SSC D2 - The Brain at High AltitudeUnder high altitude hypoxia, the brain and body experience a huge array of physiological challenges. Sometimes they are able to adapt, but sometimes homeostatic mechanisms fail.

Credit: WikipediaCredit: Wikimedia CommonsHigh Altitude Cerebral Oedema (HACE) is a life threatening disease in which the brain swells and stops functioning correctly and is one of 3 major altitude illnesses, alongside high altitude pulmonary oedema (HAPE) and acute mountain sickness (AMS).

Hackett and Roach1 described HACE as:

"A condition occurring in persons who have recently arrived at high altitude, usually secondary to acute mountain sickness or high altitude pulmonary edema, and marked by disturbances of consciousness that may progress to deep coma, psychiatric changes of varying degree, confusion, and ataxia of gait."

It is widely believed that AMS is a precursor to HACE2 . Much of our own research involved first understanding the mechanisms underlying AMS in order to understand that of HACE.

We felt that HACE was an interesting representation of what happens when the brain's homeostatic mechanisms fail due to high altitude hypoxia. We chose to base our project on HACE for these reasons. Despite HACE's severity, much of the condition is not fully understood, with presentation, diagnosis, risk factors, pathophysiology and treatment still being up for debate.

Aims

To gain knowledge about HACE's presentation and diagnosis, including its incidence and risk factors.To obtain a general understanding of the pathophysiological mechanisms underlying HACE.To become aware of the methods of prevention and treatment of HACE, and discuss their action and side effects.To discuss limitations of the current research, and ethical issues.This site was made by a group of University of Edinburgh medical students who studied this subject over 10 weeks as part of the SSC. This website has not been peer reviewed. We certify that this website is our own work and that we have authorisation to use all the content (e.g. figures / images) used in this website.

Thanks to Dr Nick Haslam for his guidance and assistance during this project.

Total Website Word count: 7585

Word count minus Contributions page, References page, Critical Appraisal Appendix, Information Search Report, Word Version appendix and other sections clearly marked as Appendices: 5840

Presentation and DiagnosisIntroduction

Ataxia

INTRODUCTIONHACE is an exclusively clinical diagnosis. It most commonly presents with ataxia of gait, disturbance of consciousness (DOC), progressive neurological deterioration, nausea and dyspnoea3,4. HACE is considered to be pathophysiologically related to AMS4 and as such can be classified as the end point of severe AMS.

The Lake Louise Scoring System (LLSS) is a 5-part questionnaire commonly used to diagnose AMS. It includes self-diagnosis of severity between 0 and 3 in the areas of:

headachegastrointestinal symptomsfatigue and/or weaknessdizziness/lightheadednessdifficulty sleepingAMS severity is directly related to the Lake Louise score. No such scoring system exists for the diagnosis of HACE. A diagnosis of HACE requires altered sensorium and/or neurological dysfunction (most frequently ataxia) in the context of high altitude. It is often associated with symptoms of severe AMS but this is neither necessary nor sufficient for the diagnosis. Ataxia is the most common neurological sign of HACE and is generally assessed using a simple heel-to-toe test3.

Some research into using MRI scans for a diagnosis (MRI) has been conducted, but this is impractical in remote settings.

Ataxia’s diagnostic role as an almost pathognomonic sign has been looked at in detail here.

ATAXIAAtaxia is defined as a lack of voluntary coordination of muscle movements. It can affect the trunk alone (truncal ataxia), the limbs alongside the trunk (gait ataxia), and sometimes speech.

Although ataxia may be an indicator of HACE, its specificity is reduced due to the potential for other diseases to cause it, such as hypothermia, severe dehydration and hypoglycaemia.

Wu et al. 20063

Although ataxia has been recognised and well documented as a sign of HACE, its diagnostic importance has been highlighted and confirmed in a study by Wu et al in 20063. They reported DOC as the most frequent symptom in HACE, followed by ataxia. In 15 (of 66) cases, DOC and ataxia presented at the same time. In 44 of their patients with HACE, unconsciousness appeared later than ataxia, and in 6 cases DOC did not appear for up to 5-6 days.

They concluded that ataxia can be used to indicate HACE before it progresses. HACE has a high mortality rate if untreated, so early indication could save lives.

For their diagnosis of HACE they used a 5 point criteria including:

1) symptoms appearing in non-acclimatised individuals who rapidly ascend to >3000m

2) appearance of classic HACE symptoms including disturbed consciousness and ataxia

3) exclusion of CNS infection and other hypoxic like brain pathologies

4) symptoms improving after treatment with oxygen, steroids and descent

5) studies of CT or MRI Imaging

To be diagnosed, individuals had to present with 2 or more of the criteria. The study is unclear on the diagnosis of ataxia, but explains the use of tests such as heel-to-toe walking, finger to nose pointing and Romberg’s test. Ataxia as a diagnostic test was very specific: 96% of ataxic patients were later confirmed to have HACE by MRI. It is however, a less sensitive test, as only 73% of HACE sufferers presented with ataxia. The high specificity of the test means that a presentation of ataxia at altitude should be assumed to be HACE. However, the lower sensitivity means that medics must be aware of symptoms of HACE other than ataxia.

The study size of 66 HACE cases was relatively large considering the disease’s low incidence. Also, 40 of the 48 patients with ataxia were scanned using CT/MRI imaging, with 38 of these patients presenting with HACE signs on imaging. This helped to exclude other possible diagnoses.

The population consisted of Han males aged between 20 and 48 years, making it relatively specific as no females or other ethnic groups were included in the study. There was also no statistical analysis considered for their results, which gives some doubt to their significance. Further research would be required for confirmation in a more general population.

