Cerebral Venous System and
Anatomical Predisposition to
Mark H. Wilson, BSc, MBBChir, FRCS (SN), FIMC, MRCA, FRGS,1,3,6,9,13,14
Indran Davagnanam, MB, BCh, BAO, BMedSci, FRCR,2Graeme Holland,3Raj S. Dattani,3
Alexander Tamm,3Shashivadan P. Hirani, MSc, PhD, CPsychol,4Nicky Kolfschoten, MD,3
Lisa Strycharczuk,2Cathy Green,2John S. Thornton, PhD,2Alex Wright, MB, FRCP,5,14
Mark Edsell, FRCA,3,14Neil D. Kitchen, MD, FRCS (SN),6David J. Sharp, PhD,1
Timothy E. Ham, PhD,1Andrew Murray, DPhil,7Cameron J. Holloway, FRACP, D.Phil,8
Kieran Clarke, PhD,8Mike P.W. Grocott, BSc, MBBS, MD, FRCA, FRCP, FFICM,11,12
Hugh Montgomery, FRCP, MD, FRGS, FRI, FFICM,3,13*
and Chris Imray, PhD, FRCS, FRCP, FRGS3,10,14on behalf of the Birmingham Medical
Research Expeditionary Society and Caudwell Xtreme Everest Research Group
Objective: As inspired oxygen availability falls with ascent to altitude, some individuals develop high-altitude headache
(HAH). We postulated that HAH results when hypoxia-associated increases in cerebral blood flow occur in the context of
restricted venous drainage, and is worsened when cerebral compliance is reduced. We explored this hypothesis in 3 studies.
Methods: In high-altitude studies, retinal venous distension (RVD) was ophthalmoscopically assessed in 24 subjects (6 female)
and sea-level cranial magnetic resonance imaging was performed in 12 subjects ascending to 5,300m. Correlation of headache
burden (summed severity scores [0–4] ?24 hours from arrival at each altitude) with RVD, and with cerebral/cerebrospinal fluid
(CSF)/venous compartment volumes, was sought. In a sea-level hypoxic study, 11 subjects underwent gadolinium-enhanced
magnetic resonance venography before and during hypoxic challenge (fraction of inspired oxygen ¼ 0.11, 1 hour).
Results: In the high-altitude studies, headache burden correlated with both RVD (Spearman rho ¼ 0.55, p ¼ 0.005) and
with the degree of narrowing of 1 or both transverse venous sinuses (r ¼ ?0.56, p ¼ 0.03). It also related inversely to
both the lateral þ third ventricle summed volumes (Spearman rho ¼ ?0.5, p ¼ 0.05) and pericerebellar CSF volume (r ¼
?0.56, p ¼ 0.03). In the hypoxic study, cerebral and retinal vein engorgement were correlated, and rose as the combined
conduit score fell (a measure of venous outflow restriction; r ¼ -0.66, p < 0.05 and r ¼ ?0.75, p < 0.05, respectively).
Interpretation: Arterial hypoxemia is associated with cerebral and retinal venous distension, whose magnitude correlates
with HAH burden. Restriction in cerebral venous outflow is associated with retinal distension and HAH. Limitations in
cerebral venous efferent flow may predispose to headache when hypoxia-related increases in cerebral arterial flow occur.
ANN NEUROL 2013;73:381–389
View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.23796
Received Aug 13, 2012, and in revised form Sep 12, 2012. Accepted for publication Oct 29, 2012.
Address correspondence to Dr Wilson, Imperial College, Department of Neurosurgery, Praed Street, London W1 1NY, United Kingdom.
Members of the Caudwell Xtreme Everest Research Group are listed in the Appendix on page 388.
Montgomery and Imray share senior authorship.
From the1The Traumatic Brain Injury Centre, St Mary’s Hospital, Imperial College, London W1 2NY;2Lysholm Department of Neuroradiology, National
Hospital for Neurology and Neurosurgery, London;3Centre for Altitude, Space, and Extreme Environment Medicine, University College London, London;
4Health Services Research, City University London, London;5Medical School, University of Birmingham, Birmingham;6Department of Neurosurgery,
National Hospital for Neurology and Neurosurgery, London;7Department of Physiology, Development, and Neuroscience, University of Cambridge,
Cambridge;8Department of Physiology, University of Oxford, Oxford;9London’s Air Ambulance, Queen Mary College, London E1 1BB;10Warwick Medical
School, UHCW NHS Trust, Coventry, UK;11Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Faculty of Medicine,
University of Southampton, Southampton;12Anaesthesia and Critical care Research Unit, University Hospital Southampton NHS Foundation Trust;13for the
Caudwell Xtreme Everest Group, London; and14for the Birmingham Medical Research Expeditionary Society, Birmingham, United Kingdom.
