Sage Journals: Discover world-class research

Abstract

Wilson, Mark H., C.H.E. Imray, A.R. Hargens. The headache of high altitude and microgravity—similarities with clinical syndromes of cerebral venous hypertension. High Alt. Med. Biol. 12:379–386.—Syndromes thought to have cerebral venous hypertension as their core, such as idiopathic intracranial hypertension and jugular foramen outlet obstruction, classically result in headaches. Do they provide an insight into the cause of the headache that commonly occurs at altitude? The classic theory of the pathogenesis of high altitude headache has been that it results from increased intracranial pressure (ICP) secondary to hypoxemia in people who have less compliant intracranial volumes (Roach and Hackett, 2001). However, there does not appear to be a correlation between the headache of acute mountain sickness (AMS) and the presence of cerebral edema (Bailey et al, 2006; Wilson et al, 2009). Research has concentrated on arterial perfusion to the brain in hypoxia, but there has been little study of venous drainage. Hypoxia results in markedly increased cerebral blood flow; however, if it has been considered at all, venous outflow has to date been assumed to be of little consequence. Retinal venous distension and the increased venous blood demonstrated by near infra-red spectroscopy and more recently by MRI imply that, in hypoxia, a relative venous insufficiency may exist. Similarly, there is increasing evidence that manifestations of the fluid shift during microgravity is of similar nature to idiopathic intracranial hypertension, which is thought to be primarily a venous insufficiency condition. The unique anthropomorphic adaptations of large brained biped humans with cerebral venous systems that have to cope with large changes in hydrostatic pressure may predispose us to conditions of inflow/outflow mismatch. In addition, slight increases in central venous pressures (e.g., from hypoxia-induced pulmonary vasoconstriction) may further compromise venous outflow at altitude. A better understanding of cerebral venous physiology may enlighten us with regards the pathogenesis of headaches currently considered idiopathic. It may also enable us to trigger headaches for study and hence enable us to develop new treatment strategies.

Introduction

In 1985 Ross proposed that variations in cerebral and spinal compliance (the ability to accommodate hypoxia-induced cerebral swelling) between individuals could account for the “random nature” of the headache that occurs at altitude (Ross, 1985). This subsequently formed the basis of the currently accepted pathogenesis of acute mountain sickness (AMS). An additional physiological component of exercise-exacerbated hypoxemia (that is hypothesized to worsen cerebral swelling) has been incorporated into the theory (Roach and Hackett, 2001) and similarly, hypoxia during sleep may compound the situation (Kupper et al, 2008). Free radical formation, nitric oxide, and inflammatory mediators (e.g., vascular endothelial growth factor) have been proposed as mechanistic links between hypoxia and edema formation (Wilson et al, 2009). Unfortunately, there is little evidence to suggest that hypoxia actually causes cerebral edema sufficiently (at least in AMS) to account for the severe headache, and such swelling does not correlate with headache symptoms (Bailey et al, 2006; Kallenberg et al, 2007). Evidence for a rise in increased intracranial pressure (ICP) is also sparse (Wilson et al, 2009). Cerebral edema itself, as evidenced with imaging, is far more common in conjunction with high altitude pulmonary edema (HAPE) (Fagenholz et al, 2007; Hackett et al, 1998). Currently, high altitude cerebral edema (HACE) is a clinical diagnosis (defined by the Lake Louise committee as symptoms of AMS plus gait ataxia or mental status changes, or both ataxia and mental status changes regardless of AMS symptoms (Roach et al, 1993)). This term “cerebral edema” implies a pathological process that may not be the cause in all patients with this clinical diagnosis. This misnomer may distract from other pathological processes (including hypoxia itself) that could account for altered neurology in some at altitude. This article provides evidence that the initial cause of high altitude headache is venous congestion. This occurs before the limits of cranial compliance are reached (hence before a rise in ICP) and before cerebral edema forms. A rise in ICP and vasogenic edema formation, if and when they do occur, may well be sequela to venous congestion (to which, as with clinical headaches relating to venous obstruction, some people are more prone than others). The possible involvement of the venous system in the extreme altitude of microgravity is discussed further towards the end of this article. It is noteworthy that currently there is no way of predicting which mountaineers will develop acute mountain sickness and which astronauts will develop early maladaptation to microgravity due to a cephalad fluid shift. Are they similar conditions of venous insufficiency?

Background to a Venous Mechanism

At rest, the brain receives approximately 14% of the cardiac output, around 700 ml per minute (McArdle et al, 2006). The jugular veins therefore have to drain 700 ml per minute, a factor often overlooked. This is a sizeable volume, considering the average adult male intracranial volume (including brain and cerebrospinal fluid) is only twice this (1473 ml) (Abbott et al, 2000). Unlike the dual arterial system (carotid and vertebral systems), there is only one significant venous exit from the cranium, the internal jugular veins. Any compromise to this outflow (the small amount of pressure from a cervical collar or the increased intrathoracic pressures from positive pressure ventilation being common clinical examples) results in greater cerebral venous pressures and intracranial pressures. This phenomenon was recognized in 1935 (Bedford, 1935) and, while it is routinely seen in the setting of mechanical ventilation, the venous contribution to ICP is often overlooked.