Wu et al. 20105

Wu et al. completed a further study to reassess the link between ataxia and HACE5. They concluded, in agreement with their other study, that “ataxia seems to be a reliable sign of advanced AMS or HACE, so does altered mental status”5. In the “majority”5 of their patients ataxia was observed earlier than DOC, with the onset of ataxia being more than 12 but less than 48 hours. They found that an increase of ataxia incidence was associated with increasing incidence of HACE and worsening of AMS symptoms.

In this study the incidence of HACE was 0.26%; they had 62 cases out of a study population of 24,080. Only 47 of these cases had ataxia, giving a sensitivity of 76%. They do not state their overall specificity but of 29 patients scanned using CT or MRI, 28 presented with HACE findings giving a crude specificity of 97%. These are both similar to their previous study, highlighting the fact that ataxia at altitude is highly associated with HACE but not all HACE cases present with ataxia.

For their field diagnosis of ataxia they used a heel-to-toe test with the necessary criteria from the Lake Louise questionnaire.

The strengths of the paper lie in their appropriate cross sectional study design: allowing research into a very specific area and combating the ethical issues of taking subjects up to study altitude. They had a large HACE sample size of 62 subjects. The study concluded that a severe AMS score was significantly correlated with severe ataxia score (r=0.077, p<0.05). Despite the significant p value, the low correlation indicates uncertainty in the way in which the paper has interpreted the results.

This study did however have some major flaws. The English in the paper was poor which made understanding what they truly meant at certain times difficult. The overall study size was unclear which in turn made it unclear as to from where they actually got their 62 HACE patients. They speak of no blinding of anyone within the study, so the results could be extremely biased as diagnosis of HACE may have skewed to those presenting with ataxia. Only half of the subjects were scanned, and as there are other causes of ataxia, these 33 other subjects may not have HACE – although, this is unlikely. Also, MRI scans can only exclude other ataxia causes and not confirm HACE due to there being no pathognomonic diagnostic feature for it. Finally they do not state the nationalities or age ranges of the study population so its application worldwide is unknown.

Overall this paper is a useful contribution to the topic area but the flaws cause concern over reliability. This paper provides evidence consistent with other studies and previous medical practice on ataxia as a diagnosis of HACE. However, HACE diagnosis already included ataxia. This is a confounding factor.

INTRODUCTIONFrom our research, AMS and HACE have similar risk factors. The main risk factors that will be explored are:

Rate of ascent

GenderAgeAcetazolamide prophylaxisAcute respiratory illness

DETAILSCredit: Wikimedia CommonsCredit: Wikimedia Commons Rate of Ascent

A study by Leshem et al6, compared evacuation and death rates in different areas of Nepal as well as investigating risk factors for developing High Altitude Illnesses (HAI). This study suggests that reducing the rate of ascent decreases the number of HAI related deaths. For example, in Langtang the death rate was 8.6 times greater than Annapurna, and the rate of ascent was approximately 1.4 times faster6. However, the death rate might have been higher in Langtang as the mean starting altitude was 1.96 times greater than that of Annapurna6.

A study by Murdoch on subjects at a hotel at 3860m near Everest further reinforced this. It found that 84% of subjects that flew directly to 3740m developed AMS as they were un-acclimatised, compared to 61% in the group that walked up7.

An epidemiological study on pilgrims, in Nepal, by Basnyat et al found that pilgrims are at greater risk of developing AMS and HACE due to their rate of ascent8. Recommendations state that ascending from 3000m to 4300m should take at least four nights, as each night decreases the risk of AMS by 19%9. As the pilgrims spent two days ascending from 2000m to 4300m, the incidence of AMS and HACE was high at 68% and 31% respectively. Therefore, as a preventative measure, it is important to educate people on rate of ascent recommendations8.

The pilgrim study sample (228 people) was large, increasing the likelihood of finding a small effect with a significant p value. However, the method of randomisation used was simplistic. A stick with a pointer was rotated then dropped, 5 steps were taken in the direction of the pointer, and the nearest pilgrim was interviewed. This could have introduced selection bias, as interviewers could have learnt to manipulate the stick into landing in the direction they favoured. Pilgrims often travel in groups8, so if the stick was pointing to one, the interviewer may have chosen to interview the most ataxic pilgrim. Secondly, the design of the study involved 6 people conducting their own interviews to reach a diagnosis. Any language barriers encountered could have resulted in misdiagnoses, and a higher incidence.

Gender

Basnyat et al found that women are four times more likely to develop AMS, and three times more likely to acquire HACE8. However, it is possible that women took the ritual of fasting more seriously than men, not even drinking water, resulting in dehydration. Dehydration can mimic symptoms of AMS and HACE,

leading to a misdiagnosis and a higher incidence in women. Additionally, men and women may have different health behaviours, causing men to under-report their symptoms, resulting in missed diagnoses of men with HAIs.

Santantonio et al found that women are 2.07 times more likely to develop AMS (p=0.0035)10. This result may have greater accuracy as it was the only study to use multivariate analysis, which adjusts the results to take into account confounding factors. However, the retrospective nature of this study may have led to recall bias, as interviewees may have been aware of associations between certain risk factors and AMS, causing them to over-report the symptoms in themselves, resulting in misdiagnoses.

Contradictory to this, Lesham et al found that 68% of the people who developed HACE and HAPE together were men suggesting that men were at greater risk (p<0.005)6. However, this may be due to higher rates of HAPE in men than women. They also found no statistically significant difference between gender for AMS and HACE alone6.

