epilepsia

1. Comment
782 www.thelancet.com/neurology Vol 15 July 2016
sites. This collaboration is an important advance
towards consolidating viable markers and tools from
translational neuroscience to develop diagnostic
and prognostic applications. To bring benefits of this
research to patients and their carers and families, these
markers will need to be validated in prospective clinical
studies.
Although careful behavioural assessment by trained
experts remains the accepted gold standard to assess
patients with disorders of consciousness,11
findings from
fMRI12
and EEG9,10
studies show characteristic differences
in resting brain activity between unresponsive
wakefulness syndrome, minimally conscious state,
and normal consciousness. However, definitive neural
signatures of the potential for, and recovery of, normal
consciousness after brain injury areyet to be conclusively
identified. Di Perri and colleagues take us a bit further,
and are to be complimented on gathering the large
cohorts of patients and the outstanding methodological
expertise that enabled the generation of these results.
However, we need to find ways in which these methods
can be implemented routinely in any clinical context,
and for decision support in individual patients.
Srivas Chennu, Emmanuel A Stamatakis, *David K Menon
Division of Neurosurgery (SC) and Division of Anaesthesia (EAS,
DKM), University of Cambridge, Cambridge Biomedical Campus,
Cambridge CB2 0QQ, UK
dkm13@cam.ac.uk
The help of biomarkers in the prevention of epilepsy
The lifetime risk of epilepsy is 2%, but the risk of a single
seizure is as high as 10%.1
The mechanisms pertinent
to the development of epilepsy, or progression after
the disease is established, both of which are subsumed
under the term epileptogenesis, are not known. Despite
findings from over 30 preclinical proof-of-concept
studies showing antiepileptogenic effects of various
treatments, none has translated into clinical trials, and
none of the more than 20 available antiepileptic drugs
prevents, modifies, or cures epilepsy.
In The Lancet Neurology, Asla Pitkänen and colleagues2
comprehensively summarise attempts to develop
biomarkers for epileptogenesis that can be used to
reliably identify the presence, severity, progression, or
localisation of an epileptogenic abnormality. From a
clinician’s standpoint, probably the best, if not only,
biomarker in epilepsy is a seizure, which, according to the
International League Against Epilepsy classification,3
can
be diagnostic after the first occurrence. However, seizures
are akin to a raised temperature—they are the symptom
of myriad different diseases. Neither self-reported nor
observed seizures are reliable biomarkers of disease
activity4
but, otherthan seizure frequency, we do not have
an independent measure of disease severity for epilepsy.
Rather than waiting for the next seizure to occur, we need
biomarkers that can be used to substitute for a clinically
meaningful endpoint that is a direct measure of how a
patient feels and functions and that can predict the effect
We declare no competing interests.We are supported by funding fromtheUK
National Institute for Health Research (NIHR), as part oftheAcute Brain Injury and
RepairTheme oftheCambridge Biomedical ResearchCentre, and a grant fromthe
James S McDonnell Foundation. DKM is supported by an NIHR Senior Investigator
award. SC is funded by a grant fromthe EvelynTrust (Cambridge,UK).
1 Di Perri C, Bahri MA, Amico E, et al. Neural correlates of consciousness in
patients who have emerged from minimally conscious state:
a cross-sectional multimodal imaging study. Lancet Neurol 2016; published
online April 27. http://dx.doi.org/10.1016/S1474-4422(16)00111-3.
2 Vanhaudenhuyse A, Demertzi A, Schabus M, et al.Two distinct neuronal
networks mediate the awareness of environment and of self.
J Cogn Neurosci 2010; 23: 570–78.
3 Stender J, Gosseries O, Bruno M-A, et al. Diagnostic precision of PET
imaging and functional MRI in disorders of consciousness: a clinical
validation study. Lancet 2014; 384: 514–22.
4 Baars BJ.The conscious access hypothesis: origins and recent evidence.
Trends Cogn Sci 2002; 6: 47–52.
5 Dehaene S, Changeux J-P. Experimental and theoretical approaches to
conscious processing. Neuron 2011; 70: 200–27.
6 Vatansever D, Menon DK, Manktelow AE, Sahakian BJ, Stamatakis EA.
Default mode dynamics for global functional integration. J Neurosci 2015;
35: 15254–62.
7 Williams ST, Conte MM, Goldfine AM, et al. Common resting brain
dynamics indicate a possible mechanism underlying zolpidem response in
severe brain injury. eLife 2013; 2: e01157.
8 Thibaut A, Bruno MA, Ledoux D, Demertzi A, Laureys S. tDCS in patients
with disorders of consciousness: sham-controlled randomized
double-blind study. Neurology 2014; 82: 1112–18.