Clinical relevance

In adults, a number of headache syndromes are related to venous obstruction, and forms of headaches in children and adolescents have been associated with venous anomalies (Fenzi and Rizzuto, 2008) or “tight” posterior fossae (Nesterovskii Iu et al, 2007). If hypoxia-induced headache can be used as a model for these syndromes, it may encourage further investigation into venous causes of otherwise idiopathic headache and offer new ways of treatment. Table 1 outlines some of the relevant clinical syndromes.

Table 1.

Clinical Syndromes to Which Venous Hypertension May Contribute

1. Idiopathic intracranial hypertension

2. Obstructive sleep apnea

3. Posterior fossa syndromes (e.g., Chiari malformations)

4. Migraine

5. Traumatic brain injury effacing cisterns

6. Jugular outflow obstruction syndromes

7. Space adaptation syndrome

8. Other idiopathic headaches (e.g., exertional headache)

Cerebral Venous Comparative Anatomy

As bipeds with large brains, humans have unique anatomical differences to other mammals. Neurosurgeons are distinctly aware that the sagittal sinus has a negative pressure when patients are in the sitting position, as this can result in (potentially fatal) air embolism if opened. When supine, bleeding from the sinuses can be torrential. Most other mammals do not have such pressure changes with which to contend.

Three main venous drainage systems converge to drain into the internal jugular veins (Fig. 1):

FIG. 1.

Schematic simplified diagram of cerebral venous drainage.

a. Cortical venous drainage occurs via bridging veins that cover the brain surface. These veins drain into the superior sagittal sinus which flows posteriorly to the torcula (confluence of sinuses) and then to the transverse sinus (in most people, to the right transverse sinus).

b. Deeper (anterior) venous drainage occurs into the cavernous sinuses anteriorly which in turn drain via superior and inferior petrosal sinuses into the jugular bulbs.

c. Central (thalamic) areas drain via a series of small veins into the internal cerebral veins superiorly and the basal veins of Rosenthal inferiorly. These unite (behind the splenium of the corpus callosum) to form the Great Vein of Galen which then drains via the straight sinus to join the torcula and then to the transverse sinus (in most people, to the left transverse sinus).

The final common venous outlets for all the above tributaries are the two internal jugular veins. Increases in right atrial or central venous pressures are therefore transmitted directly back to the brain. Very minor additional venous drainage is provided by orbital veins and vertebral venous plexi. Interestingly, as humans, we have largely lost the enlarged occipital-marginal sinus that provided significant drainage to the cerebral venous plexus which our australopithecine ancestors of 3 million years ago had (Falk, 1986). The vertebral venous plexi are still the main outflow for most supine mammals such as swine (Lavoie et al, 2008).

Unlike normal vessels, the dural venous sinuses are composed of dura mater lined with endothelium. They lack normal vessel layers (e.g., tunica media) and hence are more susceptible to external compression, and as a consequence they are therefore also more prone to distension. Certain sinuses (e.g., the cavernous sinus) have sympathetic innervation (van Overbeeke et al, 1995) and other venous structures have dense trigeminal innervation (Penfield and McNaughton, 1940; Strassman and Levy, 2006) that may relay distension as headache before any rise in ICP.

A Venous Hypertension Model of Hypoxia-Induced Headache

The matching of inflow and outflow volumes of blood within the cranium must be complex as so many factors (arterial blood pressure, vessel caliber, and central venous pressure) have an influence. A simplified venous hypertension model is outlined in Figure 2. An “unplugged running bath” with the taps representing arterial blood delivery, the plughole representing venous outflow, and the water level representing intracranial blood volume serves as a good, though simple analogy. In a steady state, flow in equals flow out. In clinical syndromes of outflow obstruction, flow in still equals flow out, but the pressure to drive the outflow is greater to overcome additional resistance.

FIG. 2.

Diagram of venous hypertension mechanism. CSF=cerebrospinal fluid.

In hypoxia a number of mechanisms may contribute to increased intracranial blood (and in particular venous) volume, but all center on the limiting step of venous drainage. Hypoxia is a relatively unique cause of increased cerebral blood flow in the non-injured brain since autoregulation normally prevents increased flow (e.g., secondary to normoxic exercise-induced hypertension).

In hypoxia, arterial blood flow increases to maintain oxygen delivery (Brugniaux et al, 2007). To increase venous drainage to match this increased flow, a greater venous pressure is required (i.e., the water level rises to increase pressure driving blood out the plug hole and keep a steady state of inflow=outflow).

Any phenomenon that reduces venous outflow will increase intracerebral venous pressures. Two principal factors restrict flow: vessel diameter and distal pressure.

High Altitude Research Suggesting Venous Congestion

At altitude, there is marked dilatation of retinal veins (Fig. 3) and this dilatation correlates with the severity of headache (Bosch et al, 2009). This occurs without the high ICP indicator of papilledema. The central retinal veins drain to the cavernous sinuses, and hence this dilatation may well reflect gross intracerebral venous changes. Retinal hemorrhages are common, and in survivors of severe altitude sickness, intracerebral microhemorrhages have been observed (Kallenberg et al, 2008). Such microhemorrhages are pathognomonic of venous obstruction (Tsai et al, 1995). Similarly, the retinal hemorrhages of shaken baby syndrome are now thought to result from hypoxia, not direct trauma (Geddes et al, 2003).