Age

Leshem et al found older age to be a risk factor for developing HACE, as the average age of HACE patients was 44 compared to 38.6 years for the control group (p<0.005)6. However, the study sample was selected from patients who had been evacuated by helicopter, which costs about $5000 each. Older people may be better able to afford this cost, reducing validity of results.

Moranga et al11, found that children, between 6 and 48 months, had higher rates of AMS and lower mean haemoglobin saturation in comparison to both teenagers, aged 13- 18, and adults, aged 21-44. All children developed AMS, using the Children’s modified Lake Louise criteria for preverbal children, whereas teenagers and adults had much lower rates, 50% and 27% respectively (p < 0.01)11. A small sample size was used, 31 participants including 6 children, which may not be representative of the population, therefore further study is needed. The modified LLS is a subjective test which requires someone else to assess symptoms, rather than self-reporting in the normal LLS. As no formal reporting before ascent or after descent was conducted, symptoms may not be caused by AMS.

Acetazolamide Prophylaxis

Leshem et al. found that only 29% of HACE patients used acetazolamide prophylaxis, suggesting that acetazolamide is effective in preventing HACE (p<0.001)6. However, as the rate of prophylaxis in AMS patients was not statistically significant its efficacy in reducing AMS could not be deduced. This may be due to the lack of data on prophylaxis in the general trekking population, meaning that they could not be compared.

In the study by Bansayat et al8, only 2% of pilgrims used acetazolamide prophylaxis. This could have contributed to the high incidences of AMS and

HACE. Therefore, preventative drugs and carrying dexamethasone should be encouraged8. However, this conclusion may not be reliable, as the incidence of AMS and HACE in the 2% of pilgrims that took acetazolamide is not stated.

Acute Respiratory Illnesses

People suffering from acute respiratory illnesses had a three times greater chance of developing AMS8.

Leshem et al6 found that AMS patients were approximately twice as likely to have respiratory infections than HACE patients. HACE patients are approximately three times more likely to have acute respiratory infections when combined with HAPE6.

CONCLUSIONRate of ascent

A faster rate of ascent increases the risk of AMS and HACE. This is supported by all studies read. The use of odds ratios by two of the studies allows the reader to observe the strength of association between AMS, HACE and this risk factor.

Gender

Women are more likely to develop AMS and HACE, but the extent of this risk factor is not agreed upon. The multivariate analysis used by Santantonio et al increases the reliability of this result. Even though the findings by Leshem et al. contradict this, they cannot be accurately compared to the other studies as their results are displayed as percentages and not odd ratios.

Age

Age is a risk factor. However, the age group that are most likely to develop AMS and HACE is disputed. In the study by Leshem et al, the use of helicopter evacuation may have led to the conclusion that older people are more likely to develop HACE, as they may be better able to afford the costs involved. Perhaps the comparison of incidences in percentages for the different age groups would have been more useful in determining this risk factor. Moranga et al found that children between 6 and 48 months are most likely to develop AMS. The lack of data on the incidences between the ages of 4-13, 18-21 years and over 44 years, along with the small sample size used means that a valid conclusion cannot be deduced.

Acetazolamide Prophylaxis

It is likely that acetazolamide does decrease the risk of AMS and HACE. However, the lack of data on prophylaxis in the general trekking population, and on incidence of AMS and HACE in those that took Acetazolamide in the studies, means that a valid conclusion cannot be drawn.

Acute Respiratory Illnesses

The studies found that acute respiratory illnesses are a risk factor for the development of AMS and HACE. However, the term “acute respiratory illness” is a broad term that encompasses many different diseases. Therefore, more specific studies need to be conducted to determine which acute respiratory illnesses are risk factors and which ones are not.

INTRODUCTIONThe pathophysiology of HACE is a debated subject and is yet to be confirmed.

Due to the nature of HACE, it is unethical to induce the disease in humans for the purposes of understanding the pathophysiology, therefore most of our knowledge comes from animal models, hypoxic chamber studies and MRI scans of patients after descent from altitude.

Pre-oedema

MRI

PRE-OEDEMABlood-brain barrier (BBB) disruption can be broadly classified into haemodynamic changes and chemical mediator involvement.

Haemodynamics refers to the fluctuation of cerebral blood flow.Chemical mediators are molecules that interact and affect the BBB.Both are altered at high altitude and some of the mechanisms are discussed below.

Haemodynamic changes

It is thought that cerebral blood flow may contribute towards the development of HACE. To investigate this, Osta et al12 conducted a study to examine if altitude exposure affects cerebral autoregulation. They found that greater cerebral blood flow inhibits autoregulation, and those with the worst AMS symptoms had significantly lower levels of autoregulation. The increased cerebral blood flow could have led to greater capillary perfusion, increasing filtration pressure, and causing cerebral oedema12.

A study by Wilson et al2. also looked into the haemodynamic changes during altitude exposure. We have summarised their findings in the flow charts below.

Hypoxaemia

Venous distentionVenous distention can be caused by two mechanisms.

An increase in cerebral blood flow

Reduction in size of the cerebral transverse venous sinusesThese findings can be used to reinforce the hypothesis that AMS and HACE have similar pathophysiologies. The activation of the trigeminal vascular system produces the symptoms of AMS, whilst the increased capillary pressure leads to the vasogenic oedema seen in HACE2.