C 2013 American Neurological Association 381
arterial blood flow (CBFa).1Diverse disease states may
also lead to dysregulation in cerebral blood flow.2How-
ever caused, increases in CBFa can lead to harmful
increases in intracranial pressure (ICP).3The magnitude
of such changes in ICP is highly variable, and the other
factors upon which it depends are poorly understood.
Ascent to high altitude results in a fall in barometric
pressure and corresponding fall in the inspired partial pres-
sure of oxygen, leading to arterial hypoxemia.4This hypo-
baric hypoxia may drive increases in CBFa and hence in
ICP, an effect that may contribute to the occurrence of
high-altitude headache (HAH). Just as for raised ICP in
the critically ill, the occurrence and severity of HAH is
highly variable, and the factors influencing its development
are not clear.5The typical features of HAH include bilat-
eral, frontal headache of dull or pressing quality and mild
to moderate intensity that is aggravated by exertion, move-
ment, straining, coughing, or bending.6,7
In 1985, Ross proposed the ‘‘tight fit’’ hypothesis to
explain the idiosyncratic nature of HAH, suggesting that
those with greater cranial and spinal compliance will bet-
ter accommodate cerebral swelling before a rise in ICP
(and associated headache) occurs.8However, data to sup-
port this hypothesis are sparse. Meanwhile, retinal veins
become distended at high altitude,9an engorgement that
may mirror the engorgement occurring in the cerebral
veins.10Although such increases may simply reflect those
in cerebral venous flow that must occur when CBFa rises,
we have postulated that the degree of distension (and
related changes in ICP) might be influenced by differen-
ces in the caliber of distal veins.10This restricted efferent
flow would also increase ICP for any given change in
CBFa, in the same manner in which renal glomerular
pressure rises as efferent vessel diameter falls.
We have explored this hypothesis in 3 studies. The
first characterized the cerebral venous drainage of healthy
volunteers and correlated this with headache burden on
ascent to high altitude. We also sought association of
other cranial compartmental volumes as measures of tight
fit. The second sought association of retinal venous dis-
tension with headache burden on such ascent. Based on
findings from these studies, we characterized the response
of cerebral and retinal veins to acute arterial hypoxemia
at sea level in a third, independent, study.
ritical illness is commonly associated with systemic
hypoxia, which may drive an increase in cerebral
Patients and Methods
All studies had ethical approval from University College Lon-
don. Written informed consent was obtained from each subject.
Caudwell Xtreme Everest Expedition.11In the retinal imaging
cohort (24 subjects, 6 female; mean age, 35.2 years; range,
19–59 years), retinal venous distension was assessed. In the
magnetic resonance imaging (MRI) cohort (12 Caucasian
males; mean age, 35.8 years; range, 24–48.2 years), cerebral
compartment volumes were determined. Past high-altitude
experience varied in both groups (from >8,000m ascents to
novice trekkers), but none had ascended >3,000m in the
preceding 6 months.
Two groups of subjects were studied as part of the
Ascent Profile, Headache Score, and Brain Oxygenation.
Ascent profiles and logistical details have previously been
reported.12All subjects ascended from 1,300m (Kathmandu) to
5,300m (Everest Base Camp). All 24 retinal imaging subjects
ascended over 13 days, and the MRI group over 11 to 13 days.
They recorded their headache grade (0 ¼ none, 1 ¼ mild, 2 ¼
moderate, 3 ¼ severe, 4 ¼ excruciating) at the beginning of
each day. From these, ascent headache score (the sum of those
scores obtained within 24 hours of arrival at a new altitude)
was derived. On the day after arrival at each altitude, after 10
minutes of recumbent rest, brain oxygenation (resting cerebral
oxygenation [rSO2]) was measured by near infrared spectros-
copy (NIRS; Invos C; Somanetics, Troy, MI), using probes on
the left and right forehead. The mean of 3 readings was
tography was performed (8TRC NW200 nonmydriatic digital
ophthalmoscope; TopCon, Tokyo, Japan) at sea level and on
day 2 or 3 after arrival at 5,300m, and retinal venous calibers
were subsequently determined by a blinded observer using on-
screen callipers. Absolute and proportional changes with ascent
were calculated. Such studies were performed on the basis that
retinal venous distension might mirror that which occurs in cer-
In the retinal imaging cohort, retinal pho-
Magnetic Resonance Imaging.