9 Chennu S, Finoia P, Kamau E, et al. Spectral signatures of reorganised brain
networks in disorders of consciousness. PLoS Comput Biol 2014;
10: e1003887.
10 Sitt JD, King JR, El Karoui I, et al. Large scale screening of neural signatures
of consciousness in patients in a vegetative or minimally conscious state.
Brain 2014; 137: 2258–70.
11 Turner-Stokes L. Prolonged disorders of consciousness: new national
clinical guidelines from the Royal College of Physicians, London. Clin Med
2014; 14: 4–5.
12 Demertzi A, Antonopoulos G, Heine L, et al. Intrinsic functional
connectivity differentiates minimally conscious from unresponsive
patients. Brain 2015; 138: 2619–31.
See Review page 843

2. Comment
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of treatment. The available biomarkers and proposed
developments in epilepsy fall shortofthistarget.
Why has the specialty been unable to translate any
of the advances made in genetic, electrophysiological,
and structural markers into clinically useful biomarkers?
There is no shortage of biomarkers, but none have
been validated in appropriate animal models or clinical
studies for many reasons. First, post-traumatic epilepsy
is rare—no more than 15% of patients in the highest risk
group will develop epilepsy after 20 years,5
compared
with up to 100% of animals in standard models and
with proportionally more rapid timeframes. Second, in
animal models, experiments are often done only in one
sex in a specific breed of animal, so that only the process
of interest is manipulated and most other experimental
variables are controlled. Third, potential epileptogenesis
biomarkers have been validated retrospectively and
almost exclusively in patients with refractory epilepsy.
Patients with drug-sensitive disease are rarely included,6
and no evidence exists that even promising markers,
such as pathological high-frequency oscillations, have
any validity as excitability biomarkers in at-risk patients.
Fourth, most biomarker studies are done in adults;
chronic epilepsy in adults is likelyto be a different disease,
with more comorbidities,than epilepsy in childhood.
Few prospective studies have tested the predictive
value of biomarkers longitudinally in either animal
models or in the clinical setting, because of the long
timescale between injury and first seizure and the
large number of participants or animals needed. This
circumstance creates is a vicious cycle; for these studies
to be successful, biomarkers are needed for stratification
of populations according to risk.
Inability to make progress in clinical trials is not
necessarily a result of the heterogeneity of the different
epilepsies or patient groups that are not well-defined,
but a result of the misinterpretation of statistical
significance for clinical importance. A genetic finding
might be significant, but does, for example, an odds
ratio of 1·42 suggesting SCN1A involvement in
temporal lobe epilepsy carry any clinical importance for
the attempt to quantify the risk of developing epilepsy
after febrile seizures?7
Pitkänen and colleagues2
rightly
conclude that none of the genetic association studies
have been replicated and none of the gene variations,
even for SCN1A, are of proven value in the prediction of
risk or treatment response in epilepsy.
The core questions of personalised medicine—ie,
who, when, and how to treat—is best exemplified in the
discussionof inflammatory processes,which are involved
both in recovery from injury and in the development
of hyperexcitable networks. A major challenge is to
find biomarkers that would allow identification of
patient populations who might benefit, at a particular
stage from anti-inflammatory or immunomodulatory
treatments, and avoid harm by intervening with
inflammatory-driven repair mechanisms.
Many mechanisms occurring simultaneously
or sequentially can lead to the development of
abnormal brain circuitry and networks, and ultimately
result clinically in the common manifestation of a
seizure. What are the chances that the assessment
of a single mechanism, or biomarker, could provide
meaningful results? New approaches in both basic
and clinical science are needed to advance epilepsy
research. Lessons can be learned from oncology.
Pitkänen and colleagues2
emphasise the need for
large datasets, generated by collaborative research,
together with novel analysis platforms, and suggest
that the use of combinatorial biomarkers is superior
to a single biomarker. In fact, a drug cocktail was able
to irreversibly terminate pilocarpine-induced status
epilepticus and modify disease outcome in such a
way that only a subpopulation of animals with status
epilepticus developed epilepsy.8
Alternatively, prospective trials could be done using
change in the putative biomarker itself as an outcome
measure, rather than waiting for the seizure to occur.
Lessons can also be learned from findings of the
Alzheimer’s Disease Neuroimaging Initiative,9
which is
advancing knowledge about the early preclinical stages
of Alzheimer’s disease. Similar to neurodegeneration in
Alzheimer’s disease, once an epilepsy diagnosis has been
made—ie, the first seizure has occurred after a trauma—
the processes leading up to recurrent seizures are
difficult to modify or reverse. Our challenge is to define
the timepoint during epileptogenesis after which it is
too late to prevent the first seizure.