After examining both studies, we believe Wilson et al2. produced a more reliable paper on haemodynamics at high altitude. Osta et al12. introduced a confounding factor when using subjects that were also participating in a pharmacological study of HAPE, and were taking drugs that had unknown effects on cerebral autoregulation. Wilson et al. used a questionnaire to assess headache, which could have resulted in self-reporting bias and misclassification. However, using a grading system is still a sensible way in determining the severity of headaches.

Chemical mediator involvement

This section will look at two potential mediators:

Vascular endothelial growth factor (VEGF)Reactive Oxygen Species (ROS) An animal model by Schoch et al13. investigated the expression of VEGF in mice exposed to high altitude in a normobaric hypoxic chamber and its effect on the permeability of the BBB. It was discovered that the VEGF gene was up-regulated in mice at altitude, and this led to increased vascular leakage and cerebral oedema. Anti-VEGF antibodies were used to decrease vascular leakage, and dexamethasone may work by a similar mechanism13. Animal models, although useful, have their disadvantages: Vascular leakage in the mice was not detected until 7100m, and HACE occurs at lower altitude in humans, questioning the transferal of results.

The contribution of ROS to BBB integrity is questionable. D Bailey et al14. conducted a randomised controlled trial on subjects in hypoxic chambers. Venous samples and lumbar puncture tests were used to determine the presence of ROS and the protein content of CSF respectively. Stable protein concentrations in the CSF indicated no difference in vascular permeability of the BBB, despite an increase of ROS in both AMS and HACE subjects.

A possible confounding factor was introduced when seven of the subjects were administered pain killers after 15 hours of hypoxic exposure. This could have affected the MRI and venous samples, so removing their results from the study may have been more appropriate. Although this study does not prove that ROS affect the BBB, there are animal studies that provide evidence to the contrary (e.g. quercetin).

To summarise, VEGF and ROS may well contribute to the disruption of the BBB, but the list of possible mediators continues and includes: histamine, bradykinin, arachidonic acid and nitric oxide.

MRI IMAGING

Magnetic resonance imaging (MRI) is used to study brain changes in HACE. There are two common types of MRI scans: T1 scans, which look at the structure of the brain and T2 scans which look at fluid in the brain15. Thus, T2 imaging can be used to detect cerebral oedema. There are two main types of oedema: vasogenic, which occurs in the extracellular space and affects mainly white matter regions and cytotoxic, which occurs within cells and involves grey matter16,4. MRI can also be used to detect microhaemorrhages in the brain16. This section discusses studies which used MRI to look at the pathophysiology of HACE.

mriCredit: Wikimedia commonsGross cerebral changes

Various studies17,4 have concluded that oedema in HACE is primarily vasogenic. A case-control study by Hackett et al4. used T2 weighted MRI imaging to look for oedema in the brains of fifteen subjects. The cases were nine males with HACE who had been evacuated from altitude; the control group had also been to altitude but did not develop HACE. White matter oedema was found in seven of the nine cases. An area that was particularly affected was the splenium of the corpus callosum. The oedema was concluded to be primarily vasogenic due to its location.

There were many limitations in the study. Evacuation by helicopter introduced selection bias, as the participants were more likely to be prepared with insurance, mobiles and medication. Also, the participants were all young healthy men and not representative of the general population.

A further case control study17 agreed that oedema in HACE is primarily vasogenic. Microhaemmorhages were also found in the corpus callosum of HACE subjects and, since these persisted for months, are useful in retrospective diagnosis. However, some patients were diagnosed retrospectively, introducing recall and misclassification bias – for example, one of the controls calculated his AMS score after returning to lower altitude.

Is HACE a severe form of AMS?

It is not clear if HACE and AMS are varying severities of the same disease1,4. We failed to find any primary research to support that they share the same pathophysiology and instead looked at two studies which concluded that they are different.

The first of these18 aimed to determine whether AMS is related to either vasogenic or cytotoxic oedema. Nine volunteers were exposed to simulated hypoxic conditions for six hours. The researchers recorded symptoms of AMS and used MRI to search for cerebral oedema. They concluded that vasogenic oedema occurred alongside AMS but no correlation was found between them.

However, they found that additional cytotoxic oedema occurred with severe AMS. This contrasts with the vasogenic mechanism of HACE4 and suggests a different pathophysiology.

There were a number of limitations with this study. It was conducted with the patients lying down, which is unlikely to be a very realistic representation of mountaineers or others likely to suffer from HACE. Also, only healthy males took part, which doesn’t represent the wider population.

The second study19 included twenty subjects in a cross-over trial. They were exposed to a simulated hypoxic environment and subjected to either exercise or rest. 50% of the resting patients and 70% of the active patients suffered from AMS, but “extracellular water accumulation” occurred in all patients. They concluded that AMS and HACE are not linked since no correlation was found between this water accumulation and AMS.

However, the time period between exposures may not have been long enough to ensure that they did not affect each other. There was no blinding which may introduce observation bias when interpreting the MRI images. The subjects were exposed to normal oxygen levels for up to 15 minutes when being transported from the hypoxic chamber to the MRI scanner, which may have been enough time for signs of oedema to be resolved. Finally, the jump from results to conclusions seems large – HACE is a clinical diagnosis so the detection of small amounts of fluid may not necessarily indicate the early stages of this disease.

INTRODUCTIONMuch of the research into the treatment of HACE focuses on preventing AMS, which is widely considered to be a precursor to the condition. It targets many of the mechanisms thought to be associated with the development of cerebral oedema, including inflammation and reactive oxygen species. Prompt use of supplementary oxygen and descent are both accepted to be vital measures in management of HACE4.

From research, four potential pharmaceutical prophylactic measures for AMS were found: acetazolamide, dexamethasone, quercetin and Gingko biloba extract.

