Scientific Commentaries
replication more effectively than cells from patients with LHON.
Collectively, these findings indicate that mitochondrial mass in-
creases in response to LHON mutations and large increases may
be protective in asymptomatic carriers. Presumably, the increased
amount of mitochondrial compensates for the defect of respiratory
chain complex I in the patients.
Although this excellent translational research study by Giordano
et al. (2014) strongly supports the notion that mitochondrial bio-
genesis is protective in LHON, proof of this concept will require
identification of the factor(s) responsible for activating mitochon-
drial proliferation and experimental manipulation of the biogenesis
factors in cells and animal models. If validated and extended,
these observations will have clinical diagnostic and therapeutic im-
plications, as noted by the authors. For example, they note that
levels of mitochondrial DNA in white blood cells of LHON muta-
tion carriers may prove to be a biomarker predictive of developing
blindness. Identification of the pathway responsible for mitochon-
drial DNA biogenesis will provide a pharmacological target to pre-
vent blindness in unaffected mutation carriers. Studies have
already demonstrated promising therapeutic effects of activating
mitochondrial biogenesis in mouse models of mitochondrial dis-
eases with defects of the respiratory chain (Wenz et al., 2008;
Viscomi et al., 2011). Remarkably, Giordano et al. have shown
that asymptomatic LHON mutation carriers may already be taking
advantage of enhancing mitochondrial mass to prevent blindness.
Michio Hirano, MD
Columbia University Medical Centre
New York, NY USA
E-mail: mh29@cumc.columbia.edu
doi:10.1093/brain/awu005
Syncope: how the EEG helps in understanding
clinical findings
Although it is now widely accepted that the key to accurate
diagnosis and risk stratification of syncope is a thoughtful
and scrupulous history, exactly what is meant by the history
remains unclear, and moving it from experts to front-line work-
ers has proven difficult. Partly this is because syncope is simply a
symptom, like fever, with a plethora of potential causes. Partly
as well this reflects the multitude of somewhat overlapping
symptoms and signs for the most common form, the ‘faint’ or
vasovagal syncope. There are several clinical features that are
known to be helpful in the differential diagnosis of loss of con-
sciousnesses, based on quantitative symptom studies. These for
example help distinguish epileptic convulsions and pseudosyn-
cope from syncope, but such studies were aimed at clinical de-
cision-making. They reported just the most highly significant
clinical points and do not help clinicians make sense of the
welter of symptoms that clinical experience suggests (Sheldon
Brain 2014: 137; 308–312 | 309
References
Barboni P, Carbonelli M, Savini G, Ramos Cdo V, Carta A, Berezovsky A,
et al. Natural history of Leber’s hereditary optic neuropathy: longitudinal
analysis of the retinal nerve fiber layer by optical coherence tomography.
Ophthalmology 2010; 117: 623–27.
DiMauro S, Schon EA. Mitochondrial disorders in the nervous system.
Annu Rev Neurosci 2008; 31: 91–123.
Giordano C, Iommarini L, Giordano L, Maresca A, Pisano A,
Valentino ML, et al. Efficient mitochondrial biogenesis drives incom-
plete penetrance in Leber’s hereditary optic neuropathy. Brain 2014;
137: 335–53.
Giordano C, Montopoli M, Perli E, Orlandi M, Fantin M, Ross-
Cisneros FN, et al. Oestrogens ameliorate mitochondrial dysfunction
in Leber’s hereditary optic neuropathy. Brain 2011; 134: 220–34.
Larsson NG, Andersen O, Holme E, Oldfors A, Wahlstrom J. Leber’s
hereditary optic neuropathy and complex I deficiency in muscle. Ann
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Leber TH. Ueber hereditäre und congenital-angelegte Sehnervenleiden.
Graefe’s Archiv Ophthalmol 1871; 17: 249–91.
Newman NJ. Hereditary optic neuropathies: from the mitochondria to
the optic nerve. Am J Ophthalmol 2005; 140: 517–23.
Viscomi C, Bottani E, Civiletto G, Cerutti R, Moggio M, Fagiolari G, et al.
In vivo correction of COX deficiency by activation of the AMPK/PGC-
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ation for the agency responsible for its unusual pattern of inheritance.