magnetic resonance T1-weighted magnetization-prepared rapid
gradient-echo images (with 1.5mm isotropic resolution) were
acquired within 2 weeks of return to sea level (1.5T Sonata
scanner; Siemens, Erlangen, Germany). Images were imported
into Analyze 9.0 (AnalyzeDirect, Overland Park, KS), a single
independent blinded observer (A.T.) then calculated venous
conduit (transverse sinus) volume by multiplying the mean of
repeatedly measured cross-sectional areas by the length of
In addition, total intracranial, supratentorial, infratento-
rial, total brain, supratentorial cerebrospinal fluid (CSF), infra-
tentorial CSF, summed lateral ventricle and third ventricle, aq-
ueduct of sylvius and fourth ventricular, total ventricular, total
CSF, sagittal sinus, transverse sinus, and total venous volumes
were quantified by the same single blinded observer (Figs 1
In the MRI cohort, cranial
ANNALS of Neurology
382Volume 73, No. 3
supratentorial volume minus supratentorial brain volume, and
infratentorial CSF volume as infratentorial volume minus infra-
tentorial brain volume. With the automated software, volumes
were calculated using the standard Cavalieri principle of multi-
plying the area of interest on each slice with slice thickness.13
ship between ascent headache score and transverse sinus vol-
ume, and thence with cranial compartmental volumes. As a sec-
ondary target of analysis, a relationship of proportional change
in retinal vein diameter with ascent headache score was sought.
The volumes for the MRI study and the percentage changes in
venous diameter were normally distributed, and hence bivariate
correlations were used (Pearson for continuous data, Spearman
rho for ordinal) as appropriate. SPSS (version 20; IBM,
Armonk, NY) was used for analysis. Statistical significance was
set at p ? 0.05.
Primary analysis addressed the relation-
Hypoxic MRV Study
range, 21–74 years) were recruited (experienced trekkers/
mountaineers from the Centre for Altitude, Space and Envi-
ronment and from the Birmingham Medical Research Expedi-
tionary Society). Following retinal imaging in normoxia, an
intravenous cannula was inserted. Subjects then lay supine for
10 minutes before continuous monitoring of peripheral arte-
rial oxygen saturations (Onyx Model 9500; Nonin, Plymouth,
MN) and brain oxygenation (rSO2using NIRS, as described
above) was commenced. Subjects were then rendered hypoxic
for 60 minutes (see below), at the end of which period (and
while still hypoxic) cranial magnetic resonance imaging was
Eleven subjects (2 women; mean age, 37.2 years;
performed. The mean of 3 consecutive rSO2values was docu-
mented at each of 3 time points (normoxia, and after 30 and 60
minutes of hypoxia). Subjects were asked to describe and grade
(0–4) any headache they had at the end of 1 hour of hypoxia. In
the same manner, and after a minimum of 10 minutes of recum-
bent rest, MRI was performed under normoxic conditions at
least 24 hours before or after hypoxic exposure.
imaging (8TRC NW200 nonmydriatic digital ophthalmoscope,
TopCon). This was done in normoxia prior to the study, and
while subjects were still hypoxic at the end of the hypoxic MRI
study. These images were subsequently analyzed by a blinded
observer (R.S.D.) with caliber measurements taken of retinal
arteries and retinal veins.
Each subject underwent bilateral retinal
to 1 hour of normobaric hypoxia (fraction of inspired oxygen
[FiO2] ¼ 11%; approximately equivalent to an altitude of
5,200m), using a tight-fitting mask (Everest Summit hypoxic
generator; Hypoxic Systems, New York, NY) and extended
MRI-compatible tubing. Inspired oxygen concentration was reg-
ularly monitored (class R-17D oxygen sensor; Oxycheq,
After baseline measurements, subjects were exposed
Magnetic Resonance Venography.
venography (MRV) was performed (3T TIM TRIO, Siemens)
using a 3-dimensional (3D) bolus-tracked gadolinium-enhanced
MRV sequence. A 0.2ml/kg intravenous bolus of Dotarem
(Guerbet, Villepinte, France) was administered. Bolus tracking
(CARE Bolus, Siemens) was performed at the posterior aspect
of the superior sagittal sinus, with the MRV scan triggered at
the first appearance of contrast. Parameters for the 3D MRV
sequence were: repetition time ¼ 3.07 milliseconds; echo time
¼ 1.11 milliseconds, field of view ¼ 300mm, flip angle ¼ 18?,
224 slices of 1mm thickness, voxel dimensions 1.0 ? 0.8 ?