Matthias J Koepp
Department of Clinical and Experimental Epilepsy, UCL Institute of
Neurology, LondonWC1N 3BG, UK
m.koepp@ucl.ac.uk
I declare no competing interests.

3. Comment
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1 Berg AT, Shinnar S.The risk of seizure recurrence following a first
unprovoked seizure: a quantitative review. Neurology 1991; 41: 965–72.
2 Pitkänen A, LöscherW,Vezzani A, et al. Advances in the development of
biomarkers for epilepsy. Lancet Neurol 2016; 15: 843–56.
3 Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical
clinical definition of epilepsy. Epilepsia 2014; 55: 475–82.
4 Cook MJ,O’BrienTJ, Berkovic SF, et al. Prediction of seizure likelihood with a
long-term, implanted seizure advisory system in patients with drug-resistant
epilepsy: a first-in-man study. Lancet Neurol 2013; 12: 563–71.
5 Annegers JF, HauserWA, Coan SP, RoccaWA. A population-based study of
seizures after traumatic brain injuries. N Engl J Med 1998; 338: 20–24.
6 Feldmann M, Asselin MC, Liu J, et al. P-glycoprotein expression and
function in patients with temporal lobe epilepsy: a case-control study.
Lancet Neurol 2013; 12: 777–85.
7 Kasperaviciute D, Catarino CB, Matarin M, et al. Epilepsy, hippocampal
sclerosis and febrile seizures linked by common genetic variation around
SCN1A. Brain 2013; 136: 3140–50.
8 Brandt C,Tollner K, Klee R, Broer S, LoscherW. Effective termination of
status epilepticus by rational polypharmacy in the lithium-pilocarpine
model in rats: window of opportunity to prevent epilepsy and prediction of
epilepsy by biomarkers. Neurobiol Dis 2015; 75: 78–90.
9 Mueller SG,Weiner MW,Thal LJ, et al.Ways toward an early diagnosis in
Alzheimer’s disease: the Alzheimer’s Disease Neuroimaging Initiative
(ADNI). Alzheimers Dement 2005; 1: 55–66.
Standardisation of research strategies in acute ischaemic
stroke
Neuroprotective therapeutics for acute ischaemic
stroke have been of great interest for researchers and
clinicians alike. Despite several decades of focused
bench research, translational success into demonstrably
beneficial clinical treatment has eluded us. Nevertheless,
rather than lose faith in this potential, we must critically
evaluate the work, prioritising those aspects that have
the highest potential for success.
Ángel Chamorro and colleagues1
provide a timely
review of neuroprotection strategies that might be
applicable to the current stroke treatment framework.
Recent randomised trials established endovascular
thrombectomy as an additional standard-of-care
treatment, bolstering capacity to achieve early
reperfusion. Chamorro and colleagues’ Review notes
these updates and also makes the excellent point
that, while thrombectomy has tremendous benefits
and is currently underused, it is also not a panacea for
reversing ischaemia. In this setting, there remains
enormous opportunity for therapeutic intervention.
However, against this backdrop of advancement in
treatments is a history of poor translational realisation.
The authors correctly reference the volume of work
done to identify neuroprotective compounds and
translate them into therapies, with a common
theme of success of treatment in animals and failure
in human beings.2
They identify three key areas of
promising research: excitotoxicity, oxidative stress, and
inflammation. I support their conclusions that these
areas are logical, given the directional emphasis on early
and emergent intervention for acute ischaemic stroke.
However, to effectively translate potential compounds
of interest into therapeutics, several key points must be
understood. Therefore, to supplement Chamorro and
colleagues’ Review, I highlight some vital issues for the
translational stroke scientist.
One central issue in the translation of neuro-
protectants in stroke has been proper modelling of
the clinical disorder and proposed treatment. For
example, if a therapeutic drug is most likely to aid in
minimising reperfusion damage after thrombectomy,
then testing its efficacy in a photothrombotic model
of stroke does not inform that therapeutic potential.
Similarly, if a neuroprotectant acted by reducing stroke
when given as a pretreatment in an animal model
of occlusion, then designing a clinical trial to give a
proposed neuroprotectant 12 h after stroke onset is
not consistent. One (although not the only) excellent
example of this situation is represented in the history
of uric acid as a neuroprotectant. Preclinical modelling
in animals used an injected thrombus model with co-
administration of t-PA and uric acid.3
For translation
of therapeutic benefits into a clinical trial, uric acid
was co-administered with t-PA in patients with
ischaemic stroke. Although the URICO-ICTUS trial4
did
not show an overall difference in outcome with uric
acid administration, there was a clear beneficial effect
in women.5
This issue highlights the importance of
factors of heterogeneity in stroke, which have led to the
development of preclinical evaluation criteria.
By recognising issues of poor translation between
preclinical animal models and human beings, experts in
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