Seizure Editor’s Choice article 🇬🇧

Seizure 2024, Vol 121, Editor’s Choice:  Two-year mortality and seizure recurrence following status epilepticus in Auckland, New Zealand: A prospective cohort study .

Markus Reuber MD PhD, Academic Neurology Unit, University of
Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF

There are reasonable grounds for asking whether “epilepsy” exists as a
meaningful disease entity. The logical conclusion of the stress the current ILAE
classification of epilepsy places on aetiology suggests that it would be more
appropriate to talk of “the epilepsies”, or to abandon the concept of “epilepsy”
altogether and to think of diseases / clinical scenarios associated with epileptic
seizures instead. The same considerations apply to status epilepticus (SE). Of
course, the scenario in which an epileptic seizure fails to self-terminate is a clinical
reality – in fact it continues to be one of the commonest serious neurological
emergencies (1). However, it is not a neat clinical entity in terms of its causes,
treatment or outcomes. This fact is reflected in the current definition and
classification of the ILAE which recognises different manifestations of status
epilepticus: Instead of a single temporal cut off defining all types of SE, this
scenario is now defined by a time point one at which the failure of the mechanisms
responsible for seizure termination has become clear (t1) and a time point two (t2)
at which long-term consequences may be expected (e.g. neuronal death, neuronal
injury or neuronal network alteration). This means that t1 and t2 are twice as long
for focal SE with impaired awareness as for bilateral tonic SE (2).
While beginning to distinguish between subtypes of SE, the current
classification is still rather crude. Most importantly it fails to take account of the
aetiology of SE: for instance, t1 and t2 may well be quite different depending on
whether SE occurs in a patient with a non-progressive structural brain abnormality
or a patients with a mitochondrial disorder.
My editor’s choice from the current volume of Seizure is a prospective
cohort study of 367 consecutive patients diagnosed with SE in the Auckland region
of New Zealand (3). This study contributes to our understanding of SE by
demonstrating the great variability of the two-year outcome of SE presentations.
Patients across the whole (paediatric to adult) age range were included. Outcomes
varied from symptom-free with no further seizures to death. Two-year all-cause
mortality over the follow-up period was 14.9%. Univariate analyses revealed that
SE presentations in children, patients of Asian ethnicity, with an SE duration
<30mins and acute (febrile) aetiology were associated with lower mortality. Age
>60 and progressive causes were associated with higher mortality in uni- and
multivariate analyses. The risk of seizure recurrence was lower in those presenting
< 2 years of age and with an acute aetiology, it was higher in those with non-
convulsive status epilepticus (NCSE) with coma and a history of epilepsy.
Multivariate analyses revealed a history of epilepsy, as well as having both acute
and remote causes to be associated with a greater risk of seizure recurrence.

The classification of the epilepsies and of SE continues to be a work in
progress. It is safe to say that improvements in the rapid determination of the
aetiology of SE with consequences for acute treatment and outcome are likely to
prompt further refinement of our thinking about SE in the future.
References

Zhang T, Ajamain AWH, Donnelly J, Brockington A, Jayabal J, Scott S,
Brennan M, Litchfield R, Beilharz E, Dalziel SR, Jones P, Yates K,
Thornton V, Bergin PS. Two-year mortality and seizure recurrence
following status epilepticus in Auckland, New Zealand: A prospective
cohort study. Seizure 2024;121:17-22.

Jackson M, Szczepaniak M, Wall J, Maskery M, Mummery C, Morrish P,
Williams A, Knight J, Emsley HCA. Numbers and types of neurological
emergencies in England and the influence of socioeconomic deprivation: a
retrospective analysis of hospital episode statistics data. BMJ Open
2022;12:e061843.

Trinka E, Cock H, Hesdorffer D, Rossetti AO, Scheffer IE, Shinnar S,
Shorvon S, Lowenstein DH. A definition and classification of status
epilepticus–Report of the ILAE Task Force on Classification of Status
Epilepticus. Epilepsia 2015;56:1515-23.

Editor’s choice vol. 120: Trends of mortality from epilepsy in the United states, 1979-2021.

Markus Reuber, academic neurology unit, university of sheffield, royal hallamshire hospital, glossop road, sheffield, s10 2jf

We like to think of the history or medicine as one of steady progress in which public health
measures (like the provision of clean drinking water) as well as medical discoveries (such as
the use of vaccinations or antibiotics in the prevention or treatment of infections) increase
population health and life expectancy. However, following many decades of steady
improvements life expectancy in several high-income countries has actually been falling in
recent years (1-2). For instance, in the USA life expectancy was 47 years in 1900 and 68
years in 1950. By 2019 it had risen to 79 years (3). Life expectancy then declined to 77 in
2020 and dropped further to 76 in 2021. The drops in US life-expectancy were greatest in
Native Indian, Black and Hispanic American populations. While the identification of specific
causes of these observations is difficult, two thirds of the recent decline in life expectancy in
the USA have been put down to COVID, drug overdoses and accidental injuries (4).

My editor’s choice paper from the current volume of seizure examines long term US
mortality trends when epilepsy was recorded as the underlying cause of death, for instance
because deaths were attributed to Sudden Unexpected Death in Epilepsy (SUDEP) status
epilepticus, accidents during seizures, surgical complications, and potential comorbidities (5).
deaths will only be a subset of all of those who died with a diagnosis of epilepsy but of
causes not directly associated with their seizure disorder. Based on cause-of-death and
demographic data was from the National Center for Health Statistics, the authors used a
joinpoint regression model to describe changes in US mortality trends from 1979 to 2021.
Age-adjusted mortality in all ethnic groups initially fell during the study period. However,
since 2006 the number of those dying with a diagnosis of epilepsy has been on the rise.

The sustained increase in mortality attributed to epilepsy is clearly of concern. While it may
in part be explained by an increased awareness of epilepsy and causes of epilepsy-related
causes of deaths (especially SUDEP), and while the American Population is getting older, the
fact that mortality discrepancies between white and non-white Americans are increasing also
hints at the effects of inequitable access to health and social care – or an uneven distribution
of other risk factors for epilepsy-related deaths. Most worrying of all is the fact that the
increase in the epilepsy-related mortality is accelerating and that the differences between
white and other populations are increasing further. Further work will need to untangle what
contributes to these trends and what can be done to reverse them.

Editor’s choice vol. 119: A meta-analytic evaluation of the effectiveness and durability of psychotherapy for adults presenting with functional dissociative seizures.

Markus Reuber MD PhD, Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF

The last three decades have witnessed a steadily accelerating interest in what the
International League Against Epilepsy (ILAE) may soon call functional / dissociative
seizures (FDS, the forward slash in this label suggests that the terms ‘functional’ or
’dissociative’ may also be used on their own). It is likely that this interest was initially
sparked by the fact that better access to video-EEG (and learning from video-EEG
studies) had increased the confidence of clinicians to distinguish FDS disorders more
clearly from epilepsy 1 . As patient cohorts grew, studies described predisposing,
precipitating and perpetuating psychological, social and biographical factors
characterised the aetiology of FDS with increasing confidence and granularity 2 .
Although this research demonstrated that there was aetiological heterogeneity 3 , FDS
have come to be understood as an involuntary response akin to a conditioned reflex 4 ,
typically manifesting in the context of abnormal emotion processing 5 . This
understanding of FDS provides a clear rationale for psychological therapies, and an
impressive number of psychological treatment studies have now been published.
However, while most experts consider them as the treatment of choice, many patients
with FDS (even in high income countries) still cannot access such interventions 6 . One
important reason for the lack of access is that healthcare commissioners still need to be
persuaded that such therapies are effective.
My editor’s choice from the current volume of Seizure, a systematic review and meta-
analysis of seizure frequency and severity outcomes of psychological treatments for FDS
by Chris Gaskell et al. may help with this. Following on from previous work by the same
group demonstrating improvements in non-seizure outcomes associated with
psychological interventions for FDS 7 , the current meta-analysis of 44 studies involving
1,300 patients arrived at a pooled estimate for seizure freedom at the end of treatment
of 40 % and a pooled rate for ≥50 % improvement in seizure frequency of 66 %.
Improvements were not lost during follow-up. At group level, the pooled seizure
frequency improvement achieved a moderate effect size (d = 0.53). FDS frequency
reduced by a median of 6.5 seizures per month.
This systematic review and meta-analysis also identified weaknesses of the research
examining the effectiveness of psychological treatments in patients with FDS. Over three
quarters of studies were deemed to be at high or medium risk of bias (mainly due to

small study size and the inclusion of unblinded observational studies). This means that
there is more work to do. However, the most impressive study contributing to the
findings by Gaskell et al (the CODES trial involving the randomisation of 368 patients) 8
had a low risk of bias.
Combined with the fact that patients in the psychological intervention group in this trial
did significantly better than patients only receiving standardised medical care in 9 of 17
outcomes (and worse in none), the paper by Gaskell et al. will hopefully ensure that
more patients with FDS come another step closer to gaining access to treatments which
can help them.

References

1 Reuber, M. & Elger, C. E. Psychogenic nonepileptic seizures: review and update.
Epilepsy and Behavior 2003; 4: 205-216.
2 Brown, R. J. & Reuber, M. Psychological and psychiatric aspects of psychogenic non-
epileptic seizures (PNES): A systematic review. Clin Psychol Rev 2016;45: 157-182.
3 Hingray, C. et al. Heterogeneity of patients with functional/dissociative seizures:
Three multidimensional profiles. Epilepsia 2022; 63: 1500-1515.
4 Brown, R. J. & Reuber, M. Towards an integrative theory of psychogenic non-
epileptic seizures (PNES). Clin Psychol Rev 2016; 47, 55-70.
5 Williams, I. A., Levita, L. & Reuber, M. Emotion dysregulation in patients with
psychogenic nonepileptic seizures: A systematic review based on the extended
process model. Epilepsy Behav 2018; 86, 37-48.
6 Hingray, C. et al. Access to diagnostic and therapeutic facilities for psychogenic
nonepileptic seizures: An international survey by the ILAE PNES Task Force. Epilepsia
2018; 59, 203-214.
7 Gaskell, C. et al. A meta-analytic review of the effectiveness of psychological
treatment of functional/dissociative seizures on non-seizure outcomes in adults.
Epilepsia 2023; 64 , 1722-1738.
8 Goldstein, L. H. et al. Cognitive behavioural therapy for adults with dissociative
seizures (CODES): a pragmatic, multicentre, randomised controlled trial. Lancet
Psychiatry 2020 7, 491-505.

Editor’s choice vol. 118: barriers and facilitators to healthcare practitioners providing care for pregnant women with epilepsy: a systematic review and narrative synthesis.

Markus Reuber MD PhD, Academic Neurology Unit, University of Sheffield,
Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF

Medical students who visit my outpatient clinic are often amazed (or perhaps better:
stunned) when they realise how much their understanding of what epilepsy is differs
from the real-life challenges patients with this condition face. While talk about seizures
or antiseizure medications certainly features in most encounters, other issues are often
much more pressing. Patients may not have had a seizure for nine months but still be
unable to find work because they are not allowed to drive. Others are worried about
going out on their own in case they have a seizure in public. Patients may seek help with
symptoms of depression because their family doctor was concerned about
antidepressants lowering the seizure threshold. Women may want advice on
contraceptive methods which do not interact with their epilepsy or antiseizure
medication.
Apart from realising that seizures, while only taking up a tiny proportion of a person’s
lifetime, have profound effects on many other aspects of life, the students learn that
epilepsy does not only affect patients themselves but also their families and social
circles.
One scenario in which both these features of epilepsy – that it is about more than the
core symptoms of the condition itself and that it also affects people close to the person
with epilepsy – are particularly relevant is pregnancy. Pregnancy may be a “natural”
phenomenon in the life cycle of mammals but, for good reasons, it has become heavily
medicalised. In developed countries pregnant women have to navigate a system of
medical and maternity care which can become quite complex when they have a medical
condition. While pregnancy may be complicated by epilepsy (1), it has also been
identified a “golden opportunity” for women with the condition to have their diagnosis
and treatment reviewed and optimised (2). However, for this process to work, women
have to know how to access advice, clinicians have to be aware of the evidence they
should impart, and service providers in different specialities or organisations have to
communicate and collaborate with each other.
My editor’s choice from the current volume of Seizure, a systematic review by Anna
Hughes et al. provides insights about how pregnancy care can be optimised (3). Of the
five themes, only one is a facilitator: Several of the 16 original publications which
contributed to the review identified high levels of practitioner motivation to improve
services. Four themes identified hurdles: While knowledge about the management of
epilepsy in pregnancy is generally quite good, practitioners may struggle to apply this
knowledge in individual circumstances. Communication of knowledge can be difficult,
especially when patients have intellectual difficulties. The necessities of sharing the care

between epilepsy and obstetric specialists create challenges of interaction. And – last but
not least – clinicians have little time, and resources (including guidelines) may be lacking.
Alternatively different sets of guidelines may conflict with each other.
Readers motivated to tackle the challenges and make the best of the “golden opportunity”
to improve pregnancy outcomes but also the epilepsy management of women beyond
pregnancy are referred to a multispeciality paper previously published in Seizure which
makes specific suggestions for patients with epilepsy, obstetricians and midwifes,
neurologists and specialist epilepsy nurses, pharmacists, emergency department physicians,
primary care providers and epilepsy service commissioners (2).

References
(1) Shahla M, Aytan M. Clinical characteristics, seizure control, and delivery outcomes in
pregnant women with focal and generalized epilepsies. Seizure 2024;117:67-74
(2) Leach JP, Smith PE, Craig J, Bagary M, Cavanagh D, Duncan S, Kelso ARC, Marson AG,
McCorry D, Nashef L, Nelson-Piercy C, Northridge R, Sieradzan K, Thangaratinam S,
Walker M, Winterbottom J, Reuber M. Epilepsy and Pregnancy: For healthy
pregnancies and happy outcomes. Suggestions for service improvements from the
Multispecialty UK Epilepsy Mortality Group. Seizure 2017;50:67-72.
(3) Hughes A, Weckesser A, Danny E, Junaid F, Nelson-Piercy C, Black M, Allotey J,
Thangaratinam S, Dyson J. Barriers and facilitators to healthcare practitioners
providing care for pregnant women with epilepsy: A systematic review and narrative
synthesis. Seizure 2024;118:38-46.

Editor’s Choice Vol. 117: Comparison of Neurodevelopmental, Educational and Adulthood Socioeconomic Outcomes in Offspring of Women with and without Epilepsy: A Systematic Review and Meta-analysis.

Markus Reuber MD PhD, Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF

Charles Darwin’s principal work “The Origin of Species” (1859) is one of the key milestones
along the route towards our discovery of human development and the relationship between
humans and other living organisms. This book was undoubtedly a great scientific step
forward, but it also gave rise to some deeply problematic ideas: one, the pseudoscience of
“eugenics”, i.e. the cleansing of humanity through the suppression of procreation of
individuals thought to have inherited diseases and other unwanted traits, was first proposed
by Darwin’s half-cousin Sir Francis Galton in his book “Hereditary Genius” in 1869. Epilepsy
was among the diseases targeted by the eugenicists who turned Galton’s ideas into laws
intended to stop people with epilepsy from passing on their “bad genes”. The forced
sterilisation and euthanasia programme instituted in Germany in the 1940s represented the
zenith of eugenic policies in action, but the last legal remnants of these ideas were only
removed quite recently: for instance, in 1956 seventeen US states still prohibited people
with epilepsy from marrying, the last US state only abolished this legal restriction in 1980. In
the UK a law forbidding people with epilepsy to get married was only repealed in 1970 [1].
While the fact that eugenic regulations have been removed from statute books over the last
decades may provide reassurance that the erroneous ideas which underpinned them are on
the wane, they are still likely to contribute to the stigma associated with epilepsy and could
easily be rekindled by reference to ever growing number of genetic risk factors for epilepsy
[2].
In this context my editor’s choice from the current volume of Seizure, a meta-analysis by
Paolo Pierrino Mazzone et al. provides its readers with urgently needed high quality
information about the actual size of the risk of epilepsy and other neuropsychiatric or
developmental disorders conferred by a maternal epilepsy diagnosis – with or without the
additional factor of antiseizure medication. Not unexpectedly, a maternal diagnosis of
epilepsy increases the odds of a child being diagnosed with autistic spectrum disorder (ASD,
odds ratio 1.67), attention-deficit/hyperactivity disorder (ADHD, odds ratio 1.59) or special
educational needs (odds ratio 2.6). The relative risks continue to be elevated in women with
epilepsy who did not take antiseizure medications in pregnancy. However, the absolute risks
of these pregnancy outcomes are low: A diagnosis of ASD was only made in 1.4%, one of
ADHD in 4.9%, childhood epilepsy in 2.6% and intellectual disability in 0.9% of all children.
These figures are based on unselected cohorts of mothers with a broad range of epilepsies,
and the risk of having a baby with one of the listed outcomes is likely to be much higher or
lower in particular circumstances, however, at a population level the size of these risks
clearly demonstrates the fallacy of the eugenic policies of the past.References
(1) Anonymous. The history and stigma of epilepsy. Epilepsia 2003;44(Suppl. 6):12–14, 2.
(2) Zhang MW, Liang XY, Wang J, Gao LD, Liao HJ, He YH, Yi YH, He N, Liao WP; China
Epilepsy Gene 1.0 Project. Epilepsy-associated genes: an update. Seizure 2023 Sep
23:S1059-1311(23)00254-6.
(3) Mazzone PP, Hogg KH, Weir CJ, Stephen J, Bhattacharya S, Richer S, Chin RFM.
Comparison of neurodevelopmental, educational and adulthood socioeconomic
outcomes in offspring of women with and without epilepsy: A systematic review and
meta-analysis. Seizure 2024;117:213-221

Editor’s Choice Vol. 116: Epilepsy-Associated Genes: An Update. 