1.0mm, centric phase-encoding order, acquisition time ¼ 1.01
minutes. To prevent any residual gadolinium affecting the later
imaging, hypoxic and normoxic MRI scans were performed at
least 24 hours apart.
window level and width were set respectively to a factor of half
and double the value of contrast signal intensity within the sag-
ittal sinus just proximal to the torcula. A single, blinded consul-
tant neuroradiologist (I.D.) analyzed the resultant images with
To equilibrate the windowing, the imaging
FIGURE 1: Analysis of magnetic resonance imaging scans
enabling volume calculations. (A) The inner table of the skull
is demarcated to measure total intracranial volume. (B) The
brain surface is demarcated using the built-in software. (C)
The ventricles are demarcated. (D) Where there are small
pockets of cerebrospinal fluid (eg, in deep sulci that are
missed with the software), these are then added. (E) Other
structures, such as venous sinuses, are demarcated. For this
study, arterial volumes were not calculated. [Color figure
can be viewed in the online issue, which is available at
FIGURE 2: Once all structures have been rendered, each
can be added and removed and its volume calculated.
[Color figure can be viewed in the online issue, which is
available at www.annalsofneurology.org.]
Wilson et al: HAH and the Venous System
projection reconstructions. Normoxic and hypoxic images were
presented simultaneously, and images graded on a scale of being
the same (0), having mild greater prominence of venous struc-
tures (1), or having considerably greater prominence of venous
structures (2). Attempts to perform this analysis quantitatively
(using digital subtraction, eg, with FMRIB Software Library)
were not successful, largely because of small differences in
extracranial contrast enhancement.
Combined Conduit Score.
the high-altitude study, the appearances of the transverse and
sigmoid sinus were graded using the combined conduit score
(CCS).14This system grades left and right drainage systems
(using the sagittal sinus as the reference) as follows: 0 ¼ aplas-
tic; 1 ¼ hypoplastic/severe stenosis: <25% of the lumen of the
distal superior sagittal sinus; 2 ¼ moderate narrowing: 25 to
50%; 3 ¼ mild narrowing: 50 to 75%; and 4 ¼ no significant
narrowing: 75 to 100%. The 2 figures (of 4) for each side are
As a result of the findings in
summed to give the combined conduit score, with 8 being the
maximum, signifying no narrowing.
bral venous distension with hypoxia and (2) its relationship with
CCS. SPSS (version 20) was used for analysis. Bivariate correla-
tions were used (Pearson for continuous data, Spearman rho for or-
dinal) as appropriate. Statistical significance was set at p ? 0.05.
The primary endpoints were (1) cere-
Headache and Retinal Venous Distension. With ascent
to altitude, cerebral oxygenation fell (from 66.6 6
12.1% at sea level to 50.9 6 9.6% at 5,300m). The
mean (6standard deviation) ascent headache score was
2.4 6 1.56 (range, 0–5). Eleven of the 12 subjects
FIGURE 3: Retinal venous distension. (A) Retinal image at
sea level; (B) retinal image at 5,300m. [Color figure can be
viewed inthe onlineissue,
FIGURE 4: Percentage change in retinal venous distension
and ascent headache score in 24 subjects (Spearman rho 5
0.553, p 5 0.005).
FIGURE 5: Left (LTS, milliliters) and right (RTS, milliliters)
transverse sinus volume in (A) the 4 subjects with the lowest
ascent headache scores (HS) and (B) the 4 subjects with the
highest ascent headache scores. Three of the 4 in group B
(bar the last subject) had marked LTS/RTS asymmetry, with
marked narrowing of the nondominant sinus to <3ml in
volume. The last subject had bilateral narrowing. [Color fig-
ure can be viewed in the online issue, which is available at
FIGURE 6: Relationship between the volume of the smallest
transverse sinus and high-altitude headache score in 12
male subjects (Pearson 5 20.7, p 5 0.006; Spearman 5
20.557, p 5 0.03).