TL: dexamethasone; TR: quercetin; BL: Ginko biloba leaves; BR: acetazolamide. Credit: Wikipedia. TL: dexamethasone; TR: quercetin; BL: Ginko biloba leaves; BR: acetazolamide. Credit: Wikimedia Commons.

MECHANISMS OF ACTIONThe four drugs researched varied widely in their mechanism of action.

Acetazolamide is a carbonic anhydrase inhibitor which is used in acclimatisation to high altitudes and is thought to stimulate ventilation. Although the mechanisms are unclear it is thought to increase bicarbonate secretion by the kidneys and induce metabolic acidosis leading to this effect20.

Dexamethasone is a glucocorticoid agonist and is known to have anti-inflammatory affects20. Levine et al.21 found that the mechanism by which dexamethasone acts is relatively unclear in the setting of high altitude. However, they speculated that it may exert its effect by improving the integrity of capillary membranes and inducing cerebral vasoconstriction. Levine et al. also proposed that dexamethasone counteracts the lassitude and malaise of AMS. However, the study was conducted in simulated conditions; it is possible that different mechanisms may occur at altitude.

Standardised Ginkgo biloba extract has been proposed as an effective and inexpensive agent against AMS. Gertsch et al.22 proposed Ginkgo’s anti-hypoxic effects to be largely due to its antioxidant activity, which has been demonstrated to prevent oxidative damage in important cellular processes and structures including the transmembrane Na+K+ATPase, ATP synthesis within mitochondria and fat membranes. However, this study used only a short period of exposure to high altitude (4 hours) which may have skewed findings; research has shown that symptoms of AMS can be delayed up to 3 days under conditions of a more gradual ascent. Furthermore, the participants were subject to a physiologically demanding rapid ascent from sea-level to 4200m in 3 hours. A rapid ascent profile over 3000m is known to trigger a symptomatic response in the majority of human subjects.

A study by Patir et al.23 investigated the molecular mechanisms of quercetin in rats at altitude in order to investigate its suitability as a prophylactic measure. It concluded that it had effective anti-oxidant and anti-inflammatory effects; the levels of white blood cells, red blood cells, lymphocytes, monocytes, granulocytes, MCV, HCV, PLT, reactive oxygen species and NF B were reduced, κand the levels of anti-oxidants were increased compared to the rats without treatment. The histology was returned to that of normoxia. These were all factors speculated to be involved in the pathophysiology of HACE. However this only provides an animal model and it is limited in the application to the human population. Moreover, the diagnosis of HACE has a strong clinical component (Presentation & Diagnosis) and the findings of cerebral edema in rats may not be comparable to HACE.

SIDE EFFECTSThe drugs showed differences in side effect profiles as well as efficacy.

The Classical Therapeutics

Acetazolamide and dexamethasone have been thoroughly trialled and researchers have concluded that they are responsible for various side effects. These include nausea and paraesthesia for acetazolamide and hyperglycaemia, glycosuria, withdrawal and other mental health effects for dexamethasone21,24.

Newer/Non-conventional Pharmaceuticals

Quercetin and Ginkgo biloba extract are less conventional prophylactic agents for AMS/HACE, with quercetin being a particularly new drug in the field. From

the studies, no notable side effects for either of these treatments were observed22,23. However, it is important to reiterate that the quercetin trial was in rats, making it extremely difficult to construct an accurate side effect profile. Gingko biloba was found to have a side effect profile similar to that of placebo; it had the least adverse effects of all of the researched drugs22.

As seen in the table21-24 the potentially toxic side effects of dexamethasone and acetazolamide may limit their use as prophylactic agents in comparison to Ginkgo and quercetin which have lower side effect profiles.

RESULTSSummary of Results of StudiesSummary of Results of Studies21,22,23,25Dexamethasone

Levine et al.21 found that dexamethasone, administered at 4mg every 6 hours, reduced the symptoms of AMS by 63% in the subjects and by only 23% in the controls. They speculated that the relief of symptoms was primarily due to the central mechanisms of the drug relieving nausea and enhancing mood, rather than by facilitating acclimatisation. Unfortunately, due to severe reactions to high altitude and side effects, two participants had to withdraw at various points of the study and their values weren’t recorded, seriously limiting the power of the study.

Ginkgo biloba

The study22 on Gingko was carried out as a double-blind, randomised, placebo-controlled trial. It used 26, well-matched participants. Subjects with recent hospitalisations or chronic medical illnesses were excluded, as were individuals with previous high altitude exposure who did not report AMS symptoms.

Subjects were asked to refrain from:

ascending above 2km for 1 week prior to ascent;

taking prophylactic agents against AMS;

using any Ginkgo products 1 month prior to ascent.

This reduced the risk acclimatisation and other drugs having a confounding effect on the study.

The study was conducted over 2 days. On day 1, data was collected at sea-level, intermediate altitude and high altitude. On day 2, data was collected at intermediate and high altitude. The subjects were transported to these altitudes by vehicle and were sheltered at them. This made the study less generalisable to skiers or mountaineers who are exposed to the mountain environment. They were also limited to 30 minutes of exertion. Research suggested that exertion tended to increase the incidence of AMS, so the subjects were limited to non-

aerobic activity to prevent significant variation in exercise exposure from influencing the results. Again, as those who go to altitude generally exert themselves, the study loses application.

The study observed severe AMS symptoms affecting only 16.7% of the Ginkgo group and 64.3% of the placebo group at the end of day 1. One major flaw in the study was that the researchers did not include any of the data collected on day 2 due to it not being statistically significant; day 2 also did not include all of the subjects as some had met predetermined safety criteria. However, it is observed that AMS has a delayed onset, frequently presenting after 24 hour.