FIG. 3.

Retinal vasculature (A) at sea level and (B) after 24 hours at 5300 m. There is marked distension (venous greater than arterial) and the venous distension correlates with headache (Bosch et al, 2009).

Recent microcirculatory studies of sublingual circulation have, in a similar manner to retinal imaging, suggested that venous congestion occurs with hypobaric hypoxia (Martin et al, 2009). Stagnation is seen (despite the presumed rise in cardiac output) and, although technically difficult to confirm, similar stagnation in brain microcirculation probably occurs.

Near infra-red spectroscopy (NIRS) reflects regional brain oxygen saturation (rSo₂) noninvasively. Recent studies suggest that a significant component of the rSo₂ desaturation that occurs during exercise at altitude occurs due to an increase in the venous compartment of intracerebral blood volume (Heine et al, 2009; Subudhi et al, 2009).

Dubowitz et al (2009) have recently demonstrated that acute hypoxia causes a significant reduction in cerebrospinal fluid (CSF) volume with small increases in estimated cerebral blood volume (+2.3 ml (SD 2.5) and estimated brain parenchymal volume (+8.2 ml (SD 6.4), respectively). Since the MRI techniques used do not distinguish venous and parenchymal structures, this increase could also reflect venous engorgement.

Clinical Syndromes Resulting from Restricted Cerebral Venous Outflow

Idiopathic intracranial hypertension (IIH) and transverse sinus stenosis

Idiopathic intracranial hypertension (also known as benign intracranial hypertension or pseudotumour cerebri) is a condition characterized by headache, nausea, and vomiting (Binder et al, 2004). Bilateral transverse sinus stenosis is found in 90% of sufferers (Bono et al, 2005; Higgins et al, 2005; Karahalios et al,1996; Pickard et al, 2008), and has been successfully treated with endoluminal stenting (Donnet et al, 2008b; Higgins et al, 2002; Higgins et al, 2003; Owler et al, 2005). Other studies have demonstrated internal jugular stenosis in 80% (Alperin et al, 2005). Nine percent of patients with chronic tension-type headache have bilateral transverse sinus stenosis (BTSS) and idiopathic intracranial hypertension without papilloedema (Bono et al, 2008), as have 6.7% of migraine sufferers (Bono et al, 2006) (the same researchers found that none of the 45 headache-free controls had BTSS). Both IIH and high altitude headache are commonly and successfully treated with acetazolomide (Bono et al, 2008). Exertional headache has been found to occur secondarily to bilateral transverse sinus stenosis (resolving with transverse sinus stenting)(Donnet et al, 2008a). Patients who suffer with headaches with bilateral transverse sinus stenosis have higher CSF opening pressures (Bono et al, 2009). Interestingly, this sinus stenosis is not due to transverse sinus compression from raised ICP as it persists even when ICP has been lowered (Bono et al, 2005).

Jugular syndromes, superior vena cava obstructions, and Chiari malformations

Jugular syndromes blocking outflow (Graus and Slatkin, 1983), superior vena cava obstruction (Al-Hilali et al, 2003), and Chiari 1 malformations (Cinalli et al, 2005) (which commonly present in early adulthood, the same age group that suffer more with AMS) all increase cerebral venous pressures, cause headaches, and ultimately raise ICP.

Obstructive sleep apnea

Obstructive sleep apnea (OSA) is commonly associated with morning headaches (Alberti et al, 2005) and Cheyne-Stoke breathing. Both of these are common at altitude. At altitude, hypobaric hypoxia can cause central sleep apnea which in turn can exacerbate OSA (Burgess et al, 2006). The larger intrathoracic pressures and neck sizes associated with obesity and OSA are also thought to increase venous pressures.

Possible Sites of Venous Obstruction in High Altitude Headache

Venous obstruction could occur at a cranial or thoracic level.

Cranial obstruction

Although typically the superior sagittal sinus drains to the right and the inferior sagittal sinus to the left, there are marked differences between individuals, with many having a dominant transverse sinus (the right in 65%) (Durgun et al, 1993). Limitations in outflow caliber (transverse/sigmoid sinus and jugular foramen) that under normal physiological conditions are adequate might be unmasked with the increased drainage required to remove the increased blood flow of hypoxia. Cerebellar engorgement (by increasing small venous vessel distension) could further compress the thin-walled transverse sinus, restricting outflow further and compounding the problem. It is interesting to note that palsies of the abducens nerve (which traverses the petro-clival venous confluence within Dorello's canal) are the palsies more often associated with cavernous sinus pathology than raised ICP (Keane, 2005). They are also the commonest cranial nerve palsy both in IIH (Krishna et al, 1998) and AMS (Basnyat et al, 2004). IIH and altitude illness are similarly associated with increased frequency of sleep apnea and sinus thrombosis (Mokri et al, 1993).