Brain 1970; 93: 121–32.
Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AMS, et al.
Mitochondrial DNA mutation associated with Leber’s hereditary optic
neuropathy. Science 1988; 242: 1427–30.
Wenz T, Diaz F, Spiegelman BM, Moraes CT. Activation of the PPAR/
PGC-1 alpha pathway prevents a bioenergetic deficit and effectively
improves a mitochondrial myopathy phenotype. Cell Metab 2008; 8:
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et al., 2002, 2006; Wieling et al., 2009; Tannemaat et al.,
2013).
In this issue of Brain, van Dijk et al. (2014) provide fascinating
and informative insights into why some symptoms cluster with
each other in patients with vasovagal syncope. The authors per-
formed detailed EEG and videometric analyses of 69 patients with
positive responses to head-up tilt table testing. The EEG provides
an objective marker of brain dysfunction during the cerebral
hypoperfusion that accompanies syncope. For nearly 60 years
investigators have described EEG patterns during provoked reflex
syncope (Gastaut and Fischer-Williams, 1957; Ammirati et al.,
1998; Sheldon et al., 1998; Martinez-Fernandez et al., 2008).
Two patterns have been described. A ‘slow-flat-slow’ pattern is
characterized by an initial slow phase in which delta waves appear
and wave amplitude increases, a sudden flattening of the EEG,
and a return to normal brain activity through a slow phase.
310 | Brain 2014: 137; 308–312
A ‘slow’ pattern consists only of an increasing and decreasing
slowing. The slow-flat-slow pattern was considered to be a sign
of more severe cerebral hypoperfusion and has been observed
more commonly in cardio-inhibitory syncope compared with the
other subtypes, and associated with the presence of convulsive
movements during syncope. However, with the exception of
small studies and the specific evaluation of convulsive-like move-
ments during syncope, few studies have investigated both EEG
patterns and signs and symptoms during syncope.
Van Dijk et al. (2014) describe signs and haemodynamic and
EEG changes using videometric data in 69 cases of tilt-induced
vasovagal syncope. Their results confirm that EEG flattening is a
sign of more severe cerebral hypoperfusion than EEG slowing
alone. Indeed, patients with the slow-flat-slow EEG pattern had
a lower minimum blood pressure, longer ECG pauses and duration
of loss of consciousness and more often had asystole than those
patients with the slow EEG pattern. In addition, the authors ana-
lysed several clinical signs occurring during syncope, according to
the EEG pattern of the patient and the phase in which they
occurred. As already underlined in previous studies, pallor, sweat-
ing and having the eyes open during syncope occurred in almost
every patient: the five patients with eyes closed during syncope
were all in the slow pattern group, suggesting that eye opening
might not occur if the brain hypoperfusion is mild. Dilated pupils,
making sounds, jerks, eye movements and oral automatisms were
observed in 450% of the population. The authors propose a clas-
sification of clinical signs based on their relation to the EEG phase.
Type A signs occur during the first slow phase, are present during
the flat phase and stop in the second slow phase. They include
loss of consciousness, eye opening and general stiffening with
possible arm raising. Type B signs occur only during EEG slowing
and they likely require some cortical involvement. They include
myoclonic jerks, nonsensical talking, non-verbal sounds, and au-
tomatisms. Patients also reported auras and near-death experi-
ences. Type C signs occur only during EEG flattening and are
mainly roving eye movements and stertorous breathing, suggest-
ive of subcortical generation. Finally, type D signs, including jaw
dropping and snoring, are less specific and may occur in either
phase.
The van Dijk et al. (2014) paper provides an important contri-
bution to our understanding of syncope symptoms. It offers a
unique opportunity to analyse reflex syncope symptoms and
signs related to EEG changes, and therefore to clarify the patho-
physiology of some of the clinical events related to syncope. It
provides insight into why some symptoms are clustered with each
other. Moreover, signs that have never been described as syn-
cope-related could now help clinicians to distinguish syncope
from other causes of loss of consciousness.