Acetazolamide

In a systematic review and meta-analysis24 acetazolamide was found to have an overall preventative effect with an odds ratio of 0.36.

Unlike other studies, the acetazolamide study had a large sample size (1512 subjects) meaning that the results may be less affected by chance and therefore have a higher statistical power. Furthermore, it was blinded and excluded trials with simulated descent or which included an indigenous population.

However, as with each of the other studies, difficulty came in diagnosis of AMS as is encompasses a spectrum of disorders. This made comparison particularly difficult in the meta-analysis there was no standard definition used across the papers compared.

It was interesting to observe , in a comparison of acetazolamide and Ginkgo biloba, that the incidence of AMS was 34% for placebo, 12% for acetazolamide, 35% for Ginkgo and 14% for combined acetazolamide and Ginkgo. This suggests a negative interaction between the two drugs, with acetazolamide’s efficacy being reduced when combined with Ginkgo22.

Quercetin

A case control trial23 on Quercetin did not evaluate the efficacy of treatment but looked into the mechanisms of the drug compared to dexamethasone. There was no mention of variation between rats within each group but overall it was concluded that Quercetin had a more beneficial effect in preventing the mechanisms thought to be involved in HACE investigated.

However, in this study, only specific mechanisms were investigated and the dose of Quercetin was tailored to these. In comparison, a standard dose of dexamethasone was used potentially causing bias.

There was also no mention of blinding of researchers or randomisation which may have also introduced bias – especially concerning the histological analysis.

CONCLUSION

Diagnosing HACE is challenging as it occurs in remote, high altitude regions. Ataxia was found to be a highly specific early indicator of HACE, more so than DOC. If ataxia presents then something more serious than AMS should be considered. Healthcare workers on expeditions at altitude should assume any ataxia to be HACE, as this ensures prompt evacuation.

The incidence of HACE is dependent on various risk factors, of which rate of ascent was found to be the most significant. Other suggested risk factors are age, acute respiratory illnesses and gender. Further research would identify at risk groups who should take prophylactic treatment to prevent HACE.

Pathophysiological mechanisms of HACE are still relatively unknown. There is strong evidence to suggest that there is vasogenic oedema caused by haemodynamic changes in disruption of the BBB. We could not find any convincing evidence to prove that HACE is a severe form of AMS. These pathophysiological mechanisms may seem abstract and of limited clinical use, but they allow potential targets for treatment.

After considering the strengths and weakness of selected studies, it was concluded that the more classical prophylaxis against HACE (acetazolamide and dexamethasone) had the greatest efficacy. However, Ginkgo biloba and quercetin had more favourable adverse effect profiles. The increase in studies on new pharmaceuticals opens many new doors for HACE research and adds to the current understanding of the effects of hypoxia on the brain at high altitude.

The remote environment in which HACE presents and the difficulty in obtaining large samples creates research challenges . This has resulted in questionable ethics in certain studies. One study had not given subjects recognised prophylaxis before ascent5. Another involved invasive implantation of telemetric ICP monitoring devices using burr holes in 3 subjects prior to ascent26. The development of ethics committees and a formal ethical review process could make similar future studies unlikely to be approved. Many studies used hypobaric chambers to avoid the ethical conundrum of taking subjects to altitude . However, this involves inducing illness in previously healthy subjects. In 1989, one subject was re-exposed to hypobaria despite having experienced HACE in the first experiment; the MRI scans were not analysed until after both exposures21. Although hypobaric chambers are more accessible and medical care is more rapidly available, the subjects are still equally exposed to the dangers of high altitude.

In conclusion, HACE is a fascinating but under-researched area. Future studies could provide further insight into the response of the brain, and raising awareness through public health programmes could help lower incidence.

APPENDIX 1: CONTRIBUTIONSAlex Christides:

Produced ‘MRI imaging’ pageCo-produced ‘conclusion’ page

Clodagh Mitchell:

Co-produced “Prevention and Treatment” pages, sourced information on acetazolamide and quercetinCo-produced the “Critical-Appraisal”Co-produced the “Conclusion”Greig Torpey

Produced Presentation and Diagnosis pagesHarry Newmark:

Produced the pathophysiology ‘Introduction’ page.Co-produced ‘Pre-oedema’ page.Contributed pictures for webpage header design.James Vipond:

Co-produced “Incidence & Risk Factors: Details” page.ReferencingOliver Grieve:

Co- produced “Prevention and Treatment” pages sourcing the information on dexamethasone.Co- produced the “Critical Appraisal”Sabrina Das:

Co-produced “Incidence & Risk Factors: Details”.Produced “Incidence & Risk Factors: Conclusion” page.Co- produced “Pre-oedema page”.Seamus Culshaw:

Co-produced “Prevention and Treatment pages”, sourcing the information on Ginkgo biloba.Co-produced Home Page.Took charge of managing the aesthetics of the website.

APPENDIX 2: CRITICAL APPRAISALA critical appraisal was carried out on the following paper

Hackett, P., Yarnell, P., Hill, R., Reynard, K., Heit, J. and McCormick, J. (1998). High-altitude cerebral edema evaluated with magnetic resonance imaging: clinical correlation and pathophysiology.Jama, 280(22), pp.1920–1925

Click here for a link to the paper

Aims:

The study aimed to investigate the pathophysiological aetiology of oedema in high altitude cerebral oedema (HACE). Specifically whether cerebral oedema in HACE is cytotoxic or vasogenic in origin. The study correlated pathological

changes in either white or grey matter on MRI scans with either vasogenic or cytotoxic oedema. As a secondary aim the authors hoped that such MRI changes could then be used to aid the diagnosis HACE.