Increased central venous pressures

Hypoxic pulmonary vasoconstriction (HPV) is a normal response to divert blood from areas of poorly oxygenated lung, to areas with better oxygenation. Hypoxia due to reduced inspired partial pressures of oxygen can result in diffuse pulmonary vasoconstriction, the degree of which varies between individuals. High altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE) are closely intertwined, and treating HAPE usually improves HACE. Increased pulmonary artery pressures might well increase central pressures which, even if only slightly raised, will increase cerebral venous pressures. Acetazolomide prevents hypoxia induced pulmonary vasoconstriction (Hohne et al. 2004). Interestingly, in patients with heart failure, acetazolomide improves central sleep apnea (Javaheri, 2006). Cerebral NIRS correlates better than hemodynamic parameters to left ventricular dysfunction (Paquet et al, 2008) and hence this supports a cardiopulmonary failing mechanism. Elevated intrabdominal pressures (as in obesity, which is very common in both IIH and OSA) could also increase venous pressures. Like headaches associated with intracerebral space occupying lesions, the headache of AMS is often worse at night or on waking. The increased central venous pressures and reduced cerebral drainage resulting from lying down may account for this.

Estimates of internal jugular vein valve incompetence in normal subjects range from 20% (Doepp et al, 2008b) to 33% (Schreiber et al, 2005). In subjects with COPD or pulmonary hypertension (akin to pulmonary hypertension secondary to hypoxic pulmonary vasoconstriction) this increases to 60% and 100%, respectively (Doepp et al, 2008a).

Other factors could compound this venous mechanism. The increase in hematocrit with acclimatization could increase flow resistance (viscosity) and hence venous pressures. The increased incidence of cerebral sinus thrombosis may also be related (Torgovicky et al, 2005).

Hypoxia itself could have a direct (possibly nitric oxide-mediated) venous effect. Nitroglycerin is a prodrug for NO (Olesen, 2008) and is well known for causing a classic headache after its use in normoxia. It also exacerbates AMS (Mazzuero et al, 2008), hence it could be hypothesized that hypoxia-induced NO formation has a greater effect on cerebral venous vessels.

Cerebral edema

One of the main arguments for cerebral edema being a component of the pathogenesis of altitude headache is that dexamethasone helps prevent it. However, dexamethasone has many effects, including cardiac effects that could account for the benefit it brings (Xia et al, 2007). The recent study demonstrating its use in preventing and treating HAPE (albeit via mechanisms not well understood at this point) might speak of its potential for reducing central pressures and subsequent cerebral venous pressures, as well (Maggiorini et al, 2006). The headache of hypoxia also occurs rapidly after exposure, which suggests that edema is not, at least in the initial stages, the principal cause of the headache. Prolonged venous hypertension however, could be a contributor to cerebral edema later in the condition.

The term “high altitude cerebral edema” is clinically defined but has a pathological component to its nomenclature that may not be correct (the patient symptoms may relate to hypoxia rather than edema); hence we need to use this term with caution.

Venous Obstruction and an Exponential Rise in ICP with Traumatic Brain Injury

Further Investigation of the cerebral venous system and its involvement in a number of clinical conditions may be aided by using hypoxia. In addition to the conditions of IIH, OSA, posterior fossa syndromes, migraine, and possibly other forms of headache, a number of other conditions such as traumatic brain injury (TBI) (Matsushige et al, 2004) may be associated with venous obstruction. In TBI, venous congestion causes reversible changes on imaging and may well contribute more to a rise in ICP than the classic parenchymal swelling to which raised ICP is normally attributed (Andeweg, 1999). Once cisterns are effaced, the venous obstruction compounds the system and may account for the exponential increase in ICP at the limits of brain compliance more than a simple hydraulic effect.

A Brief Report of an MRI Study of Venous Changes with Hypoxia

We have recently reported a study using 3 Tesla MRI to demonstrate middle cerebral dilatation in hypoxia (Wilson et al, 2011). Full methodological and objective data can be found in this article. We performed a pilot study on all 7 subjects (5 males; mean age: 34.4 years, range: 22–48 years) utilizing susceptibility-weighted images to demonstrate the venous structures. Studies were performed in normoxia and after 3 hours of hypoxia (Fio₂=12%). Five of the 7 subjects reported headaches, while 2 described a feeling of head “fullness.” Mean peripheral saturations fell from 98.3% in normoxia to 74.9% at 3 hours, while mean cerebral oxygenation (measured using near infrared spectroscopy) fell from 71.1% to 50.3%. Figure 4 demonstrates the typical change of marked venous distension seen. These changes are in-line with the retinal venous changes we have seen at altitude and similarly, the venous distension is considerably greater than arterial dilatation. This study is currently being repeated using contrast-enhanced venography to confirm these findings. However, this initial result tentatively supports a mechanism of venous engorgement in hypoxia.

FIG. 4.

Susceptibility weighted axial 3 Tesla MRI images in normoxia and after 3 hours of hypoxia (Fio₂=12%). This suggests cerebral venous congestion in hypoxia in a similar manner to retinal venous distension (see Fig. 3).