ANNALS of Neurology
384 Volume 73, No. 3
TABLE 1: Cranial Compartment Volumes in 12 Male Subjects
Volume or Angle Measured
Volume, ml or
with Ascent Headache
Brain parenchyma volume
Supratentorial CSF volume, excluding ventricles
Infratentorial CSF volume, excluding ventricles
Total nonventricular CSF volume
Lateral and third ventricle
Aqueduct and fourth ventricle
(lateral þ third þ aqueduct þ fourth)
Total supratentorial CSF
Total infratentorial CSF
Sagittal and occipital sinus venous volume
Left transverse sinus and jugular bulb
Right transverse sinus and jugular bulb
Total venous volume
Correlation coefficients (nonparametric single tailed) and p values demonstrating correlation with ascent headache scores are reported.
ap < 0.05 using a single-tailed Spearman rho.
bNot significant when analyzed as a whole. However, when the smallest transverse sinus volume is compared to headache score, the result is significant (Pearson ¼ ?0.7, p ¼ 0.006;
Spearman ¼ ?0.557, p ¼ 0.03).
CSF ¼ cerebrospinal fluid.
Wilson et al: HAH and the Venous System
ascending reported a headache at some point. Of these, 5
had a maximum of 2 grade 1 headaches, the remaining 6
having headaches of greater severity. In keeping with
high-altitude headache phenotype, most of our subjects
described them as pressure headaches and when drawing
them on a skull diagram, indicated that they were fron-
tal, occipital, or diffuse.
Retinal venous distension occurred at 5,300m
(illustrated in Fig 3), the magnitude of which was inver-
sely related to rSO2(r ¼ ?0.6, p ¼ 0.02). All but 1 of
the 24 subjects demonstrated retinal venous distension
(for the remaining, the range of distension varied from 5
to 44%). The single subject who demonstrated no
change also reported no headache and has climbed the 7
highest summits on the 7 continents and Everest twice.
The degree of distension in the others correlated with
ascent headache score (Pearson ¼ 0.496, p ¼ 0.014;
Spearman rho ¼ 0.553; p ¼ 0.005, Fig 4).
Transverse Sinus Volumes.
transverse sinus correlated strongly with ascent headache
score (Pearson ¼ ?0.7, p ¼ 0.006; Spearman ¼
?0.557, p ¼ 0.03). Typically, headaches were more likely
to occur if a subject had a transverse sinus of <3ml in
volume (Figs 5 and 6). When CCS is used, the correla-
tion with headache is similar (Pearson ¼ ?0.72, p ¼
0.008; Spearman ¼ ?0.61, p ¼ 0.04).
The volume of the smallest
Cranial Volumes. Correlation coefficients (nonparamet-
ric single-tailed Spearman rho) of headache score with
measured volumes are shown in Table 1. In summary,
headache score was inversely related to the sizes of the
lateral and third ventricles (p ¼ 0.05 and p ¼ 0.03,
respectively), and to the volume of CSF surrounding the
cerebellum. Both of these imply that CSF volume may
be acting as a buffer to cerebral parenchymal or cerebral
Hypoxic MRV Study
Cerebral venous engorgement occurred in all subjects in
response to hypoxia (Table 2).
Figure 7 illustrates the typical changes that occur in
venous drainage with hypoxia.
TABLE 2: Subject Data Recorded at the End of 1 Hour of Exposure to Hypoxia (FiO25 0.11)
Mean 2.18 1.00
Upper CI 1.740.48
Lower CI2.63 1.5222.57 1.704.05 3.617.13
Venous prominence is scored as 0 (the same), 1 (mild), or 2 (considerable). Right and left TSs and CCSs are described in Patients
CCS ¼ combined conduit scores; CI ¼ confidence interval; EtCO2¼ end tidal CO2; FiO2¼ fraction of inspired oxygen;
rSO2¼ resting cerebral oxygenation; SaO2¼ oxygen saturation; SD ¼ standard deviation; TS ¼ transverse sinus.
FIGURE 7: Exemplar of the increase in venous prominence
noted in response to normobaric hypoxia (FiO2 5 11%).
This subject has asymmetry in venous drainage, with relative
narrowing of the left transverse sinus (combined conduit
score: right 5 4; left 5 1; total 5 5). [Color figure can be
ANNALS of Neurology
386 Volume 73, No. 3
Reductions in venous CCS were associated with
increasing distension of cerebral veins (Pearson ¼
?0.637, p < 0.05; Spearman rho correlation ¼ ?0.655,
p < 0.05) and retinal veins (mean increase in retinal ve-
nous diameter 16.6 6 8.9%: Pearson correlation ¼
?0.775, p < 0.005; Spearman rho correlation ¼
?0.745, p < 0.05). Two of the subjects with the smallest
CCS also had the worst headaches; however, with the
small numbers of this study and the subjective nature of
headache after only 1 hour of hypoxia, a correlation
between CCS and headache score was not possible.