Study design:

A Case comparison study

Sample Population:

Patients with a clinical diagnosis of HACE who were admitted to 2 community hospitals, accessed by helicopter in Colorado and Alaska, within a 4 year period.

Subjects:

9 subjects, all men, aged between 18-35. 4 of them were skiers and 5 were mountain climbers. Eight of them had HAPE as well as HACE. They all had various previous exposure to altitude and 4 had experienced AMS previously. There was also a control group which consisted of 6 climbers.

Intervention:

An MRI scan was obtained from all subjects. The control group were given an MRI scan within 24 hours of returning to sea level. However, in the cases the time between onset and MRI varied between 16-132 hours.

Repeat MRI scans were performed on 5 cases during recovery and 4 cases after complete recovery.

Outcome measure:

As stated above, the MRI scans were analysed for evidence of increased T2 signals in either grey(indicating cytotoxic oedema) or white matter(indicating vasogenic oedema)

Results:

MRI imaging in 7 of 9 patients with HACE demonstrated strikingly increased T2 signals in the corpus callosum with normal grey matter therefore concluding that the oedema was most likely vasogenic due to its location in the white matter.4 patients with initial abnormal MRI results still had the abnormalities on repeat imaging between 3 and 11 days later, although they showed clinical improvement.All high altitude controls, both healthy and with HAPE, did not show MRI abnormalities.Limitations

Although the control group was matched for mean age, sex and length of altitude exposure, further stratification of the control group may have been beneficial in

comparing specific characteristics; for example, those with HACE and HAPE, HAPE only and no altitude sickness.However, confounding factors may have arisen due to variation within the cases. For example, different initial treatment was received and different previous altitude experience may have contributed to acclimatisation. Furthermore, they were each carrying out different forms of exercise and there was variation in the time between onset of symptoms and MRI imaging.There was a small sample size and all participants were male with a narrow age range, limiting the application of the results.Descent from altitude was by helicopter, which may cause bias as the participants were more likely to be prepared with insurance, mobiles and medication organised.The authors also treated the participants which could introduce selection bias and affect the interpretation of the results.There was uncertainty of whether the white matter signals were caused by HACE or other factors such as infection, anoxic encephalopathy, vasculitis or high altitude.2 patients with HACE did not demonstrate the MRI abnormalities; possibly because the other patients reached a higher altitude, had a longer exposure and took longer to be evacuated.Final comments:

As a group we conclude that this is a particularly useful paper because it both addresses a potential mechanism for HACE and suggests potential diagnostic criteria. The paper supports current theories as it is consistent with the findings of others. Furthermore, exposure to high altitude was not simulated, like in other papers. However, variation between subjects and poor sample selection limits the application of the findings

APPENDIX 3: INFORMATION SEARCH REPORTTo begin our information search we used two papers given to us by our tutor ((Hackett et al 2004)1 and (Hackett et al 1998)4). We then used the references from these papers combined with a Medline/ Ovid search (see picture below) to identify appropriate papers.

APPENDIX 4: REFERENCES1. Hackett, P. H. and Roach, R. C. 2004. High altitude cerebral edema. High altitude medicine & biology, 5, 136-146. (review)

– A comprehensive review of HACE summarising incidence, pathophysiology, prevention and treatment.

2. Wilson, M. H., Davagnanam, I., Holland, G., Dattani, R. S., Tamm, A., Hirani, S. P., Kolfschoten, N., Strycharczuk, L., Green, C. and Thornton, J. S. 2013. Cerebral venous system and anatomical predisposition to high altitude headache. Annals ‐of neurology, 73, 381-389. (Primary research paper)

3. Wu, T., Ding, S., Liu, J., Jia, J., Dai, R., Liang, B., Zhao, J. and Qi, D. (2006). Ataxia: an early indicator in high altitude cerebral edema. High altitude medicine & biology, 7(4), pp.275–280. (Primary research paper)

-Large study of high altitude railway workers that conducted research into presentation of ataxia as an early indicator of HACE.

4. Hackett, P., Yarnell, P., Hill, R., Reynard, K., Heit, J. and McCormick, J. (1998). High-altitude cerebral edema evaluated with magnetic resonance imaging: clinical correlation and pathophysiology.Jama, 280(22), pp.1920–1925. (Primary research paper)

– An important study investigating the pathological mechanisms of cerebral oedema at high altitude and concludes this to be mainly vasogenic in nature

5. Wu, T., Siqing, M., Huiping, B., Minming, Z. (2010). Ataxia, acute mountain sickness, and high altitude cerebral edema. Engineering sciences, 11(2),pp.38–46 (Primary research paper)

6. Leshem, E., Pandey, P., Shlim, D., Hiramatsu, K., Sidi, Y. and Schwartz, E. (2008). Clinical Features of Patients With Severe Altitude Illness in Nepal. Journal of Travel Medicine, [online] 15(5), pp.315-322. Available at: http://dx.doi.org/10.1111/j.1708-8305.2008.00229.x [Accessed 18 Oct. 2014]. (Primary research paper)

7. Murdoch, D. (1995). Altitude Illness Among Tourists Flying to 3740 Meters Elevation in the Nepal Himalayas. Journal of Travel Medicine, 2(4), pp.255-256.(Primary research paper)