Further Proposed Mechanisms of Study

The cerebral venous system can be investigated further in a number of ways. Invasive cerebral venous pressure monitoring, venous imaging (cerebral venography), and further retinal studies during hypoxia are required. An additional study assessing central venous pressures (CVP, invasively or inferred from echocardiography) may help elucidate if hypoxia induced right heart failure is the underlying mechanism. A further study should look for BTSS in those who suffer AMS using MRV, and another study could establish if hypoxia exacerbates IIH. Studies could also be performed assessing the competence of the internal jugular vein valve (looking for retrograde flow during valsalva) in subjects who are altitude headache prone and resistant.

When investigating migraine, it should be noted that simple T1 and T2 sequences do not demonstrate venous anatomy well and hence specific (e.g., susceptibility weighted studies) should be performed when investigating idiopathic headaches.

Space Adaptation Syndrome

Space motion sickness occurs in 67% of shuttle astronauts, and theories of its pathogenesis range from vestibular disturbance through to cranial fluid shifts occurring with the loss of gravity (Hargens, 1983; Iwase and Mano, 2000; Watenpaugh and Hargens, 1996). Microgravity-induced cranial fluid shifts would in itself be expected to cause cranial venous congestion. There have been a number of reports recently of astronauts suffering headache and loss of peripheral vision. Again, this is very similar to the symptomatology of IIH, the venous pathogenesis of which is described above. Stolz et al (2009) have shown that large changes in venous outflow velocities occur with orthostatic position and lower limb pressure. There is also some evidence that, in simulated microgravity, subjects can be divided into a group that has a net cerebral inflow and a group that has a net outflow. Those with net inflow get headaches, implying a relative venous insufficiency (Hu et al, 1999). Increased venous pressure across the capillary bed would shift the Starling-Landis Equilibrium to greater filtration into tissues (Norsk, 2005), which may well be the cause of both visible facial edema (commonly seen in astronauts) and assumed cerebral edema.

Conclusions

There is increasing interest in the role of the venous system in neurological disorders from headache to multiple sclerosis (Zamboni et al, 2010). There is little evidence that hypoxic headache is due to edema. A venous component to the pathological mechanism is implied when considering similar clinical syndromes. This may relate to a relative inability to drain the cerebral vasculature adequately in physiological extremis. Perhaps experimental treatments could be considered to improve venous drainage rather than reduce cerebral edema. Further studies into the cerebral venous system may suggest mechanisms both for clinical and altitude-related headaches, and hypoxia may be a repeatable trigger that can act as a model for further studies. Finally, investigations for venous pathology should be considered in those with otherwise idiopathic headaches.

Footnotes

Acknowledgments

The authors thank The Caudwell Xtreme Everest Group, Centre for Altitude, Space and Xtreme Environment Medicine: Professor Hugh Montgomery, Dr. Dan Martin, Dr. Mike Grocott, and Dr. Jeremy Windsor; The National Hospital for Neurology and Neurosurgery, London: Mr. Laurence Watkins, Dr. Stefan Brew, Dr. Fergus Robertson, Dr. Ian Calder, Dr. Sally Wilson, Mr. Neil Kitchen, Dr. Indran Davagnanam, and Ms. Huma Sethi. The concept for this article and the original manuscript was by Mark Wilson.

Author Disclosure Statement

No competing financial interests exist.

Christopher Imray and Alan Hargens are joint senior authors.

References

Abbott

, Netherway

, Niemann

, Clark

, Yamamoto

, Cole

, Hanieh

, Moore

, David

. 2000. CT-determined intracranial volume for a normal population. J Craniofac Surg, 11:211–223.

Al-Hilali

, Nampoory

, Ninan

, Hussein

, Ali

, Samhan

, Johny

. 2003. The superior vena cava syndrome: Late presentation after hemodialysis catheter removal. Saudi J Kidney Dis Transpl, 14:186–189.

Alberti

, Mazzotta

, Gallinella

, Sarchielli

. 2005. Headache characteristics in obstructive sleep apnea syndrome and insomnia. Acta Neurol Scand, 111:309–316.

Alperin

, Lee

, Mazda

, Hushek

, Roitberg

, Goddwin

, Lichtor

. 2005. Evidence for the importance of extracranial venous flow in patients with idiopathic intracranial hypertension (IIH) Acta Neurochir Suppl, 95:129–132.

Andeweg

. 1999. Consequences of the anatomy of deep venous outflow from the brain. Neuroradiology, 41:233–241.

Bailey

, Roukens

, Knauth

, Kallenberg

, Christ

, Mohr

, Genius

, Storch-Hagenlocher

, Meisel

, McEneny

et al. 2006. Free radical-mediated damage to barrier function is not associated with altered brain morphology in high-altitude headache. J Cereb Blood Flow Metab, 26:99–111.

Basnyat

, Wu

, Gertsch

. 2004. Neurological conditions at altitude that fall outside the usual definition of altitude sickness. High Alt Med Biol, 5:171–179.

Bedford

THB

. 1935. The effect of increased intracranial venous pressure on the pressure of cerebrospinal fluid. Brain, 58:427–447.