Markus Reuber MD PhD, Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF

Impressive scientific progress has been made in many fields of medicine, but it would be
easy to argue that the most amazing growth in understanding over the last century has been
in genetics. It is easy to forget that the discovery that genes are made of DNA was only
made in 1952 and the molecular structure of DNA described one year later. Since then,
there has been a dramatic acceleration of the growth of knowledge in this field: While it
took a few years to establish that Down Syndrome is caused by the presence of an extra
copy of chromosome 21 (1959) the growth rate of scientific developments in clinical
genetics has been on an exponential trajectory since the discovery of DNA sequencing in
1975, its increasing availability and reducing cost [1, 2].
The pace of innovation in clinical genetics in general is reflected in the field of epilepsy: By
2017 the team which produced my editor’s choice from the current volume of Seizure were
able to compile a list of 977 genes associated with epilepsy [3]. However, many genetic
discoveries made since then called for an update of this list. The new list by Wang et al. (my
editor’s choice from this Special Issue of Seizure on the Genetics of Epilepsy) is an
impressive piece of work: The updated search identified nearly 3,000 genes potentially
associated with epilepsy. About one half of these genes (1,506) were found in the Online
Mendelian Inheritance in Man (OMIM) database. These included 168 epilepsy genes (86 of
which newly added), 364 genes linked to neurodevelopment-associated epilepsy (including
291 new ones) and 974 epilepsy-related genes (438 more than that in the first version).
Cross-checks with the Human Gene Mutation Database (HGMD) and PubMed allowed the
authors to add a further 1,440 genes to their new list [4].
The identification and categorisation of genes was based on a rigorous procedure involving
an initial search of epilepsy-associated genes in the OMIM database followed by the
exclusion of items for which there was no definite molecular genetic confirmation or for
which information about clear links between specific genes and epilepsy in humans was
lacking. After the additional HGMD and PubMed searches, the likely relevance of the
identified genes was confirmed by cross-referencing the list with the Seizure-Associated
Genes Across Species (SAGAS) database (comprising of 2876 genes potentially associated
with seizures or epilepsies in multiple species), and the Gene4epilepsy database (containing
926 genes included in the epilepsy panels of major clinical diagnostic providers and research
resources).
Of course, the dramatically increased number of genes now potentially linked to epilepsy
only hints at the complex interactions between different genes or genes and environmental
and developmental factors which determine whether a particular genetic abnormality
contributes to the causation of epilepsy or epileptic seizures. As highlighted in Wei-Ping
Liao’s editorial comment in the current Special Issue [5], the pathogenicity of a particular
genetic abnormality also depends on factors such as the Genetic Dependent Quantity, i.e
the lowest limit of the required quantity of genetic function to maintain the biophysiological

function, the Genetic Dependent Nature (i.e. whether a gene is vital to survival, obligatory
for the development of disease-phenotypes, capable of causing mild biological alterations
but not apparent disorders, or dispensable/replaceable) or the Genetic Dependent Stage
(i.e. the developmental stage at which a particular gene is expressed).
These complexities – and the fact that, from where we are standing, we can only see the
outline of the start of the beginning of genetic therapies for the many forms of epilepsy –
mean that, despite the impressive recent progress in this field, there is still much more to
learn!

References
(1) https://www.dna-worldwide.com/resource/160/history-dna-timeline (accessed
11/03/2024).
(2) Claussnitzer M, Cho JH, Collins R, Cox NJ, Dermitzakis ET, Hurles ME, Kathiresan S,
Kenny EE, Lindgren CM, MacArthur DG, North KN, Plon SE, Rehm HL, Risch N, Rotimi
CN, Shendure J, Soranzo N, McCarthy MI. A brief history of human disease genetics.
Nature 2020;577:179-189.
(3) Wang J, Lin ZJ, Liu L, Xu HQ, Shi YW, Yi YH, He N, Liao WP. Epilepsy-associated genes.
Seizure 2017 Jan;44:11-20..
(4) Zhang MW, Liang XY, Wang J, Gao LD, Liao HJ, He YH, Yi YH, He N, Liao WP; China
Epilepsy Gene 1.0 Project. Epilepsy-associated genes: an update. Seizure 2023 Sep
23:S1059-1311(23)00254-6.
(5) Liao WP. Epilepsy-associated genes: discovery, clinical significance, and underlying
principles of genetic medicine. Seizure. 2024 Jan 3:S1059-1311(24)00002-5.

Editor’s Choice Vol. 115: Utilisation of Specialist Epilepsy Services and Antiseizure Medication Adherence Rates in a Cohort of People with Epilepsy Accessing Emergency Care.

Markus Reuber MD PhD, Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF

Some stories are not new but need to be told repeatedly before they have the effect they
deserve. My editor’s choice from volume 115 of Seizure is one such story. The study by
Mohamed Taha et al, describes the management and outcome of 266 consecutive seizure-
related Emergency Department (ED) attendances in hospitals in a large urban area in
Scotland. (1) A history of mental health disorder (recorded in 35% of ED attendances) and
active excessive alcohol and/or recreational drug use (observed in 25% of attendances)
were identified as risk factors for seizures in emergency presentations. ED attendances were
an indicator of poor outcome. One in 20 of the patients seen in ED with a seizure emergency
were dead within a year of their attendance. Almost half of the deaths identified (42.3%)
were associated with poor antiseizure medication adherence. Neurology staff (most likely
neurology doctors in training) only became involved in just over a quarter of emergency
attendances. When they did, they proposed treatment changes in most cases (60%).

These observations are not new. Previous research in the UK has demonstrated that
seizures are the most common neurological emergency leading to ED attendances (making
up 0.7% of unscheduled hospital admissions) (2). Despite the fact that seizures are a clear
marker of acute neurological pathology, other studies have shown that neurologists only
become involved in the assessment or treatment of a minority of cases (3). It is also well
recognised that, in those with pre-existing epilepsy, poor medication adherence is one of
the most common contributors to seizure-related ED attendances, and that antiseizure
nonadherence is associated with a threefold increase in mortality (4).

The reason this story needs to be told again is that alternative care pathways – intended to
reconnect patients experiencing seizure emergencies to appropriate specialist services
rather than simply transporting them to an ED – have been described but rarely
implemented (5). The opportunity to improve the management of seizures, seizure
disorders and underlying pathologies is still too often missed by neurological service
providers. Of course, input from neurologists alone will not be sufficient to address all of the
medical, social and mental health needs of patients presenting with seizures in EDs, but it
could make a significant contribution to better care and outcomes.

References

(1) Taha M, Hanif S, Dickson G, Todd J, Fyfe D, MacBride-Stewart S, Hassett R, Marshall
AD, Heath CA. Utilisation of specialist epilepsy services and antiseizure medication
adherence rates in a cohort of people with epilepsy (PWE) accessing emergency
care. Seizure. 2023 Dec 27;115:59-61.(2) Dickson JM, Jacques R, Reuber M, Hick J, Campbell MJ, Morley R, Grünewald RA.
Emergency hospital care for adults with suspected seizures in the NHS in England
2007-2013: a cross-sectional study. BMJ Open 2018;8(10):e023352.
(3) Dickson JM, Dudhill H, Shewan J, Mason S, Grünewald RA, Reuber M. Cross-sectional
study of the hospital management of adult patients with a suspected seizure (EPIC2).
BMJ Open 2017;7(7):e015696.
(4) Faught E, Duh MS, Weiner JR, Guérin A, Cunnington MC. Nonadherence to
antiepileptic drugs and increased mortality: findings from the RANSOM Study.
Neurology 2008;71:1572-8.
(5) Dickson JM, Rawlings GH, Grünewald RA, Miles K, Mack C, Heywood T, Reuber M.
An alternative care pathway for suspected seizures in pre-hospital care: a service
evaluation. British Paramedic Journal 2017;2:22–28.

Editor’s Choice Vol. 114: Normalization and Cross-Sectional Validation of an Extended Adverse Event Profile (E-AEP) in a Large Cohort of Patients with Epilepsy.

Markus Reuber MD PhD, Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF

In 2005 the ILAE and IBE jointly produced a conceptual definition of epilepsy as “a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures, and by the neurobiologic, cognitive, psychological, and social consequences of this condition” (1). While this definition was further refined with a “practical clinical definition” in 2014 it has not been revoked (2). As seizures are not the only manifestation of epilepsy, the abolishment of seizures cannot be the sole aim of treatment. Especially when seizures cannot be fully controlled with treatment, it often becomes apparent that a balance needs to be struck between the impact of seizures and that of the side effects of treatment. Indeed, among patients with epilepsy who are continuing to experience seizures, health related quality of life is more closely related to mental & cognitive wellbeing as well as other non-seizure physical symptoms than with the frequency or severity of seizures (3).

If the possible “off-target” effects of epilepsy treatment (chiefly antiseizure medications, ASMs) are so important for how well people feel and function – how should they be detected and monitored? In order to capture the broad range of potential side effects (including symptoms such as fatigue, mood change, problems with balance and vision, slowness of thinking, insomnia, autonomic changes, skin rashes) a number of inventories such as the Neurological and Systemic Adverse Event Rating Scales (N&SAERS) (4) and the Adverse Event Profile (AEP) (5) have been developed. 

But what actions should patients and clinicians take when a particular symptom has been reported? – In order to make appropriate choices about medication changes or dose adjustments, patients and clinicians need to make judgements about the cause of these symptoms. Many potential ASM side effects are common in the “healthy” general population. They may also be manifestations of the brain disorder causing epileptic seizures or of comorbid conditions. In all of these cases it may not be necessary or helpful to change an ASM that is making a useful contribution to a patient’s seizure control. While randomised placebo-controlled studies teach us about the side effect profiles of drugs at group level, the information gained from such trials about side effects does not tell us much about whether the symptom reported by a particular patient in clinic is likely related to their ASM or not.

My editor’s choice from the current volume of Seizure, is a retrospective comparison by Helmstaedter et al. of a large clinical dataset collected from patients with treatment resistant epilepsy using an extended version of the AEP (E AEP) with E AEP data provided by a large general population sample (6). The normalisation of the E AEP suggests that between one and two thirds of patient-reported symptoms on the E AEP scale are unlikely to be
related to ASM. While future analysis of longitudinal E AEP changes associated with specific medication alterations may provide additional information about the likely relationships between ASMs and patient-reported symptoms, this paper takes and important step forward in the analysis of potential patient-reported ASM side effects. The use of the normalized analysis of reported symptoms should help clinicians and patients to make better decisions when they contemplate whether or not to make changes to ASMs because of possible side effects.References
(1) Fisher RS, van Emde Boas W, Blume W, et al. Epileptic seizures and epilepsy:
definitions proposed by the International League Against Epilepsy (ILAE) and the
International Bureau for Epilepsy (IBE). Epilepsia 2005;46:470–472.
(2) Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel J Jr,
Forsgren L, French JA, Glynn M, Hesdorffer DC, Lee BI, Mathern GW, Moshé SL,
Perucca E, Scheffer IE, Tomson T, Watanabe M, Wiebe S. ILAE official report: a
practical clinical definition of epilepsy. Epilepsia. 2014 Apr;55(4):475-82.
(3) Rawlings GH, Brown I, Reuber M. Predictors of health-related quality of life in
patients with epilepsy and psychogenic nonepileptic seizures. Epilepsy Behav
2017;68,153-58.
(4) Cramer JA, Steinborn B, Striano P, Hlinkova L, Bergmann A, Bacos I, Baukens C, Buyle
S. Non-interventional surveillance study of adverse events in patients with epilepsy.
Acta Neurol Scand 2011; 124:13-21.
(5) Baker, G.A., Jacoby, A., Frances, P. and Chadwick, D.W. The Liverpool Adverse Drug
Events Profile. Epilepsia 1995; 36:559.
(6) Helmstaedter C, Meschede C, Mastani S, Moskau-Hartmann S, Rademacher M, von
Wrede R, Witt J-A. Normalization and cross-sectional validation of an extended
Adverse Event Profile (E AEP) in a large cohort of patients with epilepsy. Seizure.
2023 Nov 22;114:9-17.

Editor’s Choice vol. 113: Exome analysis focusing on epilepsy-related genes in children and adults with sudden unexplained death.

Markus Reuber MD PhD, Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF

When Darwin described its basic principles, “natural selection” was thought to be the key driver for evolutionary change – an idea characterised by Herbert Spencer in 1864 as the “survival of the fittest”. The basic idea was that individuals or species that are better adapted to their environment have a relative reproductive advantage over their competitors. Since then, we have learned a lot more about gene-environment and gene-gene interactions. We have begun to understand how epigenetic mechanisms can contribute to the heritability of learned patterns of behaviour – and thereby how our ancestors’ experiences can ensure that we are optimally prepared for the environment we have inherited from them (1).

In parallel with the evolution of our genetic adaptation to our environment, there has been an evolution of its comprehension. This evolution has been driven by our low tolerance of being unable to understand the things happening to or around us. As a species and as individuals, we have a great urge to be able explain our experiences. We are much more likely to get distressed by experiences that we cannot explain than by those we have an explanation for (even if this explanation is incorrect).

One context in which this becomes evident in clinical medicine is when a person dies unexpectedly and without explanation. In children this scenario is called Sudden Infant Death (SID), in adults Sudden Unexpected Death (SUD). While many might prefer a sudden and unexpected death for themselves over one following a long period of suffering, death often causes particular trauma to those left behind when it is unexpected and unexplained.

My Editor’s Choice from the current volume of Seizure is a paper by Sarah E. Buerki et al. exploring the possible explanatory genetic contributions to SID and SUD (2). Previous genetic postmortem studies had mainly focussed on genes associated with cardiomyopathies and cardiac arrhythmias. Potentially relevant genetic variants in such genes have been identified in around 20% of individuals whose deaths had been categorised as SID, with similar detection rates in adults who died of SUD (3-5). Genes associated with cardiac pathology have also been examined in people thought to have died of SUD in the context of epilepsy (SUDEP): A recent review of such studies reported likely pathogenic gene discovery rates of around 11% (6).

The genetic postmortem study by Buerki et al. focussed especially on 365 epilepsy-associated variants – on the basis that a proportion of SUD may be attributable to SUDEP rather than primarily cardiac causes. Likely pathogenic variants were found in 19/155 (12.2%) of SIDS and in 6/45 (13.3%) of SUD cases. The potential relevance of this discovery is supported by the observation that genetic variants linked to epilepsy were found more commonly in the subgroup of SUD cases which were likely to have been linked to epilepsy (i.e. SUDEP): 4 of these 9 cases (44.4%) harboured such variants. Of course, the presence of a genetic variant linked to epilepsy does not mean that all of these individuals had experienced epileptic seizures or died of SUDEP. However, this finding supports the idea that SUDEP may explain more cases of SID and SUD than previously assumed – and that greater priority should be given to the prevention of SUDEP through the improvement of epilepsy services.

References

Chahal CAA, Salloum MN, Alahdab F, Gottwald JA, Tester DJ, Anwer LA, So EL, Murad MH, St Louis EK, Ackerman MJ, Somers VK. Systematic Review of the Genetics of Sudden Unexpected Death in Epilepsy: Potential Overlap With Sudden Cardiac Death and Arrhythmia-Related Genes. J Am Heart Assoc. 2020;9:e012264.

Ladd-Acosta C, Fallin MD. The role of epigenetics in genetic and environmental epidemiology. Epigenomics 2016;8:271-83.

Buerki SE, Haas C, Neubauer J. Exome analysis focusing on epilepsy-related genes in children and adults with sudden unexplained death. Seizure. 2023; 113:66-75.

Neubauer J, Lecca MR, Russo G, Bartsch C, Medeiros-Domingo A, Berger W, Haas C. Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases. Eur J Hum Genet. 2017;25:404-409.

Tester DJ, Wong LCH, Chanana P, Jaye A, Evans JM, FitzPatrick DR, Evans MJ, Fleming P, Jeffrey I, Cohen MC, Tfelt-Hansen J, Simpson MA, Behr ER, Ackerman MJ. Cardiac Genetic Predisposition in Sudden Infant Death Syndrome. J Am Coll Cardiol. 2018;71:1217-1227.

Guo L, Torii S, Fernandez R, Braumann RE, Fuller DT, Paek KH et al. Genetic Variants Associated With Unexplained Sudden Cardiac Death in Adult White and African American Individuals. JAMA Cardiol. 2021;6:1013-1022.

Editor’s Choice Vol. 112: Modified Atkins Diet for Drug-Resistant Epilepsy: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Markus Reuber MD PhD, Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF

Fasting and other manipulations of ordinary diets have been used as treatments of epilepsy
for over two and half thousand years. The scientific era of diet treatment for epilepsy goes
back to the 1920s when the ketogenic diet (KD) was introduced in order to mimic the
beneficial effects which had been observed of fasting on epileptic seizures. This diet was
commonly used into the 1940s but fell into decline with the advent of more effective
pharmacological treatments for epilepsy such as phenytoin. Its “rediscovery” in the 1990s
has been linked to the dramatic effects this diet had on the seizure control of a two-year old
boy called Charlie. His amazing improvement with the KD caused his father to form The
Charlie Foundation, and it inspired the production of a movie starring Merryl Streep which
rekindled interest in this non-pharmacological treatment in the USA and elsewhere (1).
Over the last three decades there has been accumulating evidence of the effectiveness of
the KD with a 4:1 ratio of fat to protein and carbohydrates, and the KD has become the gold
standard treatment for epilepsy in metabolic disorders such as Glucose Transporter Protein
1 (GLUT-1) deficiency syndrome or Pyruvate Dehydrogenase Deficiency (2). While the
evidence of effectiveness beyond these rare conditions has been rated as being of relatively
low quality in view of the lack of blinding and the small size of most studies, a recent
Cochrane review concluded that up to 55% of children can achieve seizure freedom with the
KD after three months whilst up to 85% of children achieve a >50% seizure reduction (3).
The mechanisms by which the KD achieves an antiseizure effect remain uncertain. It is
possible that different mechanisms are relevant in different patients (4).
Unfortunately, the clinical use of the KD is associated with several practical problems which
have only partly been overcome by the availability of specially formulated dietary products.
The introduction of the diet typically involves hospitalisation, close metabolic monitoring
with blood and urine tests is required to maintain it, and that the low carbohydrate content
of the KD poses an adherence challenge for people who can help themselves to foods they
like. In addition this, the KD diet can be associated with side effects such as nausea,
vomiting, diarrhea and kidney stones, and there are concerns about its longterm safety.
The fact that that many patients abandon the ketogenic diet for these reasons has
stimulated interest in diets with positive effects on epilepsy which are easier to adhere to –
such as the Modified Atkins Diet (MAD). Like the KD, this diet limits the amount of
carbohydrates, but it aims at a much more easily achievable 1:1 ratio of fat to carbohydrates
without any meal-specific restrictions (5).
My editor’s choice from the current volume of Seizure, a systematic review and meta-
analysis, is based on studies involving 575 patients of whom 288 the MAD as a treatment for
epilepsy. It makes an important addition to the literature by combining the results of several

smaller studies. It concludes that both adults and children receiving MAD plus standard drug
therapy are over six times more likely to achieve a >50% seizure frequency reduction than
those receiving usual diet plus drug therapy. While there is still much to learn about which
patients are likely to respond best to MAD, the combination of previous primary research
allowed the authors to draw new conclusions about the likely effectiveness of the MAD in
adults with epilepsy, the incidence of side effects, and it improved the precision of the
estimated effect size of this diet.
References
(1) Wheless JW. History of the ketogenic diet. Epilepsia 2008;49 Suppl 8:3-5.
(2) D’Andrea Meira I, Romão TT, Pires do Prado HJ, Krüger LT, Pires MEP, da Conceição
PO. Ketogenic Diet and Epilepsy: What We Know So Far. Front Neurosci 2019; Jan
29;13:5.
(3) Martin-McGill KJ, Jackson CF, Bresnahan R, Levy RG, Cooper PN. Ketogenic diets for
drug-resistant epilepsy. Cochrane Database Syst Rev 2020;6:CD001903. PMID:
30403286; PMCID: PMC6517043.
(4) Youngson NA, Morris MJ, Ballard JWO. The mechanisms mediating the antiepileptic
effects of the ketogenic diet, and potential opportunities for improvement with
metabolism-altering drugs. Seizure 2017;52:15-19.
(5) Kossoff EH, Dorward JL. The Modified Atkins Diet. Epilepsia 2008;49(s8):37–41.
(6) Mutarelli A, Nogueira A, Felix N, Godoi A, Dagostin CS, Castro LHM, Mota Telles JP.
Modified Atkins diet for drug-resistant epilepsy: A systematic review and meta-
analysis of randomized controlled trials. Seizure. 2023;112:77-83.