8. Basnyat B, Subedi D, Sleggs J, Lemaster J, Bhasyal G, Aryal B et al. Disoriented and ataxic pilgrims: an epidemiological study of acute mountain sickness and high-altitude cerebral edema at a sacred lake at 4300 m in the Nepal Himalayas. Wilderness \& environmental medicine. 2000;11(2):89–93. (Primary research paper)

– a large study investigating the risk factors for AMS and HACE in pilgrims

9. Basnyat B, Lemaster J, Litch JA. Everest or bust: a cross sectional, epidemiological study of acute mountain sickness at 4243m in the Himalayas. Aviat Space Environ Med. 1999;70:867-873 (Primary research paper)

10. Santantonio M, Chapplain J, Tattevin P, Leroy H, Mener E, Gangneux J et al. Prevalence of and risk factors for acute mountain sickness among a cohort of high-altitude travellers who received pre-travel counselling. Travel Medicine and Infectious Disease. 2014;12(5):534-540. (Primary research paper)

11. Moraga, F., Osorio, J. and Vargas, M. (2002). Acute Mountain Sickness in Tourists with Children at Lake Chungará (4400m) in Northern Chile. Wilderness & Environmental Medicine, 13(1), pp.31-35. (Primary research paper)

12. Van Osta A, Moraine J, M\’elot C, Mairb\”aurl H, Maggiorini M, Naeije R. Effects of high altitude exposure on cerebral hemodynamics in normal subjects. Stroke. 2005;36(3):557–560. (Primary research paper)

13. Schoch, H. J., Fischer, S. and Marti, H. H. 2002. Hypoxia induced vascular ‐endothelial growth factor expression causes vascular leakage in the brain. Brain, 125, 2549-2557. (Primary research paper)

14.Bailey, D. M., Roukens, R., Knauth, M., Kallenberg, K., Christ, S., Mohr, A., Genius, J., S Hagenlocher, B., Meisel, F. & Mceneny, J. 2005. Free radical-mediated damage to barrier function is not associated with altered brain morphology in high-altitude headache. Journal of Cerebral Blood Flow & Metabolism, 26, 99-111. (Primary research paper)

15. Fuller, G. and Manford, M. (2011). Neurology. London: Elsevier Health Sciences UK. (Textbook)

16. Wilson, M. H., Newman, S. and Imray, C. H. 2009. The cerebral effects of ascent to high altitudes. The Lancet Neurology, 8, 175-191. (Primary research paper)

17. Kallenberg, K., Dehnert, C., Dörfler, A., Schellinger, P. D., Bailey, D. M., Knauth, M. and Bärtsch, P. D. 2008. Microhemorrhages in nonfatal high-altitude cerebral edema. Journal of Cerebral Blood Flow & Metabolism, 28, 1635-1642. (Primary research paper)

18. Schoonman, G., Sándor, P., Nirkko, A., Lange, T., Jaermann, T., Dydak, U., Kremer, C., Ferrari, M., Boesiger, P. and Baumgartner, R. (2008). Hypoxia-induced acute mountain sickness is associated with intracellular cerebral edema: a 3 T magnetic resonance imaging study. Journal of Cerebral Blood Flow & Metabolism, 28(1), pp.198–206. (Primary research paper)

19. Mairer, K., Göbel, M., Defrancesco, M., Wille, M., Messner, H., Loizides, A., Schocke, M. and Burtscher, M. (2012). MRI Evidence: Acute Mountain Sickness Is Not Associated with Cerebral Edema Formation during Simulated High Altitude. PLoS ONE, [online] 7(11), p.e50334. Available at: http://dx.doi.org/10.1371/journal.pone.0050334 [Accessed 18 Oct. 2014]. (Primary research paper)

20. Rang, H. and Dale, M. (2012). Rang and Dale’s pharmacology. Edinburgh: Elsevier/Churchill Livingstone. (Textbook)

21. Levine, B., Yoshimura, K., Kobayashi, T., Fukushima, M., Shibamoto, T. and Ueda, G. (1989). Dexamethasone in the treatment of acute mountain sickness. New England Journal of Medicine, 321(25), pp.1707-13. (Primary research paper)

22. Gertsch J. Randomised, double blind, placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: the prevention of high altitude illness trial (PHAIT). BMJ. 2004;328(7443):797-0. (Primary research paper)

23. Patir, H., Sarada, S., Singh, S., Mathew, T., Singh, B. and Bansal, A. (2012). Quercetin as a prophylactic measure against high altitude cerebral edema. Free Radical Biology and Medicine, [online] 53(4), pp.659-668. Available at: http://dx.doi.org/10.1016/j.freeradbiomed.2012.06.010 [Accessed 18 Oct. 2014]. (Primary research paper)

24. Low E, Avery A, Gupta V, Schedlbauer A, Grocott M. Identifying the lowest effective dose of acetazolamide for the prophylaxis of acute mountain sickness: systematic review and meta-analysis. BMJ. 2012;345(oct18 1):e6779-e6779. (Systematic review)

– a comprehensive systematic review which concludes acetazolamide to be effective in prevention of HACE.

25. Ritchie N, Baggott A, Andrew Todd W. Acetazolamide for the Prevention of Acute Mountain Sickness-A Systematic Review and Meta-analysis. Journal of Travel Medicine. 2012;19(5):298-307. (Systematic review)

26. Wilson M, Milledge J. Direct Measurement of Intracranial Pressure at High Altitude and Correlation of Ventricular Size with Acute Mountain Sickness. Neurosurgery. 2008;63(5):970-975. (Primary research paper)

APPENDIX 5: WORD VERSION

SSC D2 Word Versiob