published online Oct 22. DOI:10.1093/brain/awu294. Sillanpää M, Schmidt D. Prognosis of seizure recurrence after stopping antiepileptic drugs in seizure-free patients: a long-term population-based study of childhood-onset epilepsy. Epilepsy Behav 2006; 8: 713–19. Chowdhury FA, Woldman W, FitzGerald TH, et al. Revealing a brain network endophenotype in families with idiopathic generalized epilepsy. PLoS One 2014; 9: e110136. Wandschneider B, Centeno M, Vollmar C, et al. Motor co-activation in siblings of patients with juvenile myoclonic epilepsy: an imaging endophenotype? Brain 2014; 137: 2469–79. Berkovic SF, Jackson GD. ‘Idiopathic’ no more! Abnormal interaction of large-scale brain networks in generalized epilepsy. Brain 2014; 137: 2400–02.

Movement disorders: discoveries in pathophysiology and therapy Movement disorders are common and are frequently treated by neurologists. Clinical phenotype and pathophysiology are heterogenous. In 2014, research in the specialty of movement disorders advanced our understanding of pathogenesis, translational aspects, and therapy. Our understanding of disease mechanisms of rare movement disorders such as hereditary spastic paraplegia, with its hallmark feature of lower limb spasticity caused mainly by axonal degeneration in the cortical tract, has been hampered by low disease prevalence and genotypic and phenotypic heterogeneity. Whole-exome sequencing analysis identified mutations in no less than 18 new putative genes, and consecutive network analysis showed that many of these genes converge in key biological processes, including axon and synapse development, cellular transport, and nucleotide metabolism.1 Moreover, a significant association of these genes with other neurodegenerative movement disorders was also identified. www.thelancet.com/neurology Vol 14 January 2015

Another exciting pathophysiological similarity between movement disorders was discovered for the spreading of pathology. Parkinson’s disease was the first neurodegenerative movement disorder for which a prion-like spreading of pathology was shown to affect allografted ventral mesencephalic tissue. Several in-vitro and in-vivo models have subsequently shown that neurons release and uptake α-synuclein. Research in 2014 showed that aggregation of α-synuclein in neurons might be triggered by exogenously preformed α-synuclein fibrils or Lewy body extracts.2,3 This prionlike protein spread has now for the first time been shown for mutant huntingtin in genetically normal and unrelated allografted neural tissue transplanted into the brain of patients with Huntington’s disease. Astonishingly, the mechanisms of spreading in Huntington’s disease, which is a monogenetic disease, are similar to those of Parkinson’s disease, and this indicates that non–cell-autonomous mechanisms can drive monogenetic neurodegenerative disorders. This study could have implications for future clinical 9

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