On the Surface: Pseudotumor Cerebri, Intracranial Hypertension and SANS
Pseudotumor cerebri (PTC) and intracranial hypertension (IH) refer to conditions whose predominant symptom is increased cerebral spinal fluid (CSF) pushing against the optic nerve. The condition is said to begin with a severe headache that is worse while laying down. The head pain is accompanied by vision changes or vision loss, and sometimes also synchronous pulsatile tinnitus (pulse based ringing in the ears described as a whooshing sound), and nausea. If sufficient intracranial pressure builds up, other symptoms may develop including sharp nerve pain in the arms, legs, and back, severe neck stiffness, numbness or tingling in hands, feet, and face, depression, exercise intolerance, and memory difficulties. These symptoms occur absent a tumor, and hence, the name pseudo or false tumor.
In contrast, SANS appears to develop without the severe headache. Microgravity plays some interesting tricks on fluid dynamics (and our ability to measure it), however, and so it is not clear whether elevated intracranial pressure can develop in microgravity and/or if it does develop, is offset by other changes in pressure dynamics. One short term study of acute changes in pressure during the simulated microgravity of a prolonged head down tilt test and a 24 hour parabolic flight, concluded that intracranial hypertension does not exist during space flight. It should be noted, that even during the short exposure to microgravity in this particular study, intracranial pressure did increase over what is observed on earth. It simply did not increase to the degree seen in intracranial hypertension. Moreover, how changes during 24 hours of microgravity accord with the typical 6-12 month duration space flight where SANS is typically observed, remains to be elucidated.
Despite the question of whether or not intracranial hypertension exists in space, both SANS and its earthbound counterparts inevitably result in the same neuro-ocular deformations. These include: choroidal folds, optic disc edema, cotton-wool spots, globe flattening, and refraction changes. So here we have two conditions, affecting completely different populations, with descriptive diagnoses that focus on what are perceived to be the predominant manifestations of the disease process. In women, the focus is on the increased intracranial pressure that seemingly results in optic nerve damage, while in the astronauts, the focus is on the optic damage either absent intracranial hypertension or preceding it. Conceivably, in both conditions optic nerve damage begins long before sufficient pressure changes evoke head pain. That is, there may be a time course to this process wherein slight changes in pressure exert damage long before the process is fully fomented and the other symptoms emerge. The time course may be such that recognition and attribution of symptoms occurs late in women but early in male astronauts, if only because researchers are looking more closely at the astronauts.
Potential differences in time course aside, could these two presumably discrete conditions, developing in such widely disparate populations, share other commonalities? Yes, and interestingly enough, one of the primary threads leads us to hormones and nutrients of all places. Sure, it was obvious that hormones would be involved in the IUD induced cases, but in male astronauts too? Yep.
The Nitty Gritty: Altered Steroidogenic Enzymes
It turns out that there is a good chance that steroidogenic enzymes responsible for metabolizing glucocorticoid and mineralcorticoid hormones and regulating salt/water balance in both the kidneys and the choroid plexus (the part of the brain where spinal fluid is produced and released) are upregulated in folks who develop these conditions.
In the women, the process can be initiated by either the progestin (levonorgestrel) released by the IUD, implant, shot, or by excessive weight. Both the continuously high dose of levonorgestrel released by the IUD and excessive weight appear to independently, and likely synergistically when combined, force a shift in the downstream enzymes to compensate. In the case of the IUD, many of the enzymes along the steroidogenic pathways are re-regulated because of the progestin. For example, 17B-HSD2 (17 beta hydroxysteroid dehydrogenase type 2), the enzyme responsible for converting estradiol to the less potent estrone and testosterone to the less potent androstenedione is downregulated. This means that women who use these IUDs may have higher testosterone concentrations, which would then produce a feedback loop linked to insulin resistance and other metabolic changes that also change kidney electrolyte balance. If the woman is overweight to begin with and/or has polycystic ovarian syndrome (PCOS), testosterone concentrations were already likely elevated and will be exacerbated.
Another enzyme further down the pathway is also upregulated, 11B-HSD (11 beta hydroxysteroid dehydrogenase) and this is the important one for our purposes. 11B-HSD controls cortisol and aldosterone concentrations. Hyperactive 11B-HSD results in altered cortisol and autonomic response and elevated aldosterone concentrations (sometimes called primary, secondary or idiopathic aldosteronism). Elevated aldosterone skews salt/water balance in the kidneys, and most notably, in many instances will increase blood pressure, but may also, and in some cases, disrupt intracranial pressure. Elevated 11B-HSD has been noted with obesity in adult women, men, and children, but also, with intracranial hypertension. Similarly, both secondary aldosteronism and hypertension have been noted with progestin-only IUDs and in male astronauts.