Binder

, Horton

, Lawton

, McDermott

. 2004. Idiopathic intracranial hypertension. Neurosurgery, 54:538–551discussion 551–552.

10.

Bono

, Cristiano

, Mastrandrea

, Latorre

, D'Asero

, Salvino

, Fera

, Lavano

, Quattrone

. 2010. The upper limit of normal CSF opening pressure is related to bilateral transverse sinus stenosis in headache sufferers. Cephalalgia, 30:145–151.

11.

Bono

, Giliberto

, Mastrandrea

, Cristiano

, Lavano

, Fera

, Quattrone

. 2005. Transverse sinus stenoses persist after normalization of the CSF pressure in IIH. Neurology, 65:1090–1093.

12.

Bono

, Messina

, Giliberto

, Cristiano

, Broussard

, D'Asero

, Condino

, Mangone

, Mastrandrea

, Fera

et al. 2008. Bilateral transverse sinus stenosis and idiopathic intracranial hypertension without papilledema in chronic tension-type headache. J Neurol, 255:807–812.

13.

Bono

, Messina

, Giliberto

, Cristiano

, Broussard

, Fera

, Condino

, Lavano

, Quattrone

. 2006. Bilateral transverse sinus stenosis predicts IIH without papilledema in patients with migraine. Neurology, 67:419–423.

14.

Bosch

, Merz

, Barthelmes

, Petrig

, Truffer

, Bloch

, Turk

, Maggiorini

, Hess

, Schoch

et al. 2009. New insights into ocular blood flow at very high altitudes. J Appl Physiol, 106:454–460.

15.

Brugniaux

, Hodges

, Hanly

, Poulin

. 2007. Cerebrovascular responses to altitude. Respir Physiol Neurobiol, 158:212–223.

16.

Burgess

, Cooper

, Rice

, Wong

, Kinsman

, Hahn

. 2006. Effect of simulated altitude during sleep on moderate-severity OSA. Respirology, 11:62–69.

17.

Cinalli

, Spennato

, Sainte-Rose

, Arnaud

, Aliberti

, Brunelle

, Cianciulli

, Renier

. 2005. Chiari malformation in craniosynostosis. Childs Nerv Syst, 21:889–901.

18.

Doepp

, Bahr

, John

, Hoernig

, Valdueza

, Schreiber

. 2008a. Internal jugular vein valve incompetence in COPD and primary pulmonary hypertension. J Clin Ultrasound, 36:480–484.

19.

Doepp

, Valdueza

, Schreiber

. 2008b. Incompetence of internal jugular valve in patients with primary exertional headache: A risk factor? Cephalalgia, 28:182–185.

20.

Donnet

, Dufour

, Levrier

, Metellus

. 2008a. Exertional headache: A new venous disease. Cephalalgia, 28:1201–1203.

21.

Donnet

, Metellus

, Levrier

, Mekkaoui

, Fuentes

, Dufour

, Conrath

, Grisoli

. 2008b. Endovascular treatment of idiopathic intracranial hypertension: Clinical and radiologic outcome of 10 consecutive patients. Neurology, 70:641–647.

22.

Dubowitz

, Dyer

, Theilmann

, Buxton

, Hopkins

. 2009. Early brain swelling in acute hypoxia. J Appl Physiol, 107:244–252.

23.

Durgun

, Ilglt

, Cizmeli

, Atasever

. 1993. Evaluation by angiography of the lateral dominance of the drainage of the dural venous sinuses. Surg Radiol Anat, 15:125–130.

24.

Fagenholz

, Gutman

, Murray

, Noble

, Camargo

Jr. , Harris

. 2007. Evidence for increased intracranial pressure in high altitude pulmonary edema. High Alt Med Biol, 8:331–336.

25.

Falk

. 1986. Evolution of cranial blood drainage in hominids: Enlarged occipital/marginal sinuses and emissary foramina. Am J Phys Anthropol, 70:311–324.

26.

Fenzi

, Rizzuto

. 2008. Ataxia and migraine-like headache in a girl with a cerebellar developmental venous anomaly. J Neurol Sci, 273:127–129.

27.

Geddes

, Tasker

, Hackshaw

, Nickols

, Adams

, Whitwell

, Scheimberg

. 2003. Dural haemorrhage in non-traumatic infant deaths: Does it explain the bleeding in 'shaken baby syndrome'? Neuropathol Appl Neurobiol, 29:14–22.

28.

Graus

, Slatkin

. 1983. Papilledema in the metastatic jugular foramen syndrome. Arch Neurol, 40:816–818.

29.

Hackett

, Yarnell

, Hill

, Reynard

, Heit

, McCormick

. 1998. High-altitude cerebral edema evaluated with magnetic resonance imaging: Clinical correlation and pathophysiology. JAMA, 280:1920–1925.

30.

Hargens

. 1983. Fluid shifts in vascular and extravascular spaces during and after simulated weightlessness. Med Sci Sports Exerc, 15:421–427.

31.

Heine

, Subudhi

, Roach

. 2009. Effect of ventilation on cerebral oxygenation during exercise: Insights from canonical correlation. Respir Physiol Neurobiol, 166:125–128.