Editor’s Choice Vol. 111: Association of Comorbid-Socioeconomic Clusters with Mortality in Late Onset Epilepsy Derived Through Unsupervised Machine Learning

Markus Reuber MD PhD, Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF

My Editor’s Choice from the current volume of Seizure is a retrospective observational cohort study by Colin B. Josephson et al. intended to explore clinical and socio-economic features affecting the mortality risk of patients with late onset epilepsy (1). Based on the records of over 1,000 older adults thought to have epilepsy and over 10,000 controls (>65 years) – identified from over 1 million primary care patients – the study describes ten feature clusters associated with different outcomes. Cases with epilepsy were selected from the primary care database using a method initially developed for the Secure Anonymised Information Linkage (SAIL) databank (Wales, UK), which had previously been shown to spot people with epilepsy with a sensitivity of 88% and specificity of 98% (2). The study’s findings were derived from the linkage of primary care and electronic hospital episode statistics (HES) data. Additional information about Cause of death was obtained from the linked United Kingdom’s Office for National Statistics (ONS). An unsupervised machine learning approach was used to characterise the clusters. While the hazard ratio (HR) of premature death was elevated to 1.7 (95% CI 1.5-2.0) across individuals with late onset epilepsy, the risk was found to be much  higher in some of the clusters, including those named ‘dementia and anxiety’ (HR 5.4; 95%CI 3.3-8.7), ‘brain tumour’ (HR 5.0; 95%CI 2. 9-8. 6), ‘intracranial haemorrhage (ICH) and alcohol misuse’ (HR 2.9; 95%CI 1.8-4.8), and ‘ischaemic stroke’ (HR 2.83; 95%CI 1.8-4.0). Seizure-related cause of death was uncommon and restricted to the ICH, ‘ICH and alcohol misuse’, and ‘healthy female’ clusters. 

This study is a good example of a research approach which has been used increasingly over recent years – facilitated by linkable electronic databases and advances in machine learning. Thi s ‘big data’ approach has given rise to a debate reflected in two other publications in the current volume of Seizure: An editorial by Randi van Wrede et al (3) and a response by Julie W. Dreier (4). Van Wrede et al. make the point that ‘big data’ studies often draw broad conclusions without taking sufficient account of intra- individual variability. They state that some ‘big data’ studies in the field of epilepsy fail to differentiate between epilepsy as a cause, consequence or association of comorbidities or other relevant pathological findings. Furthermore they highlight the risk of simplistic headlines and secondary reports promoting misunderstandings of epilepsy – even if the the limitations of the original work had been discussed by the authors in the initial publication (3). In contrast, Dreier et al point to the great potential and achievements of ‘big data’ studies. They refer to the ready availability of data, ensuring cost-effective use of limited research funds, as well as the large size of the cohorts, allowing for the inclusion of millions of subjects and exploration of rare exposures or outcomes. They list the reduction of selection bias, availability of longitudinal data, enabling researchers to investigate long-term effects, and the elimination of recall bias through prospective data collection as further strength of the ‘big data’ approach. They remind readers of the confirmation of the teratogenic effects of valproate as an important discovery based on ‘big data’ studies.

My Editor’s Choice gives readers an opportunity to make up their own mind: Are the feature clusters identifying some patients as being at particularly high risk of early death clinically useful? Could they encourage clinicians to focus their attention patient groups at particular risk – such as ‘healthy females’? – Or are the ‘big data’ diagnoses so often incorrect and the features so vague that the analysis by Josephson et al is likely to promote pointless anxiety and a waste of resources?

References
(1) Josephson CB, Gonzalez-Izquierdo A, Engbers JDT, Denaxas S, Delgado-Garcia G, Sajobi TT, Wang M, Keezer MR, Wiebe S. Association of comorbid-socioeconomic clusters with mortality in late onset epilepsy derived through unsupervised machine learning. Seizure 2023, 111:58-67.

(2) Fonferko-Shadrach B, Lacey AS, White CP, Powell HWR, Sawhney IMS, Lyons RA, et al. Validating epilepsy diagnoses in routinely collected data. Seizure 2017;52:195–8.

(3) von Wrede R, Witt JA, Helmstaedter C. Big Data – Big Trouble: The two faces of publishing results from big data studies based on cohorts with poor clinical
definition. Seizure 2023;111:21-22.

(4) Dreier JW, Bjørk M-H, Alvestad S, Gissler M, Igland J, Leinonen MK, Sun Y, Zoega H, Cohen JM, Furu K, Tomson T, Christencen J. Why Big Data Carries Big Potential Rather Than Big Trouble. Seizure 2023;111:106-108.

Editor’s Choice Vol. 110: Use of Video Alone for Differentiation of Epileptic Seizures from Non-Epileptic Spells: A Systematic Review and Meta-analysis.

Markus Reuber MD PhD, Academic Neurology Unit, University of Sheffield, RoyalHallamshire Hospital, Glossop Road, Sheffield, S10 2JF

Clinicians working treating seizure disorders will be familiar with uncertainty in all itsforms: in this medical field, most advice about diagnosis, treatment, lifestyle andpersonal choices and prognosis will be characterised by uncertainty (1). Clinicalencounters in seizure clinics will regularly expose clinicians and patients to “epistemicuncertainty” (due to lack of knowledge at the individual patient level, in general or evenunknown unknowns), “aleatory uncertainty” (related to interindividual biological,psychological or social variability) and “Knightian uncertainty” (where a lack ofquantifiable knowledge means risks cannot be quantified). Uncertainties will be relatedto the unpredictability of outcomes at the individual patient level, imprecision ofevidence, conflict of opinion, lack of information and complexity of available data (2).

Good advice on how to deal with uncertainty in practice is available (3), but there aretimes when clinical scenarios force patients and clinicians to face binary choices – “is thisepilepsy?” / “do we start antiseizure medication?”/”shall we operate?”/ “shall we stopmedication?”. Occasionally there may be a “third way” such as seeking moreinformation or deferring a decision while reflecting on its consequences, but oftenchoices have to be made despite lingering uncertainty.

One of the most consequential sources of uncertainty in clinical epileptology relates tothe nature of the patient’s seizures. This uncertainty is particularly acute when seizuresinclude loss of consciousness – limiting the information available about seizure eventsfrom patients themselves. Of the three most common causes of transient loss ofconsciousness – syncope, epilepsy and functional / dissociative seizures (FDS) – the first isrelatively easy to distinguish from the other two based on the symptoms before andimmediately after the period of loss of awareness (4). The differentiation betweenepilepsy and FDS based on the patient’s history alone is much harder (5).
Arguably the most important development in the differentiation of epileptic and FDSdisorders which I have gained personal experience of over the last three decades is thegreater availability of home video recordings of seizures. My Editor’s Choice from thecurrent volume of Seizure, a meta-analysis by Cemal Karakas et al., documents that, inoptimal circumstances such video recordings have a sensitivity for the identification ofepilepsy of 82%, a specificity of 84%, and yield diagnoses of epilepsy with an odds ratioof 24.7 (6). The area under the Receiver Operating Curve for video-based diagnoses wasexcellent.

Of course, there are several limitations: experts (epileptologists) were considerablybetter than non-experts (including general neurologists) at differentiating correctlybetween videos of the two different types of seizures. What is more, it is not all studiesincluded in the meta-analysis were prospective, and it could be argued that prospectiveand retrospective studies should not be combined. It is also unclear how representativestudy populations of patients with video-EEG based “gold standard” diagnoses are of thewhole patient populations encountered in a seizure clinic.

Nevertheless, as home video recordings have become an essential part of theepileptologist’s toolkit and there is increasing access to commercial and semi-automaticvideo monitoring systems this meta-analysis removes some uncertainty about the levelof uncertainty of what has become one of the most important diagnostic tools inepileptology.References
(1) Han PKJ, Babrow A, Hillen MA, Gulbrandsen P, Smets EM, Ofstad EH. Uncertainty inhealth care: Towards a more systematic program of research. Patient Educ Couns2019;102:1756-1766.(2) Han PK, Klein WM, Arora NK. Varieties of uncertainty in health care: a conceptualtaxonomy. Med Decis Making 2011;31:828-38. doi: 10.1177/0272989×11393976.(3) Berger Z. Navigating the unknown: shared decision-making in the face ofuncertainty. J Gen Intern Med. 2015 May;30(5):675-8.(4) Chen M, Jamnadas-Khoda J, Broadhurst M, Wall M, Grünewald R, Howell SJL, KoeppM, Parry SW, Sisodiya SM, Walker M, Hesdorffer D, Reuber M. Value of witnessobservations in the differential diagnosis of transient loss of consciousness.Neurology 2019, 92:e895-e904.(5) Wardrope A, Newberry E, Reuber M. Diagnostic criteria to aid the differentialdiagnosis of patients presenting with transient loss of consciousness: A systematicreview. Seizure 2018,61:139-148.(6) Karakas C, Ferreira LD, Haneef Z. Use of video alone for differentiation of epilepticseizures from non-epileptic spells: A Systematic Review and Meta-analysis.Seizure 2023, 110:177-187.

Editor’s Choice, Volume 109: Mortality in Children with Epilepsy: A Cohort Study Using the Clinical Practice Research Datalink.

Markus Reuber, Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF

In 1520, in his last major work before his own death, the Italian renaissance artist Raphael depicted the transfiguration of Christ on Mount Tabor and the epileptic seizure of a young boy at the foot of the mountain in the same painting. Raphael’s combination of these two scenes creates a graphic link between two stories which are told successively in the Bible in three of the gospels, as if they had taken place at the same time (Matthew 17:14-21; Mark 9:17-29; Luke 9: 38-43). In this way, the transitory “death” of the boy associated with his epileptic seizure becomes a visual metaphor for the temporary death of Jesus after his crucifixion and before his ascendence to heaven which is a central tenet of Christian belief [1]. While an epileptic seizure is used as a narrative tool to communicate the idea of resurrection and life after death in these biblical stories, it has been recognised for a long time that epilepsy is associated with a significantly increased risk of premature death. Standardised mortality ratios associated with epilepsy range from 1.6 to 3.0 in high-income countries [2] to 19.8 in low- and middle-income countries [3]. Male patients with epilepsy, children and adolescents, as well as those without access to health care are at particular list of premature death [4]. While epilepsy may simply be a marker of other diseases with their own excess mortality, of disease severity or of socioeconomic risk factors associated with early death, epilepsy-related deaths (including avoidable epilepsy-related deaths) have been thought to explain up to 50% of the excess mortality in young people [5, 6]. Sudden Unexpected Death in Epilepsy (SUDEP) is recognised as the most common cause of death in young people [4]. Although there are numerous studies of the mortality associated with epilepsy in childhood have been published previously, many questions remain unanswered and some questions which have been answered for some populations at particular points in time need to be addressed again as health risks, treatments and the management of risk factors have changed.

My editor’s choice from the current volume of Seizure is a cohort study of 1,191,304 children living in Great Britain by Christian Schnier and Robert Chin which makes a further contribution to the literature on the mortality associated with epilepsy in childhood and adolescence [7]. The study captured mortality data from 13,994,916 person-years. Just over 3% of children in the cohort died during the study period. The all-cause mortality rate was 4/1,000 children per year. After adjustment for sex and socioeconomic status, compared to children of the same age without epilepsy, this meant that the all-cause mortality risk was increased by a factor of 50 in young people with epilepsy. Unlike in middle age, when suicide is the commonest cause of death associated with epilepsy, almost all of the deaths in children were classified as ‘natural’ – one quarter were directly attributed to epilepsy.

The increased mortality risk in young people documented in this study should give cause to serious concern and be sufficient in itself to prompt the development and maintenance of responsive and capable health services for children and young people with epilepsy. However, it has recently been argued that studies like the one by Schnier and Chin may still underestimate the true number of epilepsy-related deaths because of inaccuracies of the coded causes of death. It has been suggested that, especially in young children, labels of “sudden infant death syndrome” (SIDS) or “sudden unexpected death in childhood” (SUDC) may have been applied when SUDEP may actually have been a more appropriate or likely as a cause of death [8].

References: 1. Janz D, Epilepsy, viewed metaphysically: an interpretation of the Biblical story of the epileptic boy and of Raphael’s Transfiguration. Epilepsia 1986;27: 316-322. 2. Thurman DJ, Logroscino G, Beghi E, Hauser WA, Hesdorffer DC, Newton CR, et al. The burden of premature mortality of epilepsy in high-income countries: a systematic review from the Mortality Task Force of the International League Against Epilepsy. Epilepsia 2017; 58:17–26. 3. Levira F, Thurman DJ, Sander JW, Hauser WA, Hesdorffer DC, Masanja H, et al. Premature mortality of epilepsy in low-and middle-income countries: a systematic review from the Mortality Task Force of the International League Against Epilepsy. Epilepsia 2017;58:6–16.

4. Trinka E, Rainer LJ, Granbichler CA, Zimmermann G, Leitinger M. Mortality, and life expectancy in Epilepsy and Status epilepticus—current trends and future aspects. Frontiers in Epidemiology 2023; https://www.frontiersin.org/articles/10.3389/fepid.2023.1081757 5. Sidebotham P, Hunter L, Appleton R, Dunkley C. Deaths in children with epilepsies: a UK-wide study. Seizure 2015;30:113-9. 6. Hanna NJ, Black M, Sander J, Smithson W, Appleton R, Brown S, Fish DR. National Sentinel Clinical Audit of Epilepsy-Related Death: Epilepsy–death in the shadows. London; 2002. 7. Schnier C, Chin R. Mortality in Children with Epilepsy: Cohort study using the Clinical Practice Research Datalink. Seizure 2023; please add bibliographic details. 8. Harowitz J, Crandall L, McGuone D, Devinsky O. Seizure-related deaths in children: The expanding spectrum. Epilepsia 2021; 62:570-582.

Editor’s Choice, Volume 108: Defecation Matters! A Comprehensive Review of the Impact of Constipation on Epilepsy.

Markus Reuber, Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF

Over the last few centuries, much progress in medicine has depended on the clinicopathological method – an approach linking particular manifestations of illness with specific structural and pathophysiological processes. The better differentiation of medical disorders and recognition of specific causes continues to inspire the development of new and more effective treatments. However, there are limits to the progress that can be made by distinguishing diseases from each other. It is becoming increasingly clear that it is as important to study the links between “separate” disease entities to gain a fuller understanding of their pathology and how they affect individual sufferers (1).

The risks of illness or chronic disease are not distributed randomly. While the causes of multimorbidity encompass complex and interacting medical, socioecomomic, environmental, behavioural and experiential factors, the fact that there are societal clusters at greater and lower risk of all kinds of ill health is well-recognised (2). Beyond non-specific factors mediating an increased risk of disease in general (such as inadequate nutrition, poor access to medical services or chronic stress), there are more direct connections between some diseases.

In the case of epilepsy, the bidirectional relationship with mental health disorders is now well-established (2). In contrast, the understanding of links between epilepsy and cardiovascular disorders or between epilepsy and gut disorders – albeit recognised – is less well-developed. My editor’s choice article from the current volume of Seizure, a systematic scoping review by Alexandra Gabrielsson et al. makes an important contribution to the field by summarising eight previous studies exploring the clinically important but widely neglected topic of links between constipation and epilepsy (3). The key findings of the review are that up to five times as many people with epilepsy (PWE) have symptoms of irritable bowel syndrome (including constipation) and that over one third of PWE complain of functional constipation. Constipation was reported to be the second most common co-morbidity in children with epilepsy. It has also been shown to be a common side effect of antiseizure medications. Interestingly, the links between functional bowel disorders and epilepsy may be bidirectional: two studies documented a higher risk of constipation prior to the manifestation of seizures.

While these studies should prompt clinicians working with PWE to ask patients more questions about their bowel habits and to consider treatment modifications to those troubled by constipation, they should also encourage researchers to investigate the links between the two anatomically and developmentally distinct organ systems of gut and brain. There are many reasons to think that epilepsy and functional bowel disorders (including constipation) are not merely connected by non-specific factors mediating an increased multimorbidity risk. The gut is controlled by over 100 million neurons and recognised as the “little brain”. It has direct afferent and efferent neuronal links with the central nervous system. Gut neurons have ion channels, glutamate and GABA receptors capable of binding antiseizure medications. Last but not least there is the microbiota-gut-brain axis which may not only be aetiologically relevant by providing a possible link between nutrition, depravation, stress and diseases including epilepsy but which could, potentially, also become more relevant to the treatment of epilepsy in the future. 

References:

1. Gaitatzis A, Majeed A. Multimorbidity in people with epilepsy. Seizure 2023;107:136-145.
2. Zhu Y, Edwards D, Mant J, Payne RA, Kiddle S. Characteristics, service use and mortality of clusters of multimorbid patients in England: a population-based study. BMC Med 18, 78 (2020). https://doi.org/10.1186/s12916-020-01543-8
3. Hesdorffer DC, Ishihara L, Mynepalli L, et al. Epilepsy, suicidality, and psychiatric disorders: a bidirectional association. Ann Neurol. 2012;72:184–191.
4. Gabrielsson A, Tromans S, Watkins L, Burrows L, Laugharne R, Shankar R. Poo Matters! A scoping review of the impact of constipation on epilepsy. Seizure 2023, please add bibliographic details.

Mejía-Granados DM,Villasana-Salazar B, Lozano-García L, Cavalheiro EA, Striano P, Gut-microbiota-directed strategies to treat epilepsy: clinical and experimental evidence, Seizure 2021;90:80-89.

