High Altitude Cerebral Edema: Improving Treatment Options

Round 1

Reviewer 1 Report

Zelmanovich and colleagues wrote a very interesting review about a still neglected topic, the high altitude cerebral edema (HACE). It is a very unusual, but lethal condition produced by environmental-induced hypoxia. It deserves to be published, but in its present form because I have a main concern that should urgently be addressed.

To the best of my knowledge, HACE is NOT an extreme form of acute mountain sickness or AMS. AMS and HACE are the mildest and the most severe forms respectively of what is called High Mountain Illnesses or HAIs. I am going to explain myself. Mountain climbers could suffer just AMS without developing HACE or high altitude pulmonary edema (HAPE). More interestingly, a mountain climber might suffer from HACE without any prior symptom of AMS, and after an apparently adequate process of acclimatization. That's why very professional, trained mountain climbers “unspectedly” die at high altitude. In summary, there is NOT a continuum between AMS and HACE. In fact, AMS, HACE, HAPE, acute mountain sickness (Monge's disease) and high altitude sleep disorders constitute a spectrum of HAIs.

My last concern is that there is no epidemiology information about the prevalence of this disease and, for instance, whether it impacts more in Andeans compared to Tibetans. It does not only affect people climbing for recreational purposes, but also to dwellers of the highlands. A few lines dealing with this issue would help because there are about 35 million people living over 2500 m height. It is not everything about the health of mountain climbers.

A quick speculative question. Is there any evidence about a putative “reentry HACE”, as it occurs with HAPE? Researchers pay attention to the physiological changes during the ascent, but not to what happens during the descent to sea level, when there is an overflooding of oxygen. It may cause a kind of “priming” that conditions the reaction of the body the next time it is exposed to high altitudes, if you understand what I mean. You may add a couple of lines regarding this idea in the introduction.

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 2 Report

1. Line 78: “varies” instead of “vary”?
2. Line 105: AQP4 should be defined at the first use.
3. Dexamethasone are listed for both prevention and treatment of HACE, what’s the difference in mechanisms when it is used for prevention compared to when it is used for treatment?
4. What are the pressure settings of the hyperbaric chambers?
5. Figure 2 indicates the association of ischemic insult and AQP4 water channel expression in a rat model of cerebral ischemia. However, an ischemia model cannot represent the pathophysiology of HACE, which is induced by hypobaric hypoxia.

Author Response

Reviewer 2

Thank you for your important comments and insights. I have addressed your comments as detailed below.

 

Point 1: Line 78: “varies” instead of “vary”?

 

Response 1: I have made grammatical change.

 

Point 2: Line 105: AQP4 should be defined at the first use.

 

Response 2: I have defined AQP4 and edited where it was later defined (line 237)

 

Point 3: Dexamethasone are listed for both prevention and treatment of HACE, what’s the difference in mechanisms when it is used for prevention compared to when it is used for treatment?

 

Response 3: The mechanism by which dexamethasone treats HACE appears to be unknown. I have thus offered a speculative discussion of potential mechanisms based on research of dexamethasone in the setting of intracranial tumors, as well literature discussing potential mechanistic actions of dexamethasone in AMS.

 

Point 4: What are the pressure settings of the hyperbaric chambers?

 

Response 4 Based on literature review the pressure setting is about 2 psi, or 105mmhg - however, higher settings can be used. I have included this information in the respective section.

 

Point 5: Figure 2 indicates the association of ischemic insult and AQP4 water channel expression in a rat model of cerebral ischemia. However, an ischemia model cannot represent the pathophysiology of HACE, which is induced by hypobaric hypoxia.

 

Response 5: I have chosen to remove the discussion as it relates to ischemic edema. I have retained a discussion regarding statin medications but chose to rely more on clinical evidence, as well as indirect evidence of pre-clinical studies of revealing statins' modulatory action on AQP4.

 

Additional edits: I have also removed “pregnancy” from Table 1 as this is a contraindication, rather than an adverse effect, and thus does not belong in this column. 

 

 

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

The authors have adequately addressed all my questions. The work is now nicely done. Just a minor suggestion. The letters in the diagram of Fig.2 are too small. They should be enlarged a little bit to make them legible.

Thank-you