Nevertheless, before being able to extend the study’s findings to
everyday clinical practice, we must consider that the study has a
few weaknesses. First, a very selected population in a highly moni-
tored setting was analysed. The same findings may not be true in
either spontaneous vasovagal syncope or syncope from other
causes. For example, the onset of partial seizures has been
Scientific Commentaries
observed in syncope associated with profound bradyarrhythmia
or asystole during implantable loop recordings (Petkar et al.,
2012). Therefore, in the absence of control groups, such as pa-
tients with non-syncopal loss of consciousness and with syncope
from other causes, it may be a while before we are confident that
these clinical sign patterns are useful in the differential diagnosis of
transient loss of consciousness. Moreover, signs that can easily be
observed after intensive review of a video might not be easily
recalled and described by a bystander after a ‘real life’ syncope
episode. Second, the video analysis might be biased by both the
absence of blinding to EEG results and the camera position, which
did not allow the analysis of peripheral movements.
In conclusion, from a clinical standpoint, this study can help us
in recognizing syncope associated with a deeper hypoperfusion,
which might be more symptomatic and require more diagnostic
Downloaded from http://brain.oxfordjournals.org/ at Belgorod State University on February 6, 2014
and therapeutic effort. Moreover, the description of symptoms
that have rarely been described as associated with syncope, such
as oral automatisms, might eventually help with the differential
diagnosis of transient loss of consciousnesses with atypical clinical
patterns.
Monica Solbiati1 and Robert Sheldon2
1
Medicina ad Indirizzo Fisiopatologico, Dipartimento di Scienze
Biomediche e Cliniche ‘L. Sacco’, Ospedale ‘L. Sacco’, Università
degli Studi di Milano, Milano, Italy
2
Libin Cardiovascular Institute of Alberta, University of Calgary,
Calgary, AB, Canada
Correspondence to: Robert Sheldon, MD, PhD, FRCP(C),
Professor of Cardiac Sciences,
Libin Cardiocascular Institute of Alberta of the University of Calgary,
3280 Hospital Drive NW,
Calgary, AB, Canada, T2N4N1
E-mail: sheldon@ucalgary.ca
doi:10.1093/brain/awt363
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Electroencephalographic correlates of vasovagal syncope induced by
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Gastaut H, Fischer-Williams M. Electro-encephalographic study of syn-
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Martinez-Fernandez E, Garcı́a FB, Gonzalez-Marcos JR, Peralta AG,
Garcia AG, Deya AM. Clinical and electroencephalographic features
of carotid sinus syncope induced by internal carotid artery angioplasty.
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implantable electrocardiographic monitoring indicates a high rate of
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Scientific Commentaries
Sheldon R, Rose S, Ritchie D, Connolly SJ, Koshman MS, Lee MA, et al.
Historical criteria that distinguish syncope from seizures. J Am Coll
Cardiol 2002; 40: 142–8.
Tannemaat MR, van Niekerk J, Reijntjes RH, Thijs RD, Sutton R, van
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A (mini) pill for stroke?
In this issue of Brain, Bushra Wali et al. (2014) describe the effi-
cacy of progesterone in an animal model of ischaemic stroke and,
in so doing, provide data of importance for clinical translation,
while at the same time raising the bar for high quality reporting
of in vivo research (Wali et al., 2014).
The development of new treatments for stroke is a tricky busi-
ness (O’Collins et al., 2006), and so finding an established drug
that might have therapeutic efficacy is a tantalizing prospect.
Abundant preclinical data support a neuroprotective effect of pro-
gesterone in experimental stroke and traumatic brain injury, and a
phase III trial is under way. Given that the safety profile of pro-
gesterone is already known, such reprovisioning would accelerate
drug development. A potential confounding influence is sex- and
age-related differences in circulating progesterone. Women who
experience stroke are usually post-menopausal, and modelling the
menopause in animals is generally achieved by ovariectomy. In a
meta-analysis of the effects of progesterone in animal models of
focal cerebral ischaemia, Wong et al. (2013) found that proges-
terone increased mortality in young female hormonally-intact ani-
mals, and had no effect on lesion volume in adult ovariectomized
females (Wong et al., 2013). In human studies, patients taking
hormone replacement therapy (either oestrogen alone or oestro-
gen plus progesterone) at the time of their stroke seemed to have
a worse outcome (Bath and Gray, 2005); however, the effect of
progesterone on its own is unknown.