Editor’s Choice, Volume 106: Climate Change Mitigation: Evidence and Statement from the International League Against Epilepsy Climate Change Commission

Alistair Wardrope and Markus Reuber, Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF

Climate change – and the profligate, inequitable, fossil fuel-driven consumption that causes it – is everyone’s problem. The Editor’s Choice from the current volume of Seizure is an article with testimonies from the members of the ILAE Epilepsy Climate Change Commission (CCC) (1) makes clear that this includes those living and working with epilepsy and other seizure disorders. Climate change affects human health in myriad ways – through its direct effects on heat waves and extreme weather events; through its indirect effects on natural systems, such as changing land use, and distribution of infectious diseases and their vectors; and through disruption of social dynamics – intersecting with other political, social, and economic determinants of health to exacerbate food and water insecurity, political instability, and forced migration (2,3). The fossil fuel dependence that overwhelmingly causes climate change also affects health more directly – from local environmental degradation and community disruption at the point of extraction, to the 3.6 million annual deaths attributable to ambient air pollution from fossil fuel combustion (4).

Climate change is everyone’s problem. That can make it seem like no-one’s problem. The tools of healthcare ethics are well equipped for dealing with individual decisions between clinician and patient, made at a single time point, with minimal consequences for those not already in the consultation room. They are less able to engage with problems caused by the cumulative effects of many people’s actions, in all aspects of their personal and professional lives, whose consequences may be felt by people miles – or years – away. Protecting human health from climate and environmental crisis demands that we not just ask what we, personally, are responsible for; it requires seeing that our usual mechanisms for distributing responsibilities are failing, and so asking how we, collectively, can rectify these failures (5). The accounts of the ILAE CCC invite us all to take action – individually, institutionally, and politically.

Climate and environmental crises affect people with epilepsy at every point. The fossil fuel-driven economy has negative impacts on the biggest causes of epilepsy worldwide: 20.1% of stroke risk is attributable to ambient air pollution (6), motor vehicle road injuries are the second most common cause of traumatic brain injury globally (7), and increasing temperature variability and aridity is increasing incidence and spread of meningitis (8,9), and potentially other infectious precipitants of epilepsy (10). Those already living with epilepsy may have specific vulnerabilities, such as heat-sensitive seizures (10). Less directly, but probably more significantly, climatic disruption of social systems is liable to have damaging impacts on epilepsy prevention and management, from disruption of supply and storage of anti-seizure medications (10), to drought- or conflict-driven forced migration (11), which poses high risks of developing epilepsy (and other seizure disorders such as functional/dissociative seizures) due to infection, malnutrition, or traumatic experience – seizures are the leading cause for medical referral in camps for forcibly displaced persons (12).

The causes of these environmental determinants of brain health and their effects are unevenly distributed, in ways that exacerbate existing inequities affecting people with epilepsy. Wealthy consumers and large industries in the global North overwhelmingly drive climate change while small island nations and Sub-Saharan African populations are more vulnerable to the direct and indirect health effects of climate change (13,14). Wealthy G20 nations continue to subsidise the fossil fuel industry, with each dollar of subsidy causing an estimated 6 dollars of health costs (4). Those countries most vulnerable to the health effects of climate change are those where people with epilepsy are already most vulnerable to harm, with the proportion of people in low-income countries not receiving basic epilepsy treatment (the primary ‘epilepsy treatment gap’) being estimated at 86.9% (15).

No individual action can begin to mitigate the scale and complexity of these health threats. Responding to climate change requires institutional and political action at local, national, and international levels. However, existing political actions are insufficient to address the threat adequately, with current policies leaving the world on track to surface temperature rises of 2.7C by 2100 (16). Those entrusted with working for the health of people with seizure disorders cannot be complacent; the formation of groups like the ILAE CCC provide opportunities for health workers to take collective action. These actions can take place at individual, community, institutional, national and international levels.

CCC members highlighted the health and planetary benefits of plant-based diets. Such a shift not only reduces the carbon intensity of food; it could also avert over 10 million diseases per year from non-communicable diseases, and reduce causes of epilepsy like stroke (17). But reaping these benefits requires not just individual change, but also shifting food systems from intensive industrial agriculture to diversified, agroecological methods. Health workers can support this transition by creating alternative spaces for food production and sharing in their communities, like GP food co-operatives; or pressuring their healthcare institutions to provide staff and patients with locally-sourced, plant-based meals (18).

Similarly, fossil fuel-powered transport comprises a large portion of individual and global carbon emissions; but framing transport modes as an issue of individual choice neglects situational factors that support or discourage different choices – and which health workers can also influence. The pandemic has demonstrated the availability of alternatives to the academic norm of frequent long-haul flights for international conferences; more resources are available than ever before to facilitate low-carbon information sharing in ways that are also more accessible to poorer and more marginalised communities (19). Context-sensitive use of telemedicine can reduce emissions associated with healthcare attendances (20-22).

Health workers can also advocate for wider political change. The fossil fuel industry continues to undermine a just transition to a low-carbon economy; resistance can be offered through divesting from the companies fuelling the climate emergency, and advocating for fossil fuel non-proliferation (4,23).

Climate change is everyone’s problem, but none can solve it individually. Action on climate change needs to be collective – at all levels of social organisation. Health professionals can use existing forms of collective organisation to support a just transition to a more sustainable society – this volume’s Editor’s Choice gives just a small sample of reasons why they should, and how they could.

(1)    Aledo-Serrano A. Taking action on climate change: testimonials and position statement from the International League Against Epilepsy Climate Change Commission. Seizure. 2023;In Press.

(2)    Pörtner HO, Roberts DC, Tignor MMB, et al., eds. Climate Change 2022: Impacts, Adaptation and Vulnerability. Contribution of Working Group II to the Sixth Assessment Report of the Intergovernmental Panel on Climate Change. IPCC; 2022.

(3)  Watts N, Adger WN, Agnolucci P, et al. Health and climate change: policy responses to protect public health. The Lancet. 2015;386(10006):1861-1914. doi:10.1016/S0140-6736(15)60854-6

(4)  Beagley J. Cradle to Grave: The Health Harms of Fossil Fuel Dependence and the Case for a Just Phase-Out. Global Climate and Health Alliance; 2022. Accessed February 11, 2023. https://climateandhealthalliance.org/wp-content/uploads/2022/07/Cradle-To-Grave-Fossil-Fuels-Brief.pdf

(5)  Wardrope A, Reuber M. Diagnosis by Documentary: Professional Responsibilities in Informal Encounters. Am J Bioeth. 2016;16(11):40-50. doi:10.1080/15265161.2016.1222008

(6).   Feigin VL, Stark BA, Johnson CO, et al. Global, regional, and national burden of stroke and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. The Lancet Neurology. 2021;20(10):795-820. doi:10.1016/S1474-4422(21)00252-0

(7).   James SL, Theadom A, Ellenbogen RG, et al. Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet Neurology. 2019;18(1):56-87. doi:10.1016/S1474-4422(18)30415-0

(8).   Akanwake JB, Atinga RA, Boafo YA. Effect of climate change on cerebrospinal meningitis morbidities and mortalities: A longitudinal and community-based study in Ghana. PLOS Climate. 2022;1(8):e0000067. doi:10.1371/journal.pclm.0000067

(9).   Chen J, Jiao Z, Liang Z, et al. Association between temperature variability and global meningitis incidence. Environment International. 2023;171:107649. doi:10.1016/j.envint.2022.107649

(10). Gulcebi MI, Bartolini E, Lee O, et al. Climate change and epilepsy: Insights from clinical and basic science studies. Epilepsy & Behavior. 2021;116:107791. doi:10.1016/j.yebeh.2021.107791

(11). Abel GJ, Brottrager M, Crespo Cuaresma J, Muttarak R. Climate, conflict and forced migration. Global Environmental Change. 2019;54:239-249. doi:10.1016/j.gloenvcha.2018.12.003

(12). Hallab A, Sen A. Epilepsy and psychogenic non-epileptic seizures in forcibly displaced people: A scoping review. Seizure. 2021;92:128-148. doi:10.1016/j.seizure.2021.08.004

(13). Ritchie H, Roser M, Rosado P. CO₂ and Greenhouse Gas Emissions. Our World in Data. Published online May 11, 2020. Accessed February 11, 2023. https://ourworldindata.org/co2-emissions

(14). Edmonds HK, Lovell JE, Lovell CAK. A new composite climate change vulnerability index. Ecological Indicators. 2020;117:106529. doi:10.1016/j.ecolind.2020.106529

(15). Kwon CS, Wagner RG, Carpio A, Jetté N, Newton CR, Thurman DJ. The worldwide epilepsy treatment gap: A systematic review and recommendations for revised definitions – A report from the ILAE Epidemiology Commission. Epilepsia. 2022;63(3):551-564. doi:10.1111/epi.17112

(16). Romanello M, Napoli CD, Drummond P, et al. The 2022 report of the Lancet Countdown on health and climate change: health at the mercy of fossil fuels. The Lancet. 2022;400(10363):1619-1654. doi:10.1016/S0140-6736(22)01540-9

19. Willett W, Rockström J, Loken B, et al. Food in the Anthropocene: the EAT–Lancet Commission on healthy diets from sustainable food systems. The Lancet. 2019;393(10170):447-492. doi:10.1016/S0140-6736(18)31788-4
20. Jochelson K. Sustainable Food and the NHS. The King’s Fund; 2005.
21. Successful research, less flying – FlyingLess. Accessed February 11, 2023. https://flyingless.de/en/
22. Blenkinsop S, Foley A, Schneider N, Willis J, Fowler HJ, Sisodiya SM. Carbon emission savings and short-term health care impacts from telemedicine: An evaluation in epilepsy. Epilepsia. 2021;62(11):2732-2740. doi:10.1111/epi.17046
23. Purohit A, Smith J, Hibble A. Does telemedicine reduce the carbon footprint of healthcare? A systematic review. Future Healthc J. 2021;8(1):e85-e91. doi:10.7861/fhj.2020-0080
24. Courtney E, Blackburn D, Reuber M. Neurologists’ perceptions of utilising tele-neurology to practice remotely during the COVID-19 pandemic. Patient Educ Couns. 2021;104(3):452-459. doi:10.1016/j.pec.2020.12.027

Howard C, Beagley J, Eissa M, et al. Why we need a fossil fuel non-proliferation treaty. The Lancet Planetary Health. 2022;6(10):e777-e778. doi:10.1016/S2542-5196(22)00222-4

Editor’s Choice, Volume 105: Adaptive Behavior in Children Exposed to Topiramate In Utero: A Cohort Study

Markus Reuber MD PhD, Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF

It is now well-recognised that the exposure of babies to sodium valproate in the womb may not only cause major malformations, detectable at birth, that are likely to result from teratogenic effects in the early parts of pregnancy but also more subtle abnormalities of brain development manifesting as slight deficits of cognitive or social functioning in later life (1). However, the journey from the discovery of the antiseizure properties of the drug to the implementation of policies to reduce the risk of in-utero exposure to valproate has been a long one: Valproic acid was first synthetised in 1882, but its seizure suppressing effects were only discovered by serendipity in 1963 (2). Valproate was first approved for the treatment of epilepsy in France in 1967, with a first controlled trial proving its effectiveness in 1975 (3). A dose-dependent risk of major malformations in babies exposed to valproate in the womb was initially reported in the early 1980s (4). Although the link between intra-uterine valproate exposure, a reduction in verbal IQ and increased risk of behavioural problems in children was first described in 2004 (5), it was not until 2018 that the European Medicines Agency recommended that valproate should only be used in women of childbearing age if their epilepsy has not responded to other ASMs, and if they are enrolled in a pregnancy prevention programme (1).

Regulatory agencies are currently considering whether they should respond more quickly to similar concerns about topiramate. Topiramate was first synthesised in 1979. Its anticonvulsant potential was surmised because of its chemical structure and promising results in limited animal experiments, and its development as an ASM started in 1986. It became a great commercial success after it had received FDA approval in 1996 (6). However, by 2008, pregnancy registers had identified topiramate as a likely cause of congenital malformations (especially cleft palate) (7), and by 2014 a link with reduced birth weight had been demonstrated (8).

My editor’s choice from the current volume of Seizure, is a cohort study of 28 children whose exposure to topiramate in utero had been captured by the UK pregnancy register (9). In this study Rebecca Knight and her collaborators interviewed mothers about their children aged 2.5 to 17 at the time of assessment. Six topiramate-exposed children were born small for gestational age, and four had been diagnosed with Autism Spectrum Disorder (considerably more than expected, given a UK background prevalence rate of about 1%). Significant associations were observed between birthweight, topiramate dose and Vineland Adaptive Behaviour Scale-Third Edition (VABS-III) assessment scores.

The study by Knight et al adds to recent evidence from two other studies suggesting a link between topiramate and neurodevelopmental disorders: a population-based healthcare records study from the Nordic countries demonstrating an increased risk of autistic spectrum disorder (10) and a previous cohort study indicating an increased risk of learning disability among topiramate-exposed children (n= 27) (11). While confirmation of these findings would be desirable, it may well be that topiramate will soon join valproate as an ASM which should not be used in pregnancy if alternative treatment is possible.

References

Bech LF, Polcwiartek C, Kragholm K, Andersen MP, Rohde C, Torp-Pedersen C, Nielsen J, Hagstrøm S. In utero exposure to antiepileptic drugs is associated with learning disabilities among offspring. J Neurol Neurosurg Psychiatry 2018;89:1324-1331.

Davies P, Reuber M, Grunewald R, Howell S, Dickson J, Dennis G, Shanmugarajah P, Tsironis T, Brockington A. The impact and challenges of the 2018 MHRA statement on the use of sodium valproate in women of childbearing age during the first year of implementation, in a UK epilepsy centre. Seizure 2020;79:8-13.

López-Muñoz F, Baumeister AA, Hawkins MF, Alamo C. The role of serendipity in the discovery of the clinical effects of psychotropic drugs: beyond of the myth. Actas Esp Psiquiatr 2012;40:34-42.

Richens A, Ahmad S. Controlled trial of sodium valproate in severe epilepsy. Br Med J 1975;4(5991):255-6.

DiLiberti JH, Farndon PA, Dennis NR, Curry CJ. The fetal valproate syndrome. Am J Med Genet 1984;19:473-81.

Adab N, Kini U, Vinten J, Ayres J, Baker G, Clayton-Smith J, Coyle H, Fryer A, Gorry J, Gregg J, Mawer G, Nicolaides P, Pickering L, Tunnicliffe L, Chadwick DW. The longer term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2004;75:1575-83.

Maryanoff BE. Phenotypic Assessment and the Discovery of Topiramate. ACS Med Chem Lett 2016;7:662-5.

Hunt S, Russell A, Smithson WH, Parsons L, Robertson I, Waddell R, Irwin B, Morrison PJ, Morrow J, Craig J; UK Epilepsy and Pregnancy Register. Topiramate in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology 2008;71:272-6.

Veiby G, Daltveit AK, Engelsen BA, Gilhus NE. Fetal growth restriction and birth defects with newer and older antiepileptic drugs during pregnancy. J Neurol 2014;261:579-88.

Knight R, Craig J, Irwin B, Wittkowski A, Bromley RL. Adaptive behaviour in children exposed to topiramate in the womb: an observational cohort study. Seizure 2023, please add bibliographic details.

Bjørk MH, Zoega H, Leinonen MK, Cohen JM, Dreier JW, Furu K, Gilhus NE, Gissler M, Hálfdánarson Ó, Igland J, Sun Y, Tomson T, Alvestad S, Christensen J. Association of Prenatal Exposure to Antiseizure Medication With Risk of Autism and Intellectual Disability. JAMA Neurol. 2022 Jul 1;79(7):672-681.

Editor’s Choice, Volume 103: Psychiatric Symptoms as Predictors of Drug-Resistant Epilepsy in Newly Diagnosed Patients.

Markus Reuber MD PhD, Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF

In 2005 the ILAE defined epilepsy as “a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures, and by the neurobiologic, cognitive, psychological, and social consequences of this condition” (1). While not fully recognising epilepsy as a complex neurobiological disorder of the brain in which the development of seizures is often preceded by cognitive, psychological or psychiatric symptoms (2), this definition of epilepsy did embrace the most important non-seizure sequelae of epilepsy which, at least for those individuals whose epileptic seizures cannot be stopped completely with treatment, have greater effects on health-related quality of life than seizure frequency or severity itself (3).

The 2014 ILAE definition of epilepsy dropped any reference to non-seizure manifestations of epilepsy. Epilepsy is currently defined as “a disease of the brain defined by … at least two unprovoked (or reflex) seizures occurring >24 h apart, …one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years … [or the] diagnosis of an epilepsy syndrome” (4).

The failure to mention the neurobiologic, cognitive, psychological, and social aspects of this multifaceted disease is particularly regrettable because (as the authors of the 2014 definition point out) “the definition of epilepsy will affect diagnosis and treatment in both resource-rich and resource-poor societies”. By not characterising epilepsy more broadly as a complex neuropsychiatric disease and by restricting the focus on seizures, the 2014 definition represents a missed opportunity for individuals with epilepsy and for clinicians interested in offering a holistic treatment service aiming to improve patients’ quality of life rather than simply reducing their seizures.

My Editor’s Choice from the current volume of Seizure is a prospective clinical study by Rui Zhong et al. exploring predictors of the development of drug resistant epilepsy – including depression and anxiety – in patients newly presenting with seizures at the time of their epilepsy diagnosis (5). Confirming the findings of a previous study (6), this paper demonstrates that the presence of depression at the point of diagnosis of epilepsy makes it three times more likely that the seizure disorder will prove drug resistant. Patients with depression and anxiety at diagnosis were five times more likely not to respond readily to antiseizure medication than patients with neither of these common “comorbidities” of epilepsy.

This paper should help to make future prediction models of drug resistant epilepsy more accurate and facilitate an earlier consideration of treatments such as epilepsy surgery. Perhaps this paper will also persuade more clinicians to assess the mental health of their patients with seizures and make it more likely that the next ILAE definition of epilepsy will recognise the fallacy of reducing epilepsy to a disease characterised by seizures, and that it will instead fully embrace all aspects of epilepsy (seizure and non-seizure), including the bidirectional relationship between seizures, mental health, cognitive and social problems. Last but not least: This paper may motivate researchers to study whether tackling depression and anxiety therapeutically at the point of epilepsy diagnosis can improve antiseizure treatment outcomes.

References

• Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, Engel J Jr. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia. 2005;46:470-2.
• Hesdorffer DC, Ishihara L, Mynepalli L, Webb DJ, Weil J, Hauser WA. Epilepsy, suicidality, and psychiatric disorders: a bidirectional association. Ann Neurol. 2012;72:184-91.
• Rawlings GH, Brown I, Reuber M. Predictors of health-related quality of life in patients with epilepsy and psychogenic nonepileptic seizures. Epilepsy Behav. 2017;68:153-158.
• Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel J Jr, Forsgren L, French JA, Glynn M, Hesdorffer DC, Lee BI, Mathern GW, Moshé SL, Perucca E, Scheffer IE, Tomson T, Watanabe M, Wiebe S. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014;55:475-82.
• Zhong R, Chen Q, Li N, Zhang X, Lin W. Psychiatric symptoms predict drug-resistant epilepsy in newly treated patients. Seizure 2022, please add bibliographic details.