Mean retinal venous diameter rose by 16.6%
(68.9%), the magnitude of engorgement correlating
with that of the cerebral veins (Spearman rho ¼ 0.598,
p ¼ 0.05). There was a strong correlation between retinal
venous distension and CCS (Pearson correlation ¼
?0.775, p < 0.005; Spearman rho correlation ¼
?0.745, p < 0.05).
unknown. Ours are the first data to suggest a role for an
impaired balance of cerebral venous drainage with arterial
inflow in its pathogenesis. These findings have implica-
tions not only for mountaineers, but for those facing hy-
poxia at sea level as a result of disease, and potentially
for those in whom cerebral arterial flow increases in the
context of cerebral injury.
Cerebral blood flow rises in response to hypoxe-
mia.1Restricted venous drainage in the face of this
increased cerebral blood flow would result in venous
engorgement and a subsequent rise in ICP when the lim-
its of cerebral compliance are reached. Our data, from 3
sequential studies, are the first to support such a role for
impaired cerebral venous drainage in the pathogenesis of
high-altitude headache. At sea level, hypoxia (FiO2 ¼
0.11) induced cerebral venous distension, the magnitude
of which correlated with that of retinal venous disten-
sion. At altitude, headache score was strongly associated
with the degree of retinal engorgement (and thus, one
might infer, cerebral venous engorgement) on ascent to
5,300m. Headache burden was related to reductions in
size of 1 or both cerebral transverse venous sinuses. At
sea level, the degree of venous distension was similarly
related to anatomical restriction in the transverse sinuses.
Taken together, these data suggest that increases in
ICP related to elevated cerebral arterial inflow may be
augmented if anatomical restrictions in venous efferent
blood flow are present. Such rises in ICP might be fur-
ther amplified if CSF capacitance is reduced,8and our
data strongly support such a contention; headache score
ofheadache athigh altituderemains
was inversely related to CSF volume in the lateral and
third ventricles, and in the pericerebellar space, suggest-
ing that these may buffer cerebral engorgement. These
findings are by far the most detailed ever reported, but
do build on those from a previous study in which ven-
tricular volume (independently graded as large, normal,
or small) correlated with headache in 10 subjects ascend-
ing to 5,030m.15We confirmed this finding, extending it
to an association with infratentorial CSF volume (exclud-
ing 4th ventricle). Other studies have demonstrated head-
ache syndromes in those with a ‘‘crowded’’ posterior
fossa.16Similarly, our findings imply that in those with
minimal posterior fossa compliance, hypoxia may induce
Comment relating to the correlation between CCS
and headache during the 1-hour sea level study is per-
haps warranted. Headache data were documented for rea-
sons of safety. Only 8 subjects actually reported head-
ache, which was self-graded on our reported 1 to 4 scale
(5 grade 1; 3 grade 2). Although 2 of the 3 subjects with
the worst headache scores also had among the worst
CCS scores (CCS ¼ 5 in both), such data should be
considered with extreme caution. High-altitude headache
may take some time both to develop and to become
established and maximal after physiological changes (such
as those in vascular response) have occurred. Thus, any
symptoms recorded with exposure to a single isolated
and unsustained degree of normobaric hypoxia may not
be expected to mirror those observed upon sustained ex-
posure to a range of altitudes. The generally mild nature
of the headaches observed reinforces these issues.
Our study does have weaknesses. Subject numbers
were small in the 2 studies of cerebral anatomy, with the
majority being male. Extension of our studies is thus
advocated. Second, the high-altitude ascent profile was
gentle so as to avoid risk of (potentially life-threatening)
high-altitude illness. This is likely to have minimized
headache burden. Although more aggressive ascent profiles
might thus be considered in future studies, we would cau-
tion against such an approach in very remote environ-
ments. Such studies might best be performed in hypobaric
chambers, or in geographical locations where rapid descent
is possible. Headache scoring is highly subjective, and
hard to quantify in a manner amenable to analysis. The
subjective assessment of and summing of a headache score
implies assumptions that a relationship has been made.
This is not ideal, but it is a simple technique that is com-
monly used to assess headache over time. Our studies
were poikilocapnic; end tidal CO2 was not controlled.