Wali et al. (2014) avoid the confounding effect of circulating
progesterone and effects of ovariectomy by restricting attention to
aged (12-month-old) male rats. They systematically explore the
limits to efficacy in ways that will help inform clinical trial
design. For delay to treatment, the authors establish that efficacy
is retained at 6-h delays but lost at 24-h delays, thus validating the
use of a 6-h window in clinical trials. For drug dose, they show
maximum efficacy at the lowest dose tested [16 mg/kg on Day 1
(in two doses 5–6 h apart), 8 mg/kg for the next 6 days], with
32 mg/kg (Day 1)/16 mg/kg thereafter marginally less effective,
and 64 mg/kg (Day 1)/32 mg/kg thereafter clearly less effective.
These doses are at the higher end of those identified in the review
of Wong et al. (2013) who found no dose-response relationship.
These dosage regimes are, however, loosely analogous to those
that have been used in some clinical trials in traumatic brain injury,
where the total daily dose has ranged from 2 mg/kg to 12 mg/kg.
The study by Wali et al. (2014) is also important in that it
explores efficacy in aged animals with outcomes measured at ex-
tended times after the stroke has occurred. One difficulty in as-
sessing the efficacy of drugs used to treat stroke is that residual
Brain 2014: 137; 308–312 | 311
van Dijk JG, Thijs RD, van Zwet E, Tannemaat MR, van Niekerk J,
Benditt DG, et al. The semiology of tilt-induced reflex syncope in
relation to electroencephalography changes. Brain 2014; 137: 576–85.
Wieling W, Thijs RD, van Dijk N, Wilde AAM, Benditt DG, van Dijk JG.
Symptoms and signs of syncope: a review of the link between physi-
ology and clinical clues. Brain 2009; 132: 2630–42.
infarct volume may be a poor guide to functional improvement,
and in many animal models (Howells et al., 2010) the neurobe-
havioural consequences of focal cerebral ischaemia resolve rapidly,
meaning that long-term efficacy is difficult to measure. Using a
Downloaded from http://brain.oxfordjournals.org/ at Belgorod State University on February 6, 2014
combination of behavioural endpoints, Wali et al. (2014) demon-
strate firstly that there is a sustained behavioural deficit 3 weeks
after the injury, and secondly that the efficacy of progesterone
was retained at these later time points. This response appeared
to be independent of the delay to treatment—that is, the benefi-
cial effect of treatment initiated 6 h after the induction of focal
ischaemia was retained whether outcome was measured 3 days, 9
days or 21 days later. Conversely, the lack of benefit of treatment
initiated 24 h after ischaemia was largely consistent across times of
outcome measurement, although it is a simplification to say there
was no efficacy with late treatment; for locomotion (distance tra-
velled in the open field) and for measures of gait quality (stride
length, paw print area, limb swing speed) the data are consistent
with a biologically important effect, which the experiment was not
powered to detect. As the authors point out, if efficacy is sus-
tained beyond 6 h this would substantially broaden the pool of
patients potentially eligible for progesterone treatment. This effi-
cacy at longer delays to treatment suggests effects on regener-
ation and repair as well as neuroprotection, consistent with reports
that progesterone promotes post-ischaemia synaptogenesis (Zhao
et al., 2011), increases circulating endothelial progenitor cells (Li
et al., 2012), and promotes neurogenesis (Barha et al., 2011) and
neural regeneration (Li et al., 2012).
The most important thing about this study, however, is the
effort made by the authors to minimize the risk that their findings
are confounded by bias (Kilkenny et al., 2010; Landis et al.,
2012). By randomly allocating animals to the various experimental
groups, they ensure that the only systematic differences between
the groups were those designed into the experiment. Of course,
there will be differences between laboratory animals, but the in-
vestigators performed a power calculation to ensure that their
experiment was large enough to account for these chance differ-
ences and still see any treatment effects of a size considered im-
portant. The authors take care to report the number of animals
recruited to each experimental cohort, and the number surviving
ischaemia surgery and to the time that outcome is measured. This
allows the reader to judge whether improved outcome may be
because of a healthy survivor effect (O’Collins et al., 2011), and
is particularly important where a drug has previously been re-
ported to increase mortality. Finally, by blinding the assessment
of outcome the authors give us greater confidence that the