Hitiris N, Mohanraj R, Norrie J, Sills GJ, Brodie MJ. Predictors of pharmacoresistant epilepsy. Epilepsy Res. 2007;75:192-6.

Editor’s Choice, Volume 101: Economic Evaluation of NightWatch for Children with Refractory Epilepsy: Understanding Cost-Effectiveness and Cost-Benefit

Markus Reuber MD PhD, Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF

Over the last twenty years, the greatest step change in the diagnostic methodology available to clinicians advising patients with seizures has not involved advances is MRI technology, PET scanning or Magnetoencephalography but the increasing availability of smart phone video footage of seizures. While typical smart phone seizure videos may lack the start of the seizure and may not capture all of the seizure manifestations a diagnostician would be interested in, several studies have demonstrated the predictive value of such video recordings, at least when videos are rated by seizures experts. (1) If the differential diagnosis is between epileptic and functional / dissociative (nonepileptic) seizures, experts predict video-EEG diagnoses with over 90% accuracy. In this particular diagnostic scenario, the diagnostic value of home videos is greater than that of interictal EEG (2). Home video recordings provide an objective means of communicating observable seizure manifestations. They enable patients and seizure witnesses to bypass the tenuous process of transferring their recollections of particular patterns of movement or behavior to the clinician’s imagination by means of words.

I predict that a similarly large step change is afoot in the provision of ongoing care to patients who have been diagnosed with epilepsy: This step change will involve a switch from the reliance on self-reported seizure frequencies to the use of objective tools capable of capturing data about the frequency and severity of recent seizures. It is very clear that self-reported seizure frequencies – even when based on diaries – are highly unreliable especially in patients with focal impaired awareness and absence seizures but also in those with seizures from sleep but without a bed partner. In one study the group medians of individual documentation accuracies for overall seizures, simple partial seizures, complex partial seizures and bilateral tonic-clonic seizures were 33.3%, 66.7%, 0%, and 83.3%, respectively (3). Even patients who are highly motivated to record their seizures (like those undergoing inpatient video-EEG monitoring for diagnostic purposes) often fail to record their seizures – most likely because the seizure has reduced their ability to remember or to record it in the postictal state. Self-report of seizure frequencies is of even more limited value in young children or individuals with intellectual disabilities.

My Editor’s Choice from the current volume of Seizure is a prospective study evaluating the health economic benefits of NightWatch ®, one particular objective seizure monitoring and recording system, by Anouk Engelgeer et al (4). While this system is of limited value in the detection of seizures with minor motor components, it has previously been shown to pick up bilateral tonic clonic seizures with a high level of accuracy and with an acceptably low number of false alarms (5). Accurate information about the level of control of seizures – especially of tonic clonic seizures from sleep – may be more important for the prevention of SUDEP than the ability to of others to provide immediate postictal assistance.

In the context of the study by Engelgeer et al the benefits of using this objective seizure monitoring system in children with uncontrolled epilepsy were more immediately measurable: Societal care provision costs fell significantly from the pre-monitoring baseline to the intervention period. Most of the cost difference was explained by child and caregiver healthcare costs, 10% by productivity changes. Univariate sensitivity analyses on the perspective and imputation method demonstrated the robustness of the findings.

The demonstration of cost effectiveness is likely to contribute to an increase in the use of seizure monitoring systems such as NightWatch ® by allowing more clinicians to prescribe such systems for their patients. Alongside the predictable further refinement of monitoring technology and improvements in monitoring data analysis and transmission to specialist services, this development will be another important step towards embedding objective seizure monitoring in routine epilepsy care.

References

Arends J, Thijs RD, Gutter T, Ungureanu C, Cluitmans P, Van Dijk J, et al. Multimodal nocturnal seizure detection in a residential care setting: A long-term prospective trial: A longterm prospective trial. Neurology 2018;91:e2010-9.

Ricci L, Boscarino M, Assenza, Vincenzo-Lazzaro G, Tombini M, Lanzone J,  Di Lazzaro V et al. Clinical utility of home videos for diagnosing epileptic seizures: a systematic review and practical recommendations for optimal and safe recording. Neurol Sci 2021;42:1301–1309.

Chen DK, Graber KD, Anderson CT, Fisher RS. Sensitivity and specificity of video alone versus electroencephalography alone for the diagnosis of partial seizures. Epilepsy Behav 2008;13:115–118.

Hoppe C, Poepel A, Elger CE. Epilepsy: Accuracy of Patient Seizure Counts. Arch Neurol 2007;64:1595–1599.

Engelgeer A, van Westrhenen A, Thijs RD, Evers SMAA. An economic evaluation of the NightWatch for children with refractory epilepsy: insight into the cost-effectiveness and cost utility, Seizure 2022, please add bibliographic details.

Editor’s Choice Vol. 88: Effects of Double-Dose Statin Therapy for the Prevention of Post-Stroke Epilepsy: A Prospective Clinical Study

Markus Reuber MD PhD, Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF

I retain vague memories of a period in my pre-clinical studies when pharmacology seemed relatively straightforward. Anticonvulsants were used to treat seizures, antidepressant drugs for depression, antihypertensives to control high blood pressure and statin therapy to reduce the levels of cholesterol. Lowering levels of cholesterol made good sense because of its contribution to atherosclerosis and the risk of myocardial infarction or stroke. This period of relative bliss was initially challenged when I found out about “good” (HDL) and “bad” (LDL) cholesterol and the importance of the HDL/LDL ratio. However, since then, it has become clear that the effects of statins extend well beyond the regulation of cholesterol metabolism and that their benefits in the primary and secondary prevention of complications of vascular disease are not exclusively mediated by cholesterol levels or ratios, but also by decreasing oxidative stress and inflammation, and by antithrombotic actions (1).

Statins exert their beneficial effects on cholesterol metabolism by inhibiting the rate-limiting enzyme of the L-mevalonate pathway, the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. This pharmacological effect reduces inflammation through effects on downstream metabolites of the same pathway. These metabolites play critical roles in different steps of the body’s immune response including immune cell activation, migration, cytokine production, immune metabolism and cell survival (2).

Importantly, a number of studies suggest that these effects are not only pharmacologically demonstrable but also of clinical significance. The clinical benefits of statin therapy may include antiseizure and antiepileptogenic effects, especially in the context of post stroke epilepsy (3, 4). My editor’s choice from the current volume of Seizure, an observational study in 1,033 patients followed up after experiencing stroke by Yanmei Zhu et al. adds to this evidence (5). In this study the incidence of post stroke epilepsy was 0.4% among the 245 patients who received double dose statin therapy and 2.5% in the 788 patients treated with a standard dose. These findings strengthen the rationale for large prospective studies of intensive statin therapy in patients with stroke and in older individuals with probable cerebrovascular disease presenting with a first seizure.

References

(5) Yanmei Zhu et al. Effects of double-dose statin therapy for the prevention of post-stroke epilepsy: A prospective clinical study. Seizure 2021; 88:138-142

(1) Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005;45:89-118.

(2) Zeiser R. Immune modulatory effects of statins. Immunology 2018; 154:69-75.

(3) Etminan M, Samii A, Brophy J M. Statin use and risk of epilepsy: a nested case-control study. Neurology 2010; 75:1496-500.

(4) Guo J, Guo J, Li J. Statin treatment reduces the risk of poststroke seizures.
Neurology2015; 85:701-7.

Editor’s Choice vol. 85: Barbara Mostacci et al., Alternatives to valproate in girls and women of childbearing potential with Idiopathic Generalized Epilepsies: state of the art and guidance for the clinician proposed by the Epilepsy and Gender Commission of the Italian League Against Epilepsy (LICE).

Markus Reuber MD PhD,  Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF

Since the serendipitous discovery of its anticonvulsant properties in 1962 (1), sodium valproate, previously thought of as a metabolically inert solvent for organic compounds, has gone on to become the world’s most widely prescribed antiseizure medicine (2).  Unfortunately, subsequent experience has shown that sodium valproate does not only have therapeutic, but also adverse effects: After a letter published in The Lancet in 1980 had raised initial concern about the teratogenic potential of valproate in animal models (3), a birth defects monitoring system in France detected a relatively high rate of sodium valproate use in mothers of children born with neural tube defects, and a combination of features collectively termed fetal valproate syndrome was first described in 1984 (4). In 2004, the evidence of teratogenicity was strengthened by a study of longer-term developmental outcomes demonstrating a significantly lower verbal IQ in those whose mothers had taken valproate during pregnancy (5). Several subsequent confirmed that in utero exposure to this drug was causally linked to a range of neurodevelopmental problems, such as autism and developmental delay in up to 40% of exposed children (6-9).

In view of this mounting evidence, in February 2018, the European Medicines Agency (EMA) recommended that VPA should only be used in women of childbearing age if their epilepsy has not responded to other AEDs, and if they are enrolled in a pregnancy prevention programme (‘PREVENT’) (10). Concerns about the use of valproate have also increased among young women not actively planning pregancy in view of evidence documenting the potential of this drug to cause Polycystic Ovary Syndrome, a disorder associated with reduced fertility and a number of other longterm complications (11).

However, in parallel with the discoveries about the potential of sodium valproate to cause serious adverse effects this drug has also been confirmed to be the most effective antiepileptic drug when an idiopathic generalised epilepsy (IGE) syndrome is suspected (12-13). The dilemma raised for young women with IGE and their clinicians by the clear evidence of potential of harm on the one hand and the equally clear evidence of therapeutic advantages over alternative medicines on the other has given rise to complex ethical debates which have featured previously in Seizure (14).

My Editor’s Choice from the current volume of Seizure, a “state of the art and guidance” document written by Barbara Mostacci et al. on behalf of the Italian branch of the ILAE (15), is intended to help those affected by the valproate dilemma by summarising what is known about the effectiveness of alternatives to valproate in a range of different IGE treatment scenarios. Mostacci et al. have used what evidence there is from a number of rather heterogeneous studies to provide detailed treatment algorithms, which go well beyond initial alternative antiseizure medicine choices for particular types of IGE.  The evidence Mostacci et al. have gathered for this document does not remove the dilemma, but it should allow its readers to make the best possible choice in a difficult situation.

References

Mostacci B et al., Alternatives to valproate in girls and women of childbearing potential with Idiopathic Generalized Epilepsies: state of the art and guidance for the clinician proposed by the Epilepsy and Gender Commission of the Italian League Against Epilepsy (LICE). Seizure 2021;85:26-38.

Meunier H, Carraz G, Neunier Y, Eymard P, Aimard M. [Pharmacodynamic properties of N-dipropylacetic acid]. Therapie 1963;18:435-8. [Article in French].

Perucca E . Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs 2002;16: 695–714.

Brown N A, Kao J, Fabro S. Teratogenic potential of valproic acid. Lancet 1980;v. 1,8169:660-661

Diliberti J H et al. The fetal valproate syndrome. Am J Med Genet 1984;19: 473-481.

Adab N et al. The longer term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2004;75: 1575-1583

Meador K J et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 2009;360:1597-1605.

Bomley R L et al. Early cognitive development in children born to women with epilepsy: a prospective report. Epilepsia 2010;51: 2058-2065.

Cummings C et al. Neurodevelopment of children exposed in utero to lamotrigine, sodium valproate and carbamazepine. Arch Dis Child 2011;96:643-647.

Bromley R L et al. The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs. J Neurol Neurosurg Psychiatry 2013;84:637-43.

European Medicines Agency. Valproate and related substances. EMA/145600/2018.2018. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/ Valproate_and_related_substances/human_referral_prac_000066.jsp& mid=WC0b01ac05805c516f.

Isojärvi JIT, Taubøll E, Herzog AG. Effect of Antiepileptic Drugs on Reproductive Endocrine Function in Individuals with Epilepsy”. CNS Drugs 2005;19:207–223.

Marson A G et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007;369:1016-1026, Mar 2007.

Marson A G et al. The SANAD II study of effectiveness of valproate or levetiracetam in generalised and unclassifiable epilepsy: an un-blinded randomised controlled trial. Epilepsia, 2019,60:25 cited from: https://www.cochranelibrary.com/central/doi/10.1002/central/CN-02095526/full?cookiesEnabled

Davies P, Reuber M, Grunewald R, Howell S, Dickson J, Dennis G, Shanmugarajah P, Tsironis T, Brockington A. The impact and challenges of the 2018 MHRA statement on the use of sodium valproate in women of childbearing age during the first year of implementation, in a UK epilepsy centre. Seizure 2020;79:8-13.

Editor’s Choice vol. 84: Parul Agarwal, Huaqing Xi, Nathalie Jette, Jung-yi Lin, Churl-Su Kwon, Mandip S. Dhamoon, Madhu Mazumdar. A Nationally Representative Study on Discharge against Medical Advice among those Living with Epilepsy

Markus Reuber MD PhD,  Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF

Previous studies suggest that around 3% epilepsy patients leave hospital against medical advice [1]. Seizures are one of the three most common symptoms leading to emergency room presentations which ultimately end in Discharge Against Medical Advice (DAMA) [2]. DAMA gets in the way of proper discharge planning, may lead to medication errors, repeated seizures and other poor health outcomes. It is therefore no surprise that patients who decide to leave hospital prematurely are at strongly increased risk of being re-admitted to hospital within 30 days [1]. Not least because of the high risk of re-admission, DAMA also represents a financial challenge for health and social care systems.

My Editor’s Choice from the current volume of Seizure is an original research paper by Parul Agarwal et al. [3], which seeks to explore the causes and predictors of DAMA. Their study uses the National Inpatient Sample (NIS) for the years 2003 to 2014. The NIS includes all inpatient discharges across 44 states and the District of Columbia, representing more than 96% of the U.S. population. It is a nationally representative database maintained by the Agency for Healthcare Research and Quality. The large case numbers and the availability of data spanning a period 12 years allow detailed exploration and the exploration of temporal trends. For the purpose of their analysis, Agarwal et al. split the available sample of inpatient admissions into those that ended in DAMA vs. those where the final discharge occurred with the clinicians’ approval.

The figures from 2014 provide an impression of the size of the problem: Out of 7,071,762 admissions, 187,850 were coded as related to epilepsy, 3,783 of whom (2.01%) were identified as ending in DAMA. Of the variables which distinguished between the two outcomes in univariate analyses, a number of predictors continued to make a significant contribution to a multivariate model: Blacks had higher odds of DAMA than Whites (AOR = 1.12, 95% CI = 1.02, 1.22, p = 0.02), admissions of patients from poorer households were more likely to end in DAMA (adjusted OR (AOR) = 1.90; 95% CI = 1.65, 2.18; p < 0.0001), more Medicaid than Medicare (AOR = 2.14; 95% CI = 1.93, 2.37; p<0.0001) and self-pay admissions (AOR = 3.99; 95% CI = 3.47, 4.59; p<0.0001) admissions were associated with DAMA. Weekend admissions ended in DAMA more commonly than weekday admissions (AOR = 1.17; 95% CI = 1.08, 1.26; p<0.0001).  A lower risk of DAMA was associated with older age  (AOR = 0.991; 95% CI = 0.989, 0.993; p<0.0001), higher levels of comorbidity (AOR =0.97; 95% CI = 0.96, 0.97; p<0.0001), female sex (AOR = 0.67; 95% CI = 0.62, 0.71; p<0.0001), Hispanic extraction (AOR = 0.74; 95% CI = 0.64, 0.86; p<0.0001), elective admissions (AOR = 0.34; 95% CI= 0.28, 0.42; p<0.0001), and hospital location in the Midwest (AOR = 0.57; 95% CI = 0.49, 0.69; p<0.0001) compared to the Northeast US.

Although epilepsy patients whose admissions ended with DAMA had fewer comorbidities overall, some specific comorbidities (including alcohol and drug abuse disorders as well as mood disorders) were associated with an increased risk of DAMA. Alcohol-related disorders were among the top 5 causes of admission in people with epilepsy who left against medical advice.

The proportion of epilepsy-related admissions ending in DAMA increased substantially between 2003 and 2014 (from 1.13% to 2.01%, p<0.0001).

While the findings of this study can only provide an initial impression of the causes and predictors, the potential of DAMA to fragment care provision, to put patients at risk and waste limited health care resources are so obvious that this study should serve as a wake-up call not only to health but also to social service providers. Especially the near doubling of DAMA since 2003 is deeply troubling. Further research into what actually motivates patients to leave hospital against medical advice is urgently required. The largely social risk factors identified in this study suggest that DAMA is not simply an ending of one particular episode of inpatient care but an expression of a much more profound estrangement between patients with epilepsy and those providing medical care for them.

References

Agarwal P, Xi H, Jette N, Lin J-Y, Kwon C-S, Dhamoon MS, Mazumdar M. A Nationally Representative Study on Discharge against Medical Advice among those Living with Epilepsy. Seizure 2021 84:84-90

Raja A, Trivedi P D, Dhamoon M S. Discharge against medical advice among neurological patients: Characteristics and outcomes. Health Services Research 2020, 55:681-689.

Hoyer C, Stein P, Alonso,A. et al. Uncompleted emergency department care and discharge against medical advice in patients with neurological complaints: a chart review. BMC emergency medicine 2019 (19) 52, doi.org/10.1186/s12873-019-0273-y

Editor’s Choice vol. 83: Beydoun A, Dupont S, Zhou D, Matta M, Nagire V, Lagae L. Current role of carbamazepine and oxcarbazepine in the management of epilepsy. 

Markus Reuber MD PhD, Academic Neurology Unit, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF 

We are all creatures of habit. It requires much less mental effort to stick with an established routine than to deviate from it and approach a given task differently. However, as clinicians we must remain prepared to learn throughout our working lives, we have to review the way we manage illness regularly, and we must force ourselves to change when medical knowledge has moved on. While this may not be controversial in principle, the decision whether the time has come to change a well-established treatment method or to stick with a familiar, time-honoured approach is rarely clear-cut.

The use of carbamazepine (CBZ) as an antiseizure medicine (ASM) is a good example. This compound was first synthesised in the 1950s – at a time when vinyl were still competing with shellac records. Does this and the fact that there are so many more recent ASM choices mean that CBZ is now past its sell-by date? Is it ethical to prescribe CBZ when there are alternatives with fewer side effects and drug interactions? Conversely, is it ethical to use more expensive alternatives (including eslicarbazepine) when funds are limited and there are so many other health problems to tackle? Is it better to prescribe drug with known side effects or one with an unknown long-term safety profile? Is oxcarbazepine (OXC) a sensible middle way?

