open access: Nature Reviews: Key Advances in Medicine

NEUROLOGY
Competing interests
The authors declare no competing interests.
1. Cordonnier, C. & van der Flier, W. M. Brain
microbleeds and Alzheimer’s disease: innocent
observation or key player? Brain 134, 335–344
(2011).
2. Henneman, W. J. et al. MRI biomarkers of
vascular damage and atrophy predicting
mortality in a memory clinic population. Stroke
40, 492–498 (2009).
3. Yates, P. A. et al. Cerebral microhemorrhage
and brain β‑amyloid in aging and Alzheimer
disease. Neurology 77, 48–54 (2011).
4. Goos, J. D. C. et al. Microbleeds relate to
altered amyloid‑β metabolism in Alzheimer
disease. Neurobiol. Aging http://dx.doi.org/
10.1016/j.neurobiolaging.2011.10.026.
EPILEPSY IN 2011
Insights into epilepsy treatments
and biomarkers
Fernando Cendes
Research published in 2011 identified important factors related to
serious adverse effects of antiepileptic drugs and sudden unexpected
death in epilepsy, along with a potential new treatment and a promising
marker of epileptogenesis. Further advances in these areas are urgently
needed to improve the lives of people with epilepsy.
Cendes, F. Nat. Rev. Neurol. 8, 70–71 (2012); published online 10 January 2012;
doi:10.1038/nrneurol.2011.223
Epilepsy affects people of all ages, is
highly prevalent, and can have a good
out come with appropriate anti epileptic
drugs (AEDs). However, seizures are
often refractory to clinical treatment, with
detrimental—and even life-threatening—
consequences. 1 Unpredictable events,
such as serious adverse effects of AEDs
and sudden unexpected death in epilepsy
(SUDEP), make this condition even harder
to manage. The fact that epilepsy still carries
a great stigma, with many people hiding
their condition, hinders public awareness
and, in addition, makes it more difficult for
the condition to be recog nized as a serious
public health problem, resulting in reduced
availability of research resources compared
with other common diseases. Despite such
obstacles, however, considerable advances
are being made on a number of fronts, as
illustrated by several key papers published
during 2011.
Sudden unexpected death is 20 times
more frequent in people with epilepsy
than in the general population, but the risk
factors identified for SUDEP have not been
consistent across the literature. A recent
study by Hesdorffer et al. has helped to identify
groups of people with epilepsy who are
5. Altmann–Schneider, I. et al. Cerebral
microbleeds are predictive of mortality in the
elderly. Stroke 42, 638–644 (2011).
6. Sperling, R. A. et al. Amyloid‑related imaging
abnormalities in amyloid‑modifying therapeutic
trials: recommendations from the Alzheimer’s
Association Research Roundtable Workgroup.
Alzheimers Dement. 7, 367–385 (2011).
7. Goos, J. D. C. et al. Clinical relevance of
improved microbleed detection by
susceptibility‑weighted magnetic resonance
imaging. Stroke 42, 1894–1900 (2011).
8. De Reuck, J. et al. Comparison of 7.0‑T T 2 *‑
magnetic resonance imaging of cerebral bleeds
in post‑mortem brain sections of Alzheimer
patients with their neuropathological
correlates. Cerebrovasc. Dis. 31, 511–517
(2011).
‘‘ The currently available AEDs
do not prevent or cure epilepsy,
and are merely antiseizure
medications
at particular risk of SUDEP. 2 In this pooled
analysis of four case–control studies, earlyonset
refractory symptomatic epilepsy, frequent
generalized tonic–clonic seizures, and
use of AED polytherapy were all found to
be significant risk factors for SUDEP. Such
studies are extremely important for drawing
attention to the need to achieve complete
seizure control in people with epilepsy.
The currently available AEDs do not
prevent or cure epilepsy, and are merely
antiseizure medications. This fact underscores
our lack of knowledge about the
exact mechanisms of seizure genesis and
modes of action of AEDs. In this context,
a paper by Jeon et al. 3 was another important
publication in 2011. The researchers
studied the effects of cell-free extract
derived from human adipose stem cells
(ASCs) on the acute and chronic phases of
the pilocarpine epilepsy model in mice. 4
’’
Pretreatment with the extract did not affect
seizure susceptibility to pilocarpine, but it
did reduce the number of EEG spikes in the
acute phase, and subsequently diminished
sponta neous recurrent seizures (SRS) in
the chronic epileptic stage. 3 Furthermore,
continuing treatment in the chronic epileptic
stage suppressed or inhibited SRS and
had a positive effect on animal behavioral
tests. In addition, animals treated with the
extract had less damage to blood–brain
barrier integrity than did untreated controls.
Interestingly, heat-treated ASC extract had
no beneficial effect, suggesting the importance
of cytosolic proteins in the positive
effects of this agent.
Studies have suggested that stem or
precursor cells may rescue degenerating
neurons by modulating the host environment
via a chaperone-like mechanism, or
by altering immune-like functions including
inflammatory responses. 5 Thus, some
cell-based therapies might rely more on a
‘bystander’ mechanism involving secretion
of soluble factors—such as cytokines
and chemokines—than on replacement of
damaged neurons by neurogenesis. 3 The
ASC extract used by Jeon et al. may act by
modulating inflammatory events during
epileptogenesis. 3
During 2011, important contributions
were also made to our understanding of
serious adverse effects of AEDs, including
risks of allergic reactions and teratogenesis.
6,7 Carbamazepine, one of the most
important AEDs, causes various forms of
hypersensitivity reaction, ranging from
maculopapular exanthema to severe
and potentially lethal conditions such as
Stevens–Johnson syndrome and toxic epidermal
necrolysis (SJS–TEN). In a key
publication, McCormack et al. 6 showed
that the presence of the HLA-A*3101
allele is associated with carbamazepineinduced
hypersensitivity reactions among
Europeans. The overall prevalence of carbamazepine
hypersensitivity is 5.0%; presence
of the HLA-A*3101 allele increased the
risk to 26.0%, whereas absence of the allele
reduced the risk to 3.8%. Another HLA
allele, HLA-B*1502, is strongly correlated
with carbamazepine-induced SJS–TEN in
Asian populations but not in Europeans. 8
Another serious adverse effect of AEDs is
the increased risk of malformations in the
offspring of women who use these medications
during pregnancy. Clear evidence is
available that some AEDs, such as valproic
acid, pose major risks of terato genesis, and
the perception is that some of the newer
AEDs, including lamotrigine, could be safer.
S62 | JANUARY 2012 www.nature.com/reviews