32.

Higgins

, Cousins

, Owler

, Sarkies

, Pickard

. 2003. Idiopathic intracranial hypertension: 12 cases treated by venous sinus stenting. J Neurol Neurosurg Psychiatry, 74:1662–1666.

33.

Higgins

, Owler

, Cousins

, Pickard

. 2002. Venous sinus stenting for refractory benign intracranial hypertension. Lancet, 359:228–230.

34.

Higgins

, Tipper

, Varley

, Pickard

. 2005. Transverse sinus stenoses in benign intracranial hypertension demonstrated on CT venography. Br J Neurosurg, 19:137–140.

35.

Hohne

, Krebs

, Seiferheld

, Boemke

, Kaczmarczyk

, Swenson

. 2004. Acetazolamide prevents hypoxic pulmonary vasoconstriction in conscious dogs. J Appl Physiol, 97:515–521.

36.

, Zhao

, Xiao

, Chen

, Zhong

, Yang

. 1999. Different responses of cerebral vessels to −30 degrees head-down tilt in humans. Aviat Space Environ Med, 70:674–680.

37.

Iwase

, Mano

. 2000. [Microgravity and autonomic nervous system] Nippon Rinsho, 58:1604–1612.

38.

Javaheri

. 2006. Acetazolamide improves central sleep apnea in heart failure: A double-blind, prospective study. Am J Respir Crit Care Med, 173:234–237.

39.

Kallenberg

, Bailey

, Christ

, Mohr

, Roukens

, Menold

, Steiner

, Bartsch

, Knauth

. 2007. Magnetic resonance imaging evidence of cytotoxic cerebral edema in acute mountain sickness. J Cereb Blood Flow Metab, 27:1064–1071.

40.

Kallenberg

, Dehnert

, Dorfler

, Schellinger

, Bailey

, Knauth

, Bartsch

. 2008. Microhemorrhages in nonfatal high-altitude cerebral edema. J Cereb Blood Flow Metab, 28:1635–1642.

41.

Karahalios

, Rekate

, Khayata

, Apostolides

. 1996. Elevated intracranial venous pressure as a universal mechanism in pseudotumor cerebri of varying etiologies. Neurology, 46:198–202.

42.

Keane

. 2005. Multiple cranial nerve palsies: Analysis of 979 cases. Arch Neurol, 62:1714–1717.

43.

Krishna

, Kosmorsky

, Wright

. 1998. Pseudotumor cerebri sine papilledema with unilateral sixth nerve palsy. J Neuroophthalmol, 18:53–55.

44.

Kupper

, Strohl

, Hoefer

, Gieseler

, Netzer

. 2008. Low-dose theophylline reduces symptoms of acute mountain sickness. J Travel Med, 15:307–314.

45.

Lavoie

, Metellus

, Velly

, Vidal

, Rolland

, Mekaouche

, Dubreuil

, Levrier

. 2008. Functional cerebral venous outflow in swine and baboon: Feasibility of an intracranial venous hypertension model. J Invest Surg, 21:323–329.

46.

Maggiorini

, Brunner-La Rocca

, Peth

, Fischler

, Bohm

, Bernheim

, Kiencke

, Bloch

, Dehnert

, Naeije

et al. 2006. Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: A randomized trial. Ann Intern Med, 145:497–506.

47.

Martin

, Ince

, Goedhart

, Levett

, Grocott

. 2009. Abnormal blood flow in the sublingual microcirculation at high altitude. Eur J Appl Physiol, 106:473–478.

48.

Matsushige

, Kiya

, Satoh

, Mizoue

, Kagawa

, Araki

. 2004. Cerebral venous congestion following closed head injury in a child. Pediatr Neurosurg, 40:241–244.

49.

Mazzuero

, Mazzuero

, Pascariello

. 2008. Severe acute mountain sickness and suspect high altitude cerebral edema related to nitroglycerin use. High Alt Med Biol, 9:241–243.

50.

McArdle

, Katch

. 2006. Exercise Physiology. Lippincott: Williams & Wilkins, 357.

51.

Mokri

, Jack

Jr. , Petty

. 1993. Pseudotumor syndrome associated with cerebral venous sinus occlusion and antiphospholipid antibodies. Stroke, 24:469–472.

52.

Nesterovskii Iu

, Petrukhin

, Goriunova

. 2007. [Cerebral hemodynamics in the context of differential diagnosis and management of headache in children] Zh Nevrol Psikhiatr Im S S Korsakova, 107:11–15.

53.

Norsk

. 2005. Cardiovascular and fluid volume control in humans in space. Curr Pharm Biotechnol, 6:325–330.

54.

Olesen

. 2008. The role of nitric oxide (NO) in migraine, tension-type headache and cluster headache. Pharmacol Ther, 120:157–171.

55.

Owler

, Parker

, Halmagyi

, Johnston

, Besser

, Pickard

, Higgins

. 2005. Cranial venous outflow obstruction and pseudotumor Cerebri syndrome. Adv Tech Stand Neurosurg, 30:107–174.

56.