My Editor’s Choice from the current volume of Seizure, a narrative review by A. Beydoun et al., provides the information which readers to decide what choice they should make (1). Readers are not only encouraged to read this comprehensive review article, but then to test their own conclusions by going on to read three editorials on the subject CBZ “oldie but goodie?” by also Roy Berran (2) Charlotte Lawthom (3) and Martin Brodie (4).

Perhaps readers will conclude that they don’t want to their treatment approach (yet), but the review article and these editorials demonstrate that it would not be appropriate to continue using CBZ out of habit alone. Epileptologists need to weigh up the arguments and come to a considered judgement on this important aspect of their practice.

References 

1) Beydoun A, Dupont S, Zhou D, Matta M, Nagire V, Lagae L. Current role of carbamazepine and oxcarbazepine in the management of epilepsy. Seizure 2020; 83: 251-263

2) Beran R. Carbamazepine (Tegretol) –An Oldie but a Goodie –A Clinician’s Perspective. Seizure 2020; 83: 243-245

3) Lawthom C. Carbamazepine: Out with the Old, In With the New?! Seizure 2020; 83: 246-248

4) Brodie M. Carbamazepine and me! Seizure 2020; 83: 249-250

Seizure 2020, Vol 82, Editor’s Choice: In the eye of the beholder: using a multi-informant approach to examine the mediating effect of cognitive function on emotional and behavioral problems in children with active epilepsy. 

Epilepsies are conditions not only characterized by the seizures which define them but also by their neurobiological, cognitive and psychosocial consequences. Individual “consequences” may not be linked exclusively to epilepsy, but they are so common and their patterns so characteristic that they have been included in the definition of epilepsy (1). Although the word “consequence” implies a unidirectional relationship in which seizures are the cause, in many cases, there are bidirectional relationships between particular neurobiological, cognitive or psychosocial features and epileptic seizures. For instance, individuals with uncontrolled epilepsy are more likely to experience symptoms of depression than those whose seizures are well controlled (2). At the same time depressed individuals are more likely to have epileptic seizures (or to develop epilepsy) than those who are not (3). Having said that, the term “bi-directional” still oversimplifies these associations. As particular features do not only interact with epileptic seizures but also with each other (as well as the underlying cause of the epilepsy and its potential consequences), the relationships between different features need to be considered “multi-“ rather than “bi-” directional. 

All this becomes even more complicated in children and adolescents where interactions are not limited to features associated with epileptic seizures and any underlying disease but also include features associated with neurobiological, cognitive and psychosocial brain development.

My Editor’s Choice paper from the current volume of Seizure, an original article by Tamar Silberg et al., explores some of these multifactorial interactions by describing the relationship between cognitive, emotional, behavioural and seizure-related variables in a sizable group of children and adolescents (4). Using data from a range of sources (clinical information, neuropsychological testing, parent and teacher-reports) they found that parents and teachers both reported high levels of emotional and behavioral problems, although, at group level, the cognitive profile of the sample was within the normal range. Teachers reported more emotional and behavioural problems than parents. The relationship of teachers’ assessment of emotional and behavioural problems and epilepsy-related factors (such as the number of antiseizure medications and illness duration) was mediated the children’s cognitive performance. This mediation effect was not observed in relation to parents’ reports of emotional and behavioural problems, perhaps reflecting the different situation in which parents and teachers observe children’s behavior or the more complex relationships between parents and their children. The findings could also have been influenced by negative attitudes towards epilepsy among teachers, leading to an increased perception of emotional and behavioral problems, especially in children with cognitive problems.

Whatever the reasons for the differences in the perceptions of parents and teachers, the discrepancies found in this study highlight the importance of taking full account of the sources of information about patients and the context in which the information was gathered. In order to achieve an optimal understanding of an individual’s epilepsy, its consequences and associations, and to provide optimal intervention, information from multiple sources needs to be carefully triangulated. A correlation between two features does not always mean that there is a causal link. Even when thre is a link, causation may be mediated by a third (or multiple other) factor(s).

References:

1) Fisher RS, Boas WV, Blume W, Elger C, Genton P, Lee P, Engel Jr J. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 2005;46:470-2.

2) Jacoby, A., Baker, G. A., Steen, N., Potts, P., Chadwick, D. W. The clinical course of epilepsy and its psychosocial correlates: findings from a U.K. Community study. Epilepsia. 1996;37(2),148-61.

3) Hesdorffer DC, Ishihara L, Mynepalli L, Webb DJ, Weil J, Hauser WA. Epilepsy, suicidality, and psychiatric disorders: a bidirectional association. Ann Neurol 2012;72:184-91

4) Silberg T et al. In the eye of the beholder: using a multi-informant approach to examine the mediating effect of cognitive function on emotional and behavioral problems in children with active epilepsy.  Seizure 2020; 82: 31-38

Seizure 2020, Vol 81, Editor’s Choice: Antibiotic-induced epileptic seizures: mechanisms of action and clinical considerations

Like antiseizure and other medications, antibiotic drugs have a hard time getting into the brain. Orally administered preparations have to survive the acidity of the stomach, pass through the intestinal mucosa and potential first-pass metabolisation in the liver. From there, they need to get to the head and pass the blood-brain-barrier. It is perhaps not surprising that it was an attempt to overcome these hurdles that first led to the discovery of the seizure-provoking effects of penicillin very soon after this drug was first discovered: the intraventricular injection of penicillin was noted to cause myoclonic jerking (1). This discovery has been put to good use since – when penicillin is used in animal research as a precipitant for acute seizures or (with repeated administration) for epilepsy (2). However, the ictogenic and epileptogenic potential of penicillin and more recent antibiotic drugs continue to be problematic when these potentially life-saving medicines are used to treat infections in humans.

My editor’s choice paper from the current volume of Seizure by Pitchaya Wanleenuwat et al. provides a masterly overview of the different ways in which antibiotic treatment can precipitate seizures (3). The most commonly used antibiotic drugs, β-lactams and fluoroquinolones, are also the ones most closely associated with neurotoxic side effects. Directly seizure-promoting mechanisms include interference with inhibitory processes and enhancement of excitatory processes (such as gamma-aminobutyric acid (GABA) antagonism, inhibition of GABA synthesis or glutaminergic N-methyl-D-Aspartate (NMDA) receptor agonism). However other mechanisms may play an additional role, and patients with hepatic and renal insufficiencies – both the rule rather than the exception in elderly patients – are at greatest risk. Directly harmful effects of antibiotics within the brain are particularly common in clinical scenarios in which the efficacy of the blood brain barrier is reduced – for instance in infections involving the meninges. Macrolide antibiotics (clarithromycin and erythromycin) can cause neurotoxic effects (including delirium and seizures) by inhibiting the hepatic metabolism of antiepileptic drugs. Carbapenem can enhance valproate breakdown, thereby increasing the risk of seizures.

Considering the many and complex ways in which epilepsy, infections, antiseizure medications and antibiotics can interact, one wonders how often the observation of a deterioration of seizure control in an individual with epilepsy was actually due to the medicine prescribed to combat an intercurrent infection rather than the infective illness itself!

References:

1) Johnson HC, Walker AE. Intraventricular: A note of warning. JAMA 1945;127:217–9. https://doi.org/10.1001/jama.1945.92860040001007.

2) Kandratavicius L, Alves Balista P, Lopes-Aguiar C, Ruggiero RN, Umeoka EH, Garcia-Cairasco N, Bueno-Junior LS, Leite JP. Animal models of epilepsy: use and limitations. Neuropsychiatr Dis Treat. 2014;10: 1693–1705.

3) Wanleenuwat P, Suntharampillai N, Iwanowski P. Antibiotic-induced epileptic seizures: mechanisms of action and clinical considerations. Seizure 2020; 81: 167-174.

Seizure 2020, Vol 80, Editor’s Choice: The role of chronobiology in drug-resistance epilepsy: The potential use of a variability and chronotherapy-based individualized platform for improving the response to antiseizure drugs

For many people with epilepsy, the unpredictability of their seizures is a particularly disabling aspect of the condition. It is primarily because of this unpredictability that activities have to be restricted, certain jobs become impossible or people may not be allowed to drive a motor vehicle. However, several recent studies have demonstrated that – surprisingly often – epileptic seizures are not an entirely random occurrence. Leaving aside those who are able to identify (and avoid) particular seizure triggers,  these studies suggest that the likelihood of seizure occurrence often follows a steady pattern raising the possibility that the risk of seizures could be forecast, similarly to the risk of rain. While the majority of epilepsies have been shown to be subject to some degree of diurnal variation (1), seizures stick very closely to a predictable pattern in 10 or 20% of patients (who have often not noticed this) (2).

My Editor’s Choice paper from the current issue of Seizure is an article by Assaf Potruch, Salim T. Khoury and Yaron Ilan (3). I their wide-ranging narrative review  Potruch et al. initially consider the currently recognized mechanisms for the pharmacoresistance of epilepsies before exploring how natural body rhythms could be harnessed to improve the responsiveness to treatments – including the antiepileptic drugs already at our disposal today.  Similarly to researchers attempting to treat currently incurable conditions with existing but repurposed drug treatments for other disorders, they propose using interventions we already have in our arsenal, but using them in a much more targeted way by observing and taking account of the natural brain and body rhythms and by avoiding potential iatrogenic effects of regular drug dosing potentially including the loss of effectiveness. Potruch et al. argue that our exisiting antiseizure treatments could be much more effective if they were delivered in a more targeted fashion, especially at precisely the time they are needed. Given that epilepsy is a highly heterogenous condition an ideal chronobiologically informed treatment would take account of a broad range of specifics characterizing a person’s epilepsy and also monitor their brain and body rhythms. Some of these ideas are not new but the closed-loop deep brain stimulation systems now used routinely in some countries contain the technology that makes the detection of the rhythms which co-determine the timing of seizures much more feasible. Perhaps this technology could be repurposed to administer individually optimized pharmacological treatments in the future.

References:

1) Quigg M. Circadian rhythms: interactions with seizures and epilepsy. Epilepsy Res 2000;42:43-55

2) Karoly PJ, Goldenholz DM, Freestone DR, et al. Circadian and circaseptan rhythms in human epilepsy: a retrospective cohort study. Lancet Neurol 2018;17:977-85.

3) Potruch A, Khoury ST, Ilan Y. The role of chronobiology in drug-resistance epilepsy: The potential use of a variability and chronotherapy-based individualized platform for improving the response to antiseizure drugs. Seizure 2020; 80: 201-211

Seizure 2020, Volume 79, Editor’s Choice: Seizures Associated with Coronavirus Infections

In the countries which were initially ravaged by the COVID-19 pandemic, people are now emerging again from the lock-down imposed by their governments in an attempt to “flatten the curve” and protect health systems from becoming overwhelmed by patients badly affected by the virus. In these countries the attention is shifting from the emergency provision of extra hospital beds and ventilators to the development of new ways of working intended to reduce the infection risk to patients and clinicians – such as telephone or video-phone consultations. Routine surgical procedures are rescheduled, often after complex preparations including testing for COVID-19 infection and quarantine procedures. While life is still far from what was “normal” not so long ago, people are experimenting with a new kind of normality that may be sustainable for months, and possibly longer. Physicians in these countries may feel that I am a little behind with my editor’s choice from the current volume of Seizure, a narrative review about the epileptological consequences of corona virus infections by Ali Asadi-Pooya (1). However, while the panic which certainly coloured the initial responses to the pandemic may have settled in the countries described above, many other countries – mostly with far fewer resources than those that were hardest hit by the first wave of the pandemic are still experiencing dramatic increases in case numbers. Clinicians in these countries will still be looking around anxiously for anything they can learn about COVID-19.

One thing clinicians specializing in the treatment of seizure disorders will learn from the review by Dr. Asadi-Pooya is that previous experience with other corona viruses (such as SARS or MERS) suggests that their services may occasionally be called upon. These and other corona viruses do not only affect the respiratory organs through which they enter the body, they are also capable of causing encephalitides which may be associated with seizures (2,3).

Similarly COVID-19 can cause neurological symptoms. In one case series based on observations among 219 patients admitted to hospital with serious COVID-19 infections in China, 36.4% had neurologic manifestations. The commonest symptoms were dizziness (17%) and headache (13.1%). Impairment of taste (6%) and smell (5%) were also quite common. Depending on whether the cases were categorised as “severe” or “non severe”, stroke, brain haemorrhage or TIAs were seen in 6% vs 1%, impaired consciousness in 15% vs 3%, and skeletal muscle injury in 19% vs 5% (4).

Although there are only sporadic reports of seizures or status epilepticus in the context of COVID-19 infections so far, it would be surprising if the many haematological, immunological and metabolic complications attributed to this virus or – or the treatments of these complications – were never associated with epileptological complications, especially with non-convulsive status epilepticus which may well be missed in settings where neurologists are not involved in providing front line care and access to EEG is limited because of resource limitation or because of infection control measures.

References:

1) Asadi-Pooya A. Seizures associated with coronavirus infections. Seizure 2020; 79: 49-52

2) Li Y, Li H, Fan R, Wen B, Zhang J, Cao X, et al. Coronavirus Infections in the Central Nervous System and Respiratory Tract Show Distinct Features in Hospitalized Children. Intervirology 2016; 59: 163-169.

3) Saad M, Omrani AS, Baig K, Bahloul A, Elzein F, Matin MA, et al. Clinical aspects and outcomes of 70 patients with Middle East respiratory syndrome coronavirus infection: a single-center experience in Saudi Arabia. Int J Infect Dis 2014; 29: 301-306.4) Mao L, Jin H, Wang M, et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. Published online April 10, 2020. doi:10.1001/jamaneurol.2020.1127

Seizure 2020, Vol 78, Editor’s Choice: ”Keep Safe: The when, why and how of epilepsy risk communication”

Given that the current issue of Seizure includes two review articles and one editorial commentary on the discussion of risk in clinical encounters between clinicians and patients with epilepsy (1-3), I felt obliged to make one of these contributions my Editor’s Choice. The fact that scientific papers focusing on the communication of risks should be submitted to a journal about seizures is no surprise. I am not sure that I can recall a single consultation in which risks were not considered – and not many in which risks were not explicitly discussed. When a seizure disorder is first diagnosed, patients and clinicians need to think about risks related to activities such as cooking, bathing, childcare, work, recreation and driving. As the focus moves to treatment, they will consider the risk of further seizures versus those of idiosyncratic or dose-related adverse effects, teratogenicity and interactions with other medications or medical conditions. Risks become a particularly prominent concern when patients are planning pregnancy, pregnant or considering surgical procedures for epilepsy.
In view of the prominent role more or less formal risk assessments play in routine epileptological practice, the first finding of the systematic review by Cordet Anne Smart et al. (1), my Editor’s Choice from this issue, is rather surprising: notwithstanding the fact that the present issue of Seizure contains several contributions about the topic the literature about risk discussions is actually very limited. Although quantitative and qualitative studies were within the scope of this review, the authors were only able to identify 17 relevant studies – largely limited to the discussion of Sudden Unexpected Death in Epilepsy (SUDEP). What we learn from these studies is that patients would like an early discussion of SUDEP (although the timing should be individually adjusted), and that clinicians may be more anxious of discussing this subject than patients. Patients want the SUDEP risk to be explained to them face-to-face (perhaps with additional written material to back up the discussion), and may benefit from an explanation provided by a more senior and experienced clinician. Checklists to guide the conversation exist but the effects of their use have not been well studied.
Unfortunately, we need to know much more about this topic. As pointed out by Roy Beran in his editorial comment (3), it makes a lot of sense to discuss the risk of SUDEP in the context of the many other risks, which patients need to consider as they learn to live with a seizure disorder. In view of the great heterogeneity of epileptic seizure disorders and the individuals who experience them, much more work will be needed before truly “evidence-based” practice recommendation can be made for different communication scenarios – although it is clear that the discussion of risks has to be individualized if it is going to be meaningful for specific patients. It would also be important to extend the range of methodologies that are brought to bear to improve communication about risks in the context of seizure disorders. Questionnaires and surveys cannot tell us much about what exactly clinicians say, and how patients and accompanying individuals make sense of this, during clinical encounters. Previous studies have used Conversation Analysis in epileptological settings. The discussion of risk would be an ideal focus for future studies using this or similar methodologies.
While the review by Smart et al. provides a very helpful summary of the literature to date it is therefore more than anything a call for clinicians to reflect on a key area of their daily practice and for researchers to study this field more deeply.
References:
1) Smart CA, Page G, Shankar R and Newman C. Keep Safe: The when, why and how of epilepsy risk communication. Seizure 2020, please add bibliographic details. Seizure 2020; 78, 136-149
2) Cooper K, Kirkpatrick P, Brand C, Rolfe A, Florida-James S. Discussing sudden unexpected death in epilepsy with children and young people with epilepsy and their parents/carers: a mixed methods systematic review. Seizure 2020, please add bibliographic details.
3) Beran R. Discussing the risks related to epilepsy – an holistic approach. Seizure 2020, please add bibliographic details.
4) Toerien M, Shaw R, Duncan R, Reuber M. Offering patients choices: a pilot study of interactions in the seizure clinic. Epilepsy Behav. 2011;20(2),312-20.

Seizure 2020, Vol 77, Editor’s Choice: ” Cognitive outcome of pediatric epilepsy surgery across ages and different types of surgeries: A monocentric 1-year follow-up study in 306 patients of school age”

It may seem badly out of step with current lived experience and sentiment to produce a Special Issue on paediatric epilepsy surgery while we are facing a crisis, which may well become the greatest acute global challenge since the Second World War. While city streets have emptied, societies are struggling with increasingly stringent “social distancing” and “self isolation” measures, and hospitals are struggling to deal with the stream of acutely ill patients flooding through their doors: why publish articles about highly complex interventions suitable for less than 5% of all individuals with epilepsy – and only available to those who live in rich countries? – And why at this time?

I will try to address these questions, but first I would like to apologise in advance in case my answers seem ridiculously inappropriate by the time they are read. Much like the car manufacturers that have been encouraged to switch to producing ventilators, my colleagues and I have spent much of last week transforming a multidisciplinary tertiary clinical neuroscience service providing a broad range of medical, surgical, immunological, dietary, rehabilitative and psychotherapeutic in- and outpatient treatments into a support service for acute respiratory, intensity and high dependency care. All non-urgent elective neurosurgery (including epilepsy surgery) has been stopped. Most operating theatres and surgical recovery areas are being converted to intensive care units. Many outpatient appointments are being cancelled or delayed and all face-to-face outpatient contacts have been replaced with telephone or video-phone interactions. However, the emergency staffing rotas we discussed only yesterday are already out of date. And the scenarios we imagined as we made our plans last week already seem strangely naive. Now we anticipate that we will need at least twice as many neurologists to support acute medical services and to enable home treatment of neurological emergencies than was deemed necessary only 24 hours earlier. I am therefore acutely aware that anything I write today, as more people and healthcare professionals around the world become direct or indirect victims of Covid-19.