This is an important issue in as much as a more aggressive
hypoxic ventilatory response (also unquantified) may have
Wilson et al: HAH and the Venous System
March 2013 387
both offset falls in arterial oxygenation and led to greater
reductions in partial pressure of carbon dioxide in arterial
blood (which can act to limit those rises in cerebral blood
flow driven by hypoxia itself).
We would also advocate extension of our studies to
altitude-related disease states. High-altitude cerebral edema
occurs idiosyncratically, and may prove life-threatening.17
Although its pathogenesis is not understood, it might be
that increases in CBFa, when associated with impaired ve-
nous drainage, would cause a rise in cerebral capillary pres-
sure, and thus capillary leak (in a manner analogous to a
renal glomerulus). We are currently investigating this possi-
bility. A similar mechanism may contribute to space adap-
tation / obstruction syndrome found in astronauts10,18and
would appear worthy of exploration.
Our findings may also have implications not only
for mountaineers, but for disease states at sea level. Idio-
pathic intracranial hypertension appears associated with
restrictions in the transverse sinus,14,19
stenting of which can prove curative.20Both head injury
and intracerebral hemorrhage may be associated with a
dysregulation of cerebral blood flow, with resulting
increases in arterial afferent supply leading to a detri-
mental rise in ICP. Although current clinical practice
focuses on manipulating systemic arterial and venous
pressures, our study would suggest that the study of in-
tracranial venous drainage
changes in ICP are worthy of investigation in such
and its relationship to
Restriction in cerebral venous outflow is associated with
increased cerebral venous engorgement and with greater
headache burden in response to hypoxia. Greater intra-
cranial CSF volume appears to offer some protection
against headache. These data suggest a possible role for
restricted cerebral venous drainage in the regulation of
cerebral venous blood volume and possibly intracranial
pressure, findings that may have relevance to disease
states at both altitude and at sea level.
The JABBS Foundation kindly supported the costs of
the hypoxic MRV study. The Caudwell Xtreme Everest
study was supported by John Caudwell, BOC Medical
(now part of Linde Gas Therapeutics), Eli Lilly, the
London Clinic, Smiths Medical, Deltex Medical, and
the Rolex Foundation (unrestricted grants), the Associa-
tion of Anaesthetists of Great Britain and Ireland, the
United Kingdom Intensive Care Foundation, and the
Sir Halley Stewart Trust.
Some of this work was undertaken at University Col-
lege London Hospital–University College London Com-
prehensive Biomedical Research Centre, which received a
proportion of funding from the United Kingdom Depart-
ment of Health’s National Institute for Health Research
Biomedical Research Centres funding scheme.
Caudwell Xtreme Everest is a research project coor-
dinated by the Centre for Altitude, Space, and Extreme
Environment Medicine, University College London.
Membership, roles, and responsibilities of the Caudwell
Xtreme Everest Research Group can be found at
H.M. and C.I. are joint senior authors.
Potential Conflicts of Interest
A.W.: speaking fees, Novo Nordisk, Eli Lilly. M.G.: employ-
ment, University of Southampton, University Hospitals NHS
Foundation Trust, Royal College of Anaesthetists, Hampshire
and Isle of Wight CLRN; grants/grants pending, National
Institute of Health Research, National Institute of Academic
Anaesthesia, Francis and Augustus Newman Foundation;
travel expenses, BOC Linde, Cortex GmBH, Fresenius Kabi,
Edwards Lifescience, Ely Lilly Critical Care; other, Director of
Board and Research Council, member of the National
Institute of Academic Anaesthesia, Cochairman of Evidence
Based Perioperative Medicine (annual scientific meeting),
Cochairman of Current Controversies in Anaesthesia and
Perioperative Medicine (annual scientific meeting), Cochair-
man of National Perioperative CPET Meeting (annual
scientific meeting), Cochairman of KnO2wledge (annual
scientific meeting), member of organizing group for UK
Perioperative Clinical Research Forum (annual scientific
meeting), on faculty for perioperative CPET course, on
executive faculty for UK-UIAA Diploma in Mountain
Medicine, Editor in Chief of Extreme Physiology and Medicine,
of Hospital Medicine, member of the Improving Surgical
Members of the Caudwell Xtreme Everest Research
Group are as follows.
V. Ahuja, G. Aref-Adib, R. Burnham, A. Chisholm, K.
Clarke, D. Coates, M. Coates, D. Cook, M. Cox, S.
Dhillon, C. Dougall, P. Doyle, P. Duncan, M. Edsell, L.