Paquet

, Deschamps

, Denault

, Couture

, Carrier

, Babin

, Levesque

, Piquette

, Lambert

, Tardif

. 2008. Baseline regional cerebral oxygen saturation correlates with left ventricular systolic and diastolic function. J Cardiothorac Vasc Anesth, 22:840–846.

57.

Penfield

, McNaughton

. 1940. Dural headache and innervation of the dura mata. Arch Neurol Psychiatr, 44:43–75.

58.

Pickard

, Czosnyka

, Owler

, Higgins

. 2008. Coupling of sagittal sinus pressure and cerebrospinal fluid pressure in idiopathic intracranial hypertension. A preliminary report. Acta Neurochir Suppl, 102:283–285.

59.

Roach

, Bartsch

, >O

, Hackett

. 1993. Lake Louise AMS Scoring Consensus Committee. The Lake Louise acute mountain sickness scoring system. Hypoxia and Molecular Medicine. Charles S Houston: Burlington, 272–274.

60.

Roach

, Hackett

. 2001. Frontiers of hypoxia research: Acute mountain sickness. J Exp Biol, 204:3161–3170.

61.

Ross

. 1985. The random nature of cerebral mountain sickness. Lancet, 1:990–991.

62.

Schreiber

, Doepp

, Klingebiel

, Valdueza

. 2005. Internal jugular vein valve incompetence and intracranial venous anatomy in transient global amnesia. J Neurol Neurosurg Psychiatry, 76:509–513.

63.

Stolz

, Fox

, Hoffmann

, Gerriets

, Blaes

, Kraus

, Kaps

. 2009. Cranial venous outflow under lower body positive and negative pressure conditions and head-up and -down tilts. J Neuroimaging, 19:31–36.

64.

Strassman

, Levy

. 2006. Response properties of dural nociceptors in relation to headache. J Neurophysiol, 95:1298–1306.

65.

Subudhi

, Miramon

, Granger

, Roach

. 2009. Frontal and motor cortex oxygenation during maximal exercise in normoxia and hypoxia. J Appl Physiol, 106:1153–1158.

66.

Torgovicky

, Azaria

, Grossman

, Eliyahu

, Goldstein

. 2005. Sinus vein thrombosis following exposure to simulated high altitude. Aviat Space Environ Med, 76:144–146.

67.

Tsai

, Wang

, Matovich

, Lavin

, Berberian

, Simonson

, Yuh

. 1995. MR staging of acute dural sinus thrombosis: Correlation with venous pressure measurements and implications for treatment and prognosis. AJNR Am J Neuroradiol, 16:1021–1029.

68.

van Overbeeke

, Dujovny

, Troost

. 1995. Anatomy of the sympathetic pathways in the cavernous sinus. Neurol Res, 17:2–8.

69.

Watenpaugh

, Hargens

. 1996. The Cardiovascular System in Microgravity. Handbook of Physiology: Section4, Environmental Physiology. Fregly

. Blatteis

. Oxford University Press: New York, 631–674.

70.

Wilson

, Edsell

, Davagnanam

, Hirani

, Martin

, Levett

, Thornton

, Golay

, Strycharczuk

, Newman

et al. 2011. Cerebral artery dilatation maintains cerebral oxygenation at extreme altitude and in acute hypoxia—an ultrasound and MRI study. J Cereb Blood Flow Metab, 31:2019–2029.

71.

Wilson

, Newman

, Imray

. 2009. The cerebral effects of ascent to high altitudes. Lancet Neurol, 8:175–191.

72.

Xia

, Na

, Guo

, Bi

, Zhang

, Dai

. 2007. Improvement of chronic heart failure by dexamethasone is not associated with downregulation of leptin in rats. Acta Pharmacol Sin, 28:202–210.

73.

Zamboni

, Menegatti

, Weinstock-Guttman

, Schirda

, Cox

, Malagoni

, Hojnacki

, Kennedy

, Carl

, Dwyer

et al. 2010. CSF dynamics and brain volume in multiple sclerosis are associated with extracranial venous flow anomalies: A pilot study. Int Angiol, 29:140–148.

The Headache of High Altitude and Microgravity—Similarities with Clinical Syndromes of Cerebral Venous Hypertension

Abstract

Abstract

Introduction

Background to a Venous Mechanism

Clinical relevance

Cerebral Venous Comparative Anatomy

A Venous Hypertension Model of Hypoxia-Induced Headache

High Altitude Research Suggesting Venous Congestion

Clinical Syndromes Resulting from Restricted Cerebral Venous Outflow

Idiopathic intracranial hypertension (IIH) and transverse sinus stenosis

Jugular syndromes, superior vena cava obstructions, and Chiari malformations

Obstructive sleep apnea

Possible Sites of Venous Obstruction in High Altitude Headache

Cranial obstruction

Increased central venous pressures

Cerebral edema

Venous Obstruction and an Exponential Rise in ICP with Traumatic Brain Injury

A Brief Report of an MRI Study of Venous Changes with Hypoxia

Further Proposed Mechanisms of Study

Space Adaptation Syndrome

Conclusions

Footnotes

Acknowledgments

Author Disclosure Statement

References