With these provisos out of the way, let me try to answer the questions posed above: Life will continue after the Covid-19 pandemic. While many of us will come to think of our lives as split into two distinct parts – before and after the pandemic – the modern world will not end. People will continue to suffer from long-term conditions such as epilepsy. We will still want to provide effective treatments and reduce the burden of the disease.  – And in the case of paediatric epilepsy surgery, we can actually go much further than this. This particular treatment remains our only chance of providing a cure of epilepsy. Even more clearly than adult epilepsy surgery, this treatment does not only have the potential to help patients in the short term, but it can make a profound difference to our patients’ whole life trajectories. Even if shortages of funding, material or staffing should force restrictions upon overstretched health care services after the pandemic: for this reason the resumption of paediatric epilepsy surgery should be given priority over other elective neurosurgical procedures.

My editor’s choice from the current Special Issue of Seizure – guest edited by Jun Park – is an original research paper by Christoph Helmstaedter et al. entitled “Cognitive outcome of pediatric epilepsy surgery across ages and different types

of surgeries: A monocentric 1-year follow-up study in 306 patients of school age” (1). This paper reminds us that epilepsy is not simply a disease characterized by recurrent seizures. In most cases, epilepsy is also associated with some degree of cognitive compromise. As demonstrated in the Study of Standard and New Antiepileptic Drugs (SANAD), even at the point of diagnosis (i.e. before commencement of treatment with potential cognitive side effects, and not explained by the number of seizures, type of epilepsy or mood) patients with epilepsy perform worse than healthy volunteers on a range of cognitive measures, particularly of memory and psychomotor speed: In that study, 53.5% patients but only 20.7% of controls scored >2 standard deviations below the control mean in at least one testing domain (2).  These cognitive deficits are even more important in children than in adults because they can affect subsequent cognitive development (3). In view of the much better ability of the young brain to recover after epilepsy surgery successful operative interventions in children and adolescents often improve cognitive performance substantially whereas aequivalent improvements are unexpected in older patients even when seizures stop postoperatively (4).

In my Editor’s Choice paper, the large paediatric and adolescent epilepsy surgery series described by Helmstaedter et al. (1), 85% of patients were found to have preoperative impairments in at least one domain (i.e. they performed >2 standard deviations below the level of healthy controls), and 71% had behavioral problems. Postoperatively, the status of 21-50% of the patients changed from impaired in at least one domain to unimpaired across all domains. At the individual patient level significant gains in test performance were observed in 16-42% of patients in different domains. The proportion of patients who had become seizure-free through surgery was 81%.  At last follow up, patients in the surgically treated group were more likely than the others to have decreased their antiseizure medicine load.

Postoperative seizure freedom, a younger age at evaluation, a later age at epilepsy onset, a lower antiepileptic drug load, and less baseline damage predicted better cognitive and behavioral outcomes after epilepsy surgery in children and adolescents. In keeping with the finding of previous studies that neuropsychological deficits tended to be less focal / domain specific in children than adults (3); localization and lateralization had little or no impact on neuropsychological outcomes. Likewise, gender and type of pathology were not found to predict postoperative neuropsychological outcome (1).

This study shows how much good we are able to do with the advanced neurosurgical techniques described in the current Special Issue of Seizure on paediatric epilepsy surgery. The final reason for publishing this Special Issue while we are all grappling with the Covid-19 pandemic one way or another is to remind us that a better time will come – a time when we will be able to dust ourselves down and refocus on providing surgical treatments which can completely transform the lives of individuals with epilepsy.

References:

1) Helmstaedter C, Beeres K, Elger C, Kuczaty S, Schramm J, Hoppe C. Cognitive outcome of pediatric epilepsy surgery across ages and different types of surgeries: A monocentric 1-year follow-up study in 306 patients of school age. Seizure 2020; 77: 86-92.

2) Taylor J, Kolamunnage-Dona R, Marson AG, Smith PE, Aldenkamp AP, Baker GA, et al. Patients with epilepsy: cognitively compromised before the start of antiepileptic drug treatment? Epilepsia 2010;51,48-56.

3) Holmes GL, Effect of Seizures on the Developing Brain and Cognition. Semin Pediatr Neurol 2016; 23: 120–126. 

4) Helmstaedter C, Reuber M, Elger CE. Interaction of cognitive aging and memory deficits related to epilepsy surgery. Ann Neurol 2002;52,89-94.

Seizure 2020, Vol 76, Editor’s Choice: “Exploring epilepsy attendance at the emergency department and interventions which may reduce unnecessary attendances: A scoping review”

At a time when the world’s attention is focused on the response of emergency medical services to the Covid-19 pandemic my Editor’s Choice from the current volume of Seizure is a scoping review by Lisa Burrows et al, summarizing research exploring interventions aimed at reducing unnecessary emergency department (ED) attendances by individuals with epilepsy (1).

In England (population 53 million) a high-income country with a universal public health system providing free access to routine and emergency health care and antiseizure medicines only 50% of patients with epilepsy become free of seizures (2). Those individuals with uncontrolled epilepsy are not the only ones who are at risk of frequenting EDs with seizures. One study suggested that, although three quarters of patients of the patients brought to an ED with a suspected seizure diagnosis had experienced and epileptic seizure only about one third of patients carried a diagnosis of epilepsy at the time of their admission (3). However it has been estimated that epileptic seizures lead to 60,000 ED  (113 per 100,000), and 40,000 hospital admissions in England per year (76-148 per 100,000), making epileptic seizures one of the three commonest neurological causes for attendance in emergency departments (EDs) (4).

This means that a substantial proportion of seizure-associated ED attendances are related to an “ambulatory care sensitive condition”, i.e. they occurred in a context in which optimal ambulatory care may have prevented the need for the involvement of emergency services. Most presentations to EDs turn out to be related to problems which could have been managed outside EDs (such as resolved seizures) (5). Given that ED management by non-seizure experts often adds little to longer term seizure control but is associated with considerable expenditure and a risk of iatrogenic complications (such as hospital acquired infection!), it is important to explore how ambulatory care could be improved to avoid unnecessary admissions.

The scoping review by Burrows et al. is therefore of great clinical importance. Their overview of recent research is based 29 pieces of original research which could be subdivided into four themes: care pathways, conducting care and treatment reviews, educational interventions and role of ambulance staff. Although there is clearly more work to do some of these intervention have been welcome by patients and associated with reduced healthcare expenditure.

While the identification of demographic and clinical risk factors for repeated attendance to EDs due to seizures has allowed interventions to be focused on the third of patients who are responsible for two thirds of all epilepsy related admissions (6), the nature of these factors (including mental health problems, low educational attainment and social problems) means that successful intervention will be particularly challenging. However, the urgent (and increasing) need to use limited healthcare resourced most effectively means that the search for better and more effective interventions improving the effectiveness of ambulatory care and reducing epilepsy-related demands on emergency services must continue.

References:

1) Burrows L, Lennard S, Hudson S, McLean B, Jadav M, Henley W, Sander JW, Shankar R. Exploring epilepsy attendance at the emergency department and interventions which may reduce unnecessary attendances: A scoping review. Seizure 2020; 76; 39-46

2) Dixon P, Kirkham J, Marson A, et al. National Audit of Seizure management in Hospitals (NASH): results of the national audit of epilepsy in the UK. BMJ Open 2015;5:e007325.

3) Dickson JM, Dudhill H, Shewan J, Mason S, Grunewald RA, Reuber M. Cross-sectional study of the hospital management of adult patients with a suspected seizure (EPIC2). BMJ Open. 2017;7(7),e015696. doi: 10.1136/bmjopen-2016-015696.

4) Dickson JM, Jacques R, Reuber M, Hick J, Campbell MJ, Morley R, et al.  Emergency hospital care for adults with suspected seizures in the NHS in England 2007-2013: a cross-sectional study. BMJ Open 2018;8(10),e023352. doi: 10.1136/bmjopen-2018-023352

5) Dickson JM, Taylor LH, Shewan J, Baldwin T, Grünewald RA, Reuber M. A Cross-Sectional Study of the Pre-hospital Management of Adult Patients with a Suspected Seizure (EPIC1). BMJOpen 2016;6:e010573. doi:10.1136/bmjopen-2015-01057

6) Noble A, Goldstein L, Seed P et al. Characteristics of people with epilepsy who attend emergency departments: Prospective study of metropolitan hospital attendees. Epilepsia. 2012;53(10):1820-1828.

Seizure 2020, Vol 75, Editor’s Choice: “Epilepsy and autoimmune diseases: comorbidity in a national patient cohort”

In its latest classification of the epilepsies, the International League Against Epilepsy (ILAE) stresses the importance of aetiology and aspires to go beyond a largely phenomenological electroclinical description of different seizure types and syndromic seizure combinations which characterized previous classification systems (1). However, in clinical reality the aetiology of most patients’ epilepsy remains undetermined at present, despite all the progress which has been made in genetics and our neurophysiological understanding of the epilepsies over the last few decades. One field in which progress has been particularly impressive is that of auto-antibody-associated epilepsies (2). Not least the relatively recent description of these epilepsies has highlighted the possibility that a large proportion of the as yet aetiologically unexplained epilepsies could be immune-mediated.

My Editor’s Choice article from the current volume of Seizure, an original research study by Anna Børsheim et al. uses routinely collected healthcare data from the public Norwegian Prescription Database to add to the evidence of possible links between epilepsy and autoimmunity (3). Such links have previously not only been suggested for conditions associated with neuronal autoantibodies but also for systemic autoimmune disorders (4).

In order to reach their conclusions, Børsheim et al. initially identified all individuals with epilepsy in their country by crossreferencing everyone who had received at least two antiepileptic drug prescriptions during the 10 data capture period with all those for whom a reimbursement code for epilepsy had been used. This process yielded almost 80,000 people with (probable) epilepsy (PWE) who were compared to a population of 4.7 million people likely not to have epilepsy. Børsheim et al. then identified individuals with a wide range of conditions thought of as immune mediated (including type 1 diabetes mellitus, multiple sclerosis (MS), myasthenia gravis and hypothyroidism) by searching for all those who had received medications for these disorders (for instance insulin and insulin analogues but no oral antihyperglycaemic drugs). They found evidence of an association between epilepsy and autoimmunity across many of the indicators examined: PWE were almost twice as likely to be treated with insulin or insulin analogs, one and a half time as likely to receive thyroid hormones or pyridostigmine. Medications for MS were used almost five times as often in those with epilepsy as in the general population.

These findings add further weight to previous studies demonstrating an association of epilepsy and autoimmune disorders (4) – on both sides of the blood brain barrier, involving intra- and extracellular immune targets, cellular and humoral autoimmune processes. However, they do not prove the direction of the association. While the authors provide a number of arguments why autoimmune disorder may make the development of epilepsy more likely, there are also a number of mechanisms (including immunogenic effects of seizures and side effects of antiepileptic drugs), which could mediate a bidirectional relationship between the epilepsies and the many interacting parts of the immune system. Last but not least, the chances of receiving treatment for epilepsy may be increased in those under medical care with autoimmune disorders and vice versa. Regardless of the direction of the relationship, this association autoimmune disorders could explain one part of the increased mortality as well as psychiatric morbidity associated with epilepsy.

References:

1) Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017;58:512-21.

2) Bakpa O D, Reuber M, Irani S R. Antibody-associated epilepsies: Clinical features, evidence for immunotherapies and future research questions. Seizure 2016;41,26-41.

3) Børsheim A, Engeland A, Gilhus NE. Epilepsy and autoimmune diseases: comorbidity in a national patient cohort. Seizure 2020; 75…. Please complete bibliographic details.

4) Devinsky O, Schein A, Najjar S. Epilepsy associated with systemic autoimmune_ disorders. Epilepsy Curr 2013;13:62–68.

Seizure 2020, Vol 74, Editor’s Choice: “Socioeconomic outcome and access to care in adults with epilepsy in Sweden: a nationwide cohort study”

The link between higher socioeconomic status and better health is beyond any doubt. The many strands of evidence which support this link have recently been summarized in a document produced by the British Medical Association (1): In the United Kingdom (UK), a high income country with free access to healthcare for all citizens, life expectancy in the most deprived areas is 7 to 8 years lower for men, and 4 to 6 years lower for women, than in the least deprived areas. Wealth-related differences in health status are detectable before birth: birth weight, a recognized marker of subsequent cognitive development, is, on average, 200 grams lower in babies born in the poorest areas in the UK than in those born in the most affluent areas. Babies living in poverty are more likely to die within their first year of life. In the mothers, poverty increases the risk of postnatal depression and is associated with lower rates of breastfeeding. Children born into poverty are more likely to develop a range of chronic diseases as well as diet-related problems; in their first year of school, children living in the most deprived areas are twice as likely to be obese than children living in the least deprived areas (12.5% versus 5.5%). Poor children also have higher rates of fatal and non-fatal accidents, their risk of dying from unintentional injury is 13 times greater. A link with poverty even exists for genetic conditions such as cystic fibrosis, and poorer children experience worse growth, poorer lung function, higher risk of infection. The pattern continues into adulthood where most long-term conditions have been found to be more common among lower socio-economic groups, including diabetes, chronic obstructive pulmonary disease, arthritis and hypertension. Two-fifths of adults in England aged 45 to 64 with below-average incomes have a limiting long-term illness. This is twice the rate of adults of the same age with above-average incomes. The risk of developing epilepsy is also much greater in poorer areas in the UK (2). Not surprisingly, similar findings have been reported from other countries. For instance one study from the USA found the prevalence of active epilepsy to be 1% across the country, but twice as high in low-income households (3).

My Editor’s Choice paper from the current volume of Seizure is an original research paper by Klara Andersson et al (4). Their cohort study data based on 126,406 adult patients with a diagnosis of epilepsy from the Swedish patient register and a control population of 379,131 adults without epilepsy confirmed that low income levels were associated with a higher risk of epilepsy and that people with epilepsy (PWE) had more somatic and psychiatric comorbidities and lower levels of education than controls. However, the findings of this study go beyond these well-known associations and shed additional light on some of the reasons for the poorer health outcomes observed in PWE of low socioeconomic status. For instance, the study demonstrates that – although the Swedish healthcare system aspires to offer the same free healthcare to all patients in need, regardless of their level of income – hospitalizations were more common among PWE from lower than higher income groups. Conversely, PWE in the high-income (and high education) groups were more likely to have received at least one medication prescription from a specialist in neurology in the five-year study period than those in the most disadvantaged groups. These findings mean that healthcare systems which are passively available to the whole population, but which do not reach out more actively to provide healthcare to patients in lower socioeconomic groups are unlikely to diminish health inequalities. In fact, even active healthcare outreach efforts are unlikely to level differences between socioeconomic groups in health outcomes and mortality without addressing differences in nutrition, housing, education and many other spheres of life from childhood onwards.

References:

1) British Medical Association, Board of Science. Health at a price – reducing the impact of poverty, a briefing from the Board of Science. British Medical Association, London, 2017.

2) Steer S, Pickrell WO, Kerr MP, et al. Epilepsy prevalence and socioeconomic deprivation in England. Epilepsia 2014;55:1634-1641.

3) Centers for Disease C, Prevention. Epilepsy in adults and access to care–United States, 2010. MMWR Morb Mortal Wkly Rep 2012;61:909-913.

4) Andersson K, Ozanne A, Edelvik A, Chaplin J,
Malmgren K, Zelano J. Socioeconomic outcome and access to care in adults with epilepsy in Sweden: a nationwide cohort study. Seizure 2020; 74:71-76

Seizure 2019, Vol 73, Editor’s Choice: “The Role of Electroencephalography in the Early Diagnosis of Non-Convulsive Status Epilepticus in Elderly Patients with Acute Confusional State: Two Possible Strategies?”

Those working near the “frontline” of emergency medicine in nations with an aging population will be acutely aware of the effects of the demographic changes on healthcare services. The United Kingdom is typical of many other countries facing similar demographic challenges. Between 2015 and 2020 – a period of only five years, in which the general population is expected to rise by 3%, the numbers of those aged over 65 are expected to increase by 12% (1.1 million); the numbers aged over 85 by 18% (300,000); and the number of centenarians by 40% (7,000) (1). One of the commonest emergency presentations of older adults is an acute confusional state. Unfortunately, the differential diagnosis of this clinical presentation is extremely wide – ranging from general medical disorders (including urinary tract and chest infections, metabolic disorders, iatrogenic effects of drug treatments), psychiatric conditions (including delirium or psychosis) to neurological conditions such as stroke, neurodegenerative disorders, encephalopathy, traumatic brain injury, epileptic seizures or postictal states. 

Most of the medical and neurological disorders causing hospital admissions with acute confusion can be diagnosed easily with simple investigations such as blood tests, urine analysis or imaging studies which are requested as a matter of routine and without much thought. However, there is one common neurological condition, which cannot be diagnosed effortlessly in this way: nonconvulsive status epilepticus (NCSE) (2). The possible manifestations of NCSE are diverse: Most patients have selective rather than global cognitive deficits. Those involving consciousness, speech, praxis, memory, attention and affect are particularly prominent. Impairment of consciousness may be characterized by reduced vigilance, reactivity or orientation (3). With the limited exception of admissions to the few centres where emergency EEGs are readily available, this diagnosis can only be made if clinicians think about it – and make the considerable effort to arrange an EEG recording (often requiring transfer to another hospital). However, it is possible that many – perhaps most cases currently remain undiagnosed. 

Unfortunately, as Francesco Manfredonia et al, in my editor’s choice from the current issue of Seizure demonstrate, there is no easy way to optimize the diagnosis of NCSE (4). Abbreviated EEG procedures or recordings with a limited number of electrodes improve the feasibility of capturing EEG from a confused patient in an emergency setting but have a diagnostic yield, which may be well below 50%. The test of choice is also the least practicable: continuous EEG recording. Simpler solutions are urgently needed. Unfortunately – the fact that the diagnosis is likely to be routinely missed means that the urgency of the problem remains unnoticed – out of sight out of mind.

References:

1)https://www.parliament.uk/business/publications/research/key-issues-parliament-2015/social-change/ageing-population/, accessed 17 November 2019.

2) Beyenburg S, Elger CE, Reuber M. Acute Confusion or Altered Mental State: Consider Nonconvulsive Status Epilepticus. Gerontology. 2007;53(6),150-58.

3) Profitlich T, Hoppe C, Reuber M, Helmstaedter C, Bauer J. Ictal neuropsychological findings in focal nonconvulsive status epilepticus. Epilepsy Behav 2008;12,269-75.

4) Manfredonia F, Saturno E, Lawley A, Gasverde S, Cavanna AE. The role of encephalography in the early diagnosis of nonconvulsive status epilepticus in elderly patients with acute confusional state: two possible strategies? Seizure 2019; 73…. Please complete bibliographic details.