Edwards, L. Evans, P. Gardiner, M. Grocott, P. Gunning,
ANNALS of Neurology
388 Volume 73, No. 3
N. Hart, J. Harrington, J. Harvey, C. Holloway, D. Download full-text
Howard, D. Hurlbut, C. Imray, C. Ince, M. Jonas, J.
van der Kaaij, M. Khosravi, N. Kolfschoten, D. Levett,
H. Luery, A. Luks, D. Martin, R. McMorrow, P. Meale,
K. Mitchell, H. Montgomery, G. Morgan, J. Morgan, A.
Murray, M. Mythen, S. Newman, M. O’Dwyer, J. Pate,
T. Plant, M. Pun, P. Richards, A. Richardson, G. Rod-
way, J. Simpson, C. Stroud, M. Stroud, J. Stygall, B.
Symons, P. Szawarski, A. Van Tulleken, C. Van Tulleken,
A. Vercueil, L. Wandrag, M. Wilson, J. Windsor.
Scientific Advisory Group
B. Basnyat, C. Clarke, T. Hornbein, J. Milledge, L. Wat-
kins, J. West.
1.Wilson MH, Edsell ME, Davagnanam I, et al. Cerebral artery dila-
tation maintains cerebral oxygenation at extreme altitude and in
acute hypoxia-an ultrasound and MRI study. J Cereb Blood Flow
2. Shardlow E, Jackson A. Cerebral blood flow and intracranial pres-
sure. Anaesth Intensive Care Med 2011;12:220–223.
3.Lewis PM, Smielewski P, Rosenfeld JV, et al. Monitoring of the
association between cerebral blood flow velocity and intracranial
pressure. Acta Neurochir Suppl 2012;114:147–151.
4.Roach RC, Hackett PH. Frontiers of hypoxia research: acute moun-
tain sickness. J Exp Biol 2001;204(pt 18):3161–3170.
5.Imray C, Booth A, Wright A, Bradwell A. Acute altitude illnesses.
6. Headache Classification Subcommittee of the International Head-
ache Society. The international classification of headache disor-
ders: 2nd edition. Cephalalgia 2004;24(suppl 1):9–160.
OO.Altitudeheadache. Headache 1972;12:
8.Ross RT. The random nature of cerebral mountain sickness. Lancet
9. Morris DS, Somner J, Donald MJ, et al. The eye at altitude. Adv
Exp Med Biol 2006;588:249–270.
10. Wilson MH, Imray CHE, Hargens AR. The headache of high alti-
tude and microgravity—similarities with clinical syndromes of cere-
bral venous hypertension. High Alt Med Biol 2011;12:379–386.
11. Grocott M, Richardson A, Montgomery H, Mythen M. Caudwell
Xtreme Everest: a field study of human adaptation to hypoxia.
Crit Care 2007;11:151.
12. Levett DZ, Martin DS, Wilson MH, et al. Design and conduct of
Caudwell Xtreme Everest: an observational cohort study of varia-
tion in human adaptation to progressive environmental hypoxia.
BMC Med Res Methodol 2010;10:98.
13. McNulty V, Cruz-Orive LM, Roberts N, et al. Estimation of brain
compartment volume from MR Cavalieri slices. J Comput Assist
14. Farb RI, Vanek I, Scott JN, et al. Idiopathic intracranial hyperten-
sion: the prevalence and morphology of sinovenous stenosis.
15.Wilson MH, Milledge J. Direct measurement of intracranial pres-
sure at high altitude and correlation of ventricular size with acute
mountain sickness: Brian Cummins’ results from the 1985 Kishtwar
expedition. Neurosurgery 2008;63:970–974; discussion 974–975.
16.Chen Y-Y, Lirng J-F, Fuh J-L, et al. Primary cough headache is
associated with posterior fossa crowdedness: a morphometric MRI
study. Cephalalgia 2004;24:694–699.
17. Hackett PH, Roach RC. High altitude cerebral edema. High Alt
Med Biol 2004;5:136–146.
18.Wiener TC. Space obstructive syndrome: intracranial hypertension,
intraocular pressure, and papilledema in space. Aviat Space Envi-
ron Med 2012;83:64–66.
19. Nedelmann M, Kaps M, Mueller-Forell W. Venous obstruction and
jugular valve insufficiency in idiopathic intracranial hypertension. J
20. Rohr A, Bindeballe J, Riedel C, et al. The entire dural sinus tree is
compressed in patients with idiopathic intracranial hypertension: a
Wilson et al: HAH and the Venous System