Seizure 2019, Vol 72, Editor’s Choice: “Risks and Management of Antiepileptic Drug-Induced Skin Reactions in the Adult Out-Patient Setting”

Although seizures and epileptic discharges in the brain are the cornerstones of the definition of epilepsy, the lived experience of the condition very much encompasses epilepsy-associated cognitive, emotional and social problems as well as the unwanted effects of the treatments offered for the disorder. In fact, in individuals whose epileptic seizures cannot be stopped completely with drugs or other medical interventions, health related quality of life (HRQoL) is affected more strongly by psychological variables and the side effects of antiseizure medicines (ASMs) than by the frequency or severity of their seizures (1). While side effects affecting cognition/ coordination or mood/emotion are more frequent (and more closely associated with reduced quality of life) previous research has demonstrated a clear negative correlation between HRQoL and unwanted effects of ASMs on skin or mucosa (r = 0.42, p = 0.01) (2).  What is more, in routine clinical practice, ASM-related skin reactions are particularly likely to lead to the discontinuation of potentially effective medicines. 

My Editor’s Choice paper from the current issue of Seizure, is a narrative review by Dora Lozsadi, Amolak Bansal and Thomas Fowler which summarises the evidence on the nature, frequency and optimal management of skin reactions associated with ASMs (3). About one in thirty of all individuals with epilepsy will experience such a drug reaction, but skin reactions are considerably more common in those taking aromatic ASMs (especially carbamazepine, oxcarbazepine, eslicarbazepine, phenytoin, lamotrigine, phenobarbitone and primidone) or sulphonamide-type drugs (especially zonisamide).

The typical management of unwanted skin reaction involves the discontinuation of the antiepileptic drug and recording of an “allergy” to the drug in question. The review by Loszsadi et al. suggests that this is not always necessary and may stop patients from using medication they may well have benefited from. Lozsadi et al argue that severe cutaneous drug reaction (such as Stevens Johnson Syndrome) are relatively rare and that many patients could tolerate treatments that have been associated with skin reaction if their particular skin rash is assessed carefully and the drug re-introduced very slowly. Their review provides a pragmatic management pathway for patients presenting with a suspected drug-induced rash. It includes suggestions for pretreatment screening and assessment of potentially drug-associated rashes and associated symptoms to aid the early identification of patients at risk of severe allergic reactions. 

References:

1) Suurmeijer TPBM, Reuvekamp MF, Aldenkamp BP. Social functioning, psychological functioning, and quality of life in epilepsy. Epilepsia 2001;42:1160-68.  

2) Perucca P, Carter J, Vahle V, Gilliam FG. Adverse antiepileptic drug effects Toward a clinically and neurobiologically relevant taxonomy. Neurology 2009; 72:1223–1229.3) Lozsadi D, Bansal A and Fowler T. Risks and management of antiepileptic drug induced skin reactions in the adult out-patient setting. Seizure 2019; 72:61-70

Seizure 2019, Vol 71, Editor’s Choice: “Supporting and empowering people with epilepsy: Contribution of the Epilepsy Specialist Nurses (SENsE study)”

It is now well-established that epilepsy is much more than seizures. At least in temporal and epidemiological terms there is a clear bidirectional relationship between epilepsy and mental health problems including depression, anxiety and suicidality – and it is highly plausible that there is a causal bidirectional relationship between these problems as well (1). Aside from this, epilepsy is a social disorder. Indeed, the social consequences of having epilepsy exceed the medical impact of the condition for most people living with seizures (2). Furthermore, epilepsy and its treatment have many implications for people’s lives – affecting important personal matters such as family planning and employment opportunities but also more mundane issues such how to cook, clean themselves or look after their young children.

Despite the recognition of the broad impact of epilepsy on the lives of those affected, epilepsy services (even or perhaps especially in high income countries) struggle to provide support with the non-seizure manifestations of epilepsy. Neurologists or psychiatrists (the professionals who most commonly diagnose epilepsy and oversee its pharmacological treatment) may screen for mental health symptoms but rarely offer meaningful advice on the social consequences of epilepsy or any practical questions their patients have to deal with because of their epilepsy, and patients may not consider it appropriate to ask a doctor about these matters. Non-epilepsy experts (for instance in primary care or non-medical professions such as social work) may feel that they lack the knowledge to offer advice on questions related to epilepsy. This leaves many people with epilepsy to their own devices and means that they do not have access to high quality individualized advice about epilepsy-related questions, which may well affect their quality of life more than the seizures themselves.

My editor’s choice paper from the current volume of Seizure is a study by Agnes Higgins et al. describing and assessing the role of epilepsy nurse specialists (ENSs) (3). Of course, ENSs know a lot about seizures, but they are also ideally placed to fill the gaps in service provisions for non-seizure manifestations of epilepsy, which exist in many medically dominated epilepsy services. This qualitative study based on data from 12 ENSs, 24 multidisciplinary team members as well as 35 people with epilepsy and their family members captured working practices across five Irish epilepsy services. The findings indicate how crucial the support is which ESNs provide in terms of empowering people to self-manage their illness, performing comprehensive needs’ assessments, providing person-centred education, monitoring the impact of care and treatment, providing education to significant others and psychosocial care to optimise psychological wellness, co-ordinating care and quality assuring patient information. However the findings also show that, in order to function ESNs need to be embedded in and complemented by a multidisciplinary team. ESNs enhance medically oriented services they do not replace them. As such, this paper makes a useful addition to the evidence-base for ESN services, which has recently been summarized by the ESPENTE team (4). My editor’s choice paper should be read in the context of all the other evidence underlining the importance of ESNs for comprehensive epilepsy services. This evidence has recently been compiled and beautifully presented by the ESPENTE collaborators in a freely available interactive evidence map (do take a look at: https://espente.epilepsy.org.uk/).
References:

1. Hesdorffer DC, Ishihara L, Mynepalli L, Webb DJ, Weil J, Hauser WA. Epilepsy, suicidality, and psychiatric disorders: a bidirectional association. Ann Neurology 2012;72:184-91
2. Jacoby A, Snape D, Baker G. Epilepsy and social identity: the stigma of a chronic disorder. Lancet Neurology 2005;4:171-78.
3. Higgins A, Downes C, Varley J, Doherty C, Begley, Elliott N. Supporting and empowering people with epilepsy: Contribution of the Epilepsy Specialist Nurses (SENsE study). Seizure 2019:71:42-49.

Campbell F, Sworn K, Booth A, Reuber M, Grünewald R, Mack C, Dickson JM. Epilepsy Specialist Nurses The Evidence (ESPENTE): a Systematic Mapping Review. https://www.epilepsy.org.uk/sites/epilepsy/files/research/The%20ESPENTE%20Study%208.7.19%20Version%201.pdf, accessed 14 September 2019.

Seizure 2019, Vol 70, Editor’s Choice: “Valproate Utilisation Trends Among Women and Girls from 2013 to 2018.”

It has been recognized for several decades that the use of antiepileptic drugs during pregnancy can harm foetal development. Several antiepileptic drugs (AEDs) have been linked to diverse major congenital malformations including cardiac abnormalities, spina bifida and other skeletal abnormalities. In addition, over the last fifteen years, it has become increasingly clear that exposure to AEDs in utero can have a detrimental effect on the intellectual development of babies born to mothers with epilepsy (1). Valproate, one of the most widely used antiepileptic drugs, has been shown to put babies at particularly high risk of suboptimal cognitive development. Early reports of adverse effects on verbal IQ have been confirmed by further studies and meta-analyses (2-3). It is now clear that children exposed to valproate in the womb have a lower IQ than those born to untreated women with epilepsy, or those exposed to carbamazepine, lamotrigine, levetiracetam, topiramate or phenytoin in pregnancy. Valproate has been shown to affect cognitive development in terms of attention, memory, executive functioning, adaptive behavior, social skills and motor functions. Increased rates of developmental disorders including autistic spectrum disorders have been reported (1).

My editor’s choice article from the current volume of Seizure, an interrupted time series analysis of valproate prescriptions issued by the public health service in Lithuania by Kristijonas Puteikis, Irma Medziausaite and Ruta Mamensikiene, shows how these scientific discoveries and the regulatory responses which they prompted have led to change in the use of an antiepileptic drug, which continues to be the most effective drug for genetic generalized epilepsies (4).

We learn that valproate use began to decline gradually in women and girls even before the first interventions from European regulators in 2013. The first intervention by regulators in 2013/14 did not significantly accelerate the overall trend – except in girls below the age of 15 – a relevant group, but arguably not the most important target population. In contrast the regulatory tightening of the valproate prescription procedures in 2017/18 had a much more dramatic effect on the use of valproate in female patients of all age groups.

The fact that the drop in valproate prescriptions to women above the age of fifty was as great as that in younger women suggests indicates that the new prescription guidelines may be a fairly blunt tool. Perhaps the guidelines have caused clinicians to review the prescription or continuation of inappropriate medication. However, it is also possible that women who are not at risk of having children who could be harmed by valproate exposure are now inappropriately deprived of a highly effective antiepileptic drug.

References:

1) Bromley RL and Baker G. Fetal antiepileptic drug exposure and cognitive outcomes. Seizure 2017;44:225-231.

2) Adab N, Kini U, Vinten J, Ayres J, Baker G, Clayton-Smith J, et al. The longer term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2004;75: 1575-83

3) Bromley R, Weston J, Adab N, Greenhalgh J, Sanniti A, McKay AJ, et al. Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child. Cochrane Database Syst Rev 2014;10:Cd0102364) Puteikis K, Medziausaite I, Mamensikiene R. Valproate untilisation trends among girls and women from 2013 to 2018. Seizure 2019; 70: 77-81.

Seizure 2019, Vol 69, Editor’s Choice: “The Efficacy of a Pharmacist-Implemented Educational Treatment Programme for People with Epilepsy: A Report of a Randomised Controlled Trial.”

Unhelpful and factually erroneous ideas about epilepsy are common around the world and not exclusively a problem encountered in Lower and Middle Income Countries (LaMICs). Stigma continues to affect the opportunities and life chances of individuals with epilepsy in all countries, and superstitions about epilepsy survive even in High Income Countries (HICs) where the persistence of such inaccurate and negative beliefs cannot readily be blamed on lack of access to educational opportunities (1, 2).

In 2015 the World Health Assembly (WHA) recognized this continuing global problem when it adopted a resolution on epilepsy, WHA68.20, which urges coordination of action at country level to address the health, social and public knowledge implications of this disease. This resolution should be a powerful tool, directing countries to implement improvements to medical and social services for people living with epilepsy, and to promote public awareness about epilepsy. A Global Information Kit on Epilepsy has been developed to support the implementation of WHA68.20 recommendations showing how myths like “epilepsy is contagious”, “epilepsy is a punishment or caused by spirit possession”, “people with epilepsy should not work” or “people with epilepsy should not get married” can be tackled (3).

While such documents are important to shape global awareness, policy and funding priorities, the implementation of any programme will have to take account of local social and cultural factors as well as medical and educational resources. To this end I am pleased to select a randomized controlled trial by Unyime Eshiet, Matthew Okonta and Chinwe Ukwe as my Editor’s Choice from the current volume of Seizure (4). They adapted the MOSES educational progamme for people with epilepsy, originally developed in Germany (5), for their local Nigerian context and used pharmacists as a locally available resource to deliver the intervention. In their intervention group they tied one-to-one educational sessions with a pharmacist to regular appointments with the medical epilepsy care provider. They were able to show that knowledge of epilepsy increased over six months in the intervention group and that, at the end of the intervention, those who had received the additional education from the pharmacist had more accurate perceptions of epilepsy.

Given that those living with epilepsy are likely to be most affected by poorly informed ideas about the disease, it makes sense that they were the primary target of the intervention. More work will be required to develop similar programmes at even lower cost, for other sociocultural settings and other target groups, including teachers, employers, political and religious leaders and, indeed, the population in general.

References:

1) Jacoby A, Snape D, Baker,G. Epilepsy and social identity: the stigma of a chronic disorder. Lancet Neurology. 2005;4,171-78.

2) Prus N, Grant AC. Patient beliefs about epilepsy and brain surgery in a multicultural urban population. Epilepsy Behav. 2010;17(1):46–49.

3) https://www.who.int/mental_health/neurology/epilepsy/epilepsy_global_toolkit.pdf 

4) Eshiet U, Okonta M, Ukwe C. The Efficacy of a Pharmacist-Implemented Educational Treatment Programme for People with Epilepsy: A Report of a Randomised Controlled Trial. Seizure 2019; 69, 147-153. 

5) Ried S, Specht U, Thorbecke R, Goecke K, and Wohlfa R. (2001). MOSES: An

Educational Program for Patients with Epilepsy and Their Relatives. Epilepsia,

42(Suppl. 3):76–80, 2001. Blackwell Science, Inc.

Seizure 2019, Vol 68, Editor`s choice: “Timing in the treatment of status epilepticus: from basics to the clinic”

Over the last three decades many neurologists will have gained first hand experience of how the treatment of a neurological emergency can change completely: the management of suspected stroke has metamorphosed from tucking people up in bed with an aspirin to an investigation and treatment pathway bearing closer resembling to the Formula One pit lane than the management which was still established practice one generation ago.

Although the detrimental effects of delaying the treatment of convulsive status epilepticus (CSE) have been recognized for much longer than thirty years, and despite the fact that effective treatments for most presentations with status epilepticus have been available throughout this period, improvements in the actual clinical management of CSE have been much more sporadic. The lack of focus on CSE cannot be related to the rarity of the condition: with an incidence of 6.8–41/100.000 per year, status epilepticus (SE) is one of the commonest neurological emergencies, especially among children where the incidence is 135–156/100 000 per year (1). The relatively low investment in service improvements is also not explained by the benign nature of the condition: while mortality from SE is lower in children than in adults, it is still high at 3-9% within 30 days and 7% in the long-term (1). Delayed treatment is also associated with greater morbidity and long-term care costs (2, 3).

It can only be hoped that the current Special Issue of Seizure “Paediatric Status Epilepticus” offering a collection of comprehensive review articles will help clinicians and patient representatives to attract more attention to the question how the gap between the clear evidence for rapid and adequate treatment of SE and the actual provision of this treatment can be closed. My editor’s choice from this issue of Seizure, a narrative expert review by Marina Gaínza-Lein et al. summarizes the arguments for service improvements most clearly by demonstrating how changes in the composition and localization of GABA-A and NMDA-receptors can render interventions much less effective if they are not administered in a timely manner (4).

References:

1) Chin, R.F., B.G. Neville, and R.C. Scott, A systematic review of the epidemiology of status epilepticus. Eur J Neurol, 2004. 11(12): p. 800-10.

2) Raspall-Chaure, M., et al., Outcome of paediatric convulsive status epilepticus: a systematic review. Lancet Neurol, 2006. 5(9): p. 769-79.

3) Penberthy, L.T., et al., Estimating the economic burden of status epilepticus to the health care system. Seizure, 2005. 14(1): p. 46-51.

4) Gaínza-Lein, M., Sánchez Fernández, I., Ulate-Campos, A., Loddenkemper, T., Ostendorf A. Timing in the Treatment of Status Epilepticus: From Basics to the Clinic. Seizure 2019. 68: p. 22-30. 

Seizure 2019, Vol 67, Editor’s Choice:  “Comparing long-term outcomes of epilepsy patients from a single-visit outreach clinic with a conventional epilepsy clinic: A cross-sectional observational study from India”

Health educators often highlight the message that epilepsy is a disease that can affect anyone around the world. This message may be communicated with the best of intentions – for instance in the hope that it will reduce the significant stigma associated with epilepsy – a problem which can be more disabling than the seizures themselves (1). However, what this message fails to highlight is that epilepsy is not evenly distributed among the rich and the poor – neither globally nor in individual countries. Of the 60 million people with epilepsy worldwide, 80% live in lower or middle income countries (LMICs). Although two thirds of all presentations of epilepsy should be “controllable” with optimal antiepileptic drugs treatment, almost three quarters of individuals living in rural regions of LMICs receive inadequate or no antiepileptic drug treatment at all (2).

In the face of the social, economic and medical challenges reflected by these basic facts, many of the scientific debates about the relative pros and cons of one advanced epilepsy treatment over another that are conducted in scientific journals like Seizure seem somewhat less relevant. Of course, progress at the cutting edge of medical science is still urgently needed and should not be disparaged. However, we must not lose sight of problems like the massive epilepsy treatment gap (the difference between those with a diagnosis of epilepsy and those receiving treatment for it) – especially as means of tackling some of these problems are within our grasp.

My Editor’s Choice from the current issue of Seizure is an article by Chintan Prajapati et al. describing one low cost means of reducing the treatment gap (3). In their article, the authors describe the outcome of single therapeutic encounters between individuals with epilepsy living in rural districts of India and clinicians making diagnoses and providing treatment advice in epilepsy outpatient clinics on the “Lifeline Express” (LLE). The LLE is a train service run by the Impact India Foundation, an Indian non-governmental organisation, which takes medical specialists to the most inaccessible Indian communities (4). This service does not just deal with epilepsy but with a wide range of medical disorders. One thing it cannot offer is regular follow-up. The vast majority of the patients seen will only receive treatment advice on one occasion, and then have to find ways of following this advice without further support from the experts they have met on the LLE. The study shows that, in comparison with patients with epilepsy seen (and followed up) by some of the LLE doctors at AIIMS, a national specialist neurology centre in New Delhi, the outcome of those who received advice on the LLE is worse: at least two years after the initial contact 72% of the LLE versus 87% of the AIIMS patients were still taking antiepileptic drugs, 22% versus 6% had discontinued medication against medical advice and 7.5% versus 2.8% had died. However, more importantly, the single contact with an expert on the LLE had reduced the epilepsy treatment gap from 49% at first contact to 22% at follow up. Of course there is so much more to do – but facilitating a single contact with an epilepsy expert may be a good way to start!

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References:

1) Jacoby A, Snape D, Baker G. Epilepsy and social identity: the stigma of a chronic disorder. Lancet Neurology. 2005;4,171-78.

2) Espinosa-Jovel C, Toledano R, Aledo-Serrano Á, García-Morales I, Gil-Nagel
A. Epidemiological profile of epilepsy in low income populations. Seizure
2018; 56: 67–72.

3) Prajapati C, Bhushan Singh M, Padma Srivastava MV, Sreenivas V,
Goyal V, Shukla G, Vishnu VY, Gursahani R, Patterson V,
Bajpai S, Jain P. Comparing long-term outcomes of epilepsy patients from a single-visit outreach clinic with a conventional epilepsy clinic: A cross-sectional observational study from India. Seizure 2019; 67: 5-104) Impact India Foundation – NGO in India: An International Initiative Against
Avoidable Disablement. Available from: https://www.impactindia.org/lifelineexpress.
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