Both male and female astronauts appear to develop SANS at almost equally high rates, however, most of the space flights and much of the subsequent research includes only or mostly males. Moreover, in the few instances that included female astronauts, data regarding birth control were not given. So the question is, how do very healthy, normal weight, male astronauts develop a condition that is so commonly associated with a progestin only IUD and obesity in earthbound women? Again, part of the answer points to hormones, or more specifically, the re-regulation of hormones, enzymes, and the like, relative to zero gravity.
Among the endocrine adaptations that occur relative to space include those involved in regulating fluid and electrolyte balance, water/salt homeostasis in the kidneys and elsewhere. Specifically aldosterone, renin and angiotensin hormones increase during space flight resulting in a sort of secondary aldosteronism, just like we saw in the terrestrial women. Only in the male astronauts, it is not in response to synthetic hormones or weight related metabolic adaptations but instead is relative to gravity related adaptations. Whether the 11B-HSD enzyme is upregulated is not clear, as it has not been measured, but I suspect it would be.
The re-regulation of 11B-HSD, I believe, is the common thread between the evolution of this disease process in these two distinct populations. There are still more questions to be answered, however. First, what does kidney salt/water balance have to do with fluid balance in the choroid plexus of the brain, and second, neither all earthbound, obese, or IUD using women nor all astronauts develop this condition, what else is involved? There has to be another set of triggers. Indeed, there is.
Fluid and Electrolyte Balance in the Kidneys and the Brain
In one of the more astute papers on this condition, researchers investigating pediatric pseudotumor cerebri, posited regulation of fluid balance in the kidneys occurs via analogous mechanisms in the choroid plexus of the brain. This makes sense given the brain can be considered an endocrine organ, containing the full complement of hormones, enzymes and receptors. When we think about it, why wouldn’t brain endocrine capacity be similar to that of the body? Biological systems are conserved and repeated. Indeed, the choriod plexus, the cavity where CSF dynamics are controlled, is home to some of the same transporters, enzymes, receptors as the kidneys.
From this recognition, those same researchers implicated upregulated 11B-HSD enzymes as one of the key factors in pediatric cases. I should note, obesity plays a role in childhood intracranial hypertension as well, though to what degree, is not clear. Nevertheless, the recognition of upregulated 11B-HSD in pediatric cases suggests that we are on the right track with the women and the astronauts. Now we have three entirely different populations with altered brain pressure dynamics resulting in neuro-ocular damage, all mediated by altered steroid enzyme function. The only question that remains is why some folks are able to withstand these changes and others are not. In other words, if the IUDs, obesity, and zero gravity all upregulate 11B-HSD, and evidence suggests that may be the case, why do only a percentage these people have problems with intracranial pressure and develop the neuro-ocular symptoms?
Enter Nutrients. Yes, Nutrients.
Health is all about adapting to a hostile environment. How well we adapt determines whether we maintain health or become ill. From that perspective, it is not difficult to imagine that what distinguishes how and to what degree illness is expressed might come down not to genetics per se, but to the selective expression of those genetic patterns. Expression of disease may rest on only two factors: stressors and nutrients and the relative balance between them.
In the case of the women who develop intracranial hypertension, the stressors are obvious. Weight or more specifically, the metabolic adaptations that ensue, is one set of stressors. The high dose of synthetic progestin is the other. In the male astronauts, weightlessness is the stressor. In each population, even though the stressors are highly discrepant, the resultant changes in fluid regulation appear to be the same. That is, in these instances, the stressor(s) lead to common compensatory reactions: hyper-aldosteronism mediated by upregulated enzymes that changes fluid dynamics not only in the kidneys but also in the brain.
There is one more piece to this puzzle, however, because not all folks with elevated aldosterone develop intracranial hypertension, neither do all obese and/or progestin-IUD using women, nor do all astronauts develop intracranial hypertension or the subsequent neuro-ocular changes associated with SANS. Some folks adapt to these stressors more successfully than others. Why is that? Well, if you’ve read my work, you might guess, it all comes down to mitochondria and B vitamins. Yes, my favorite mechanisms seem to determine yet another disease process.
NASA and the B Vitamins: The Beginning of a Beautiful Relationship
Here is where it gets really interesting. NASA researchers investigating the SANS, assessed genetic polymorphisms called SNPs that limit B vitamin absorption or metabolism, as well as vitamin (B2, B6, and B12) and hormone status (androgens only, unfortunately) and connected those variables to the likelihood of developing the SANS. The reasoning behind this work was that alterations in what is called 1-carbon metabolism affects homocysteine and androgen levels and those variables are then associated with the development and progression of SANS. This makes sense, as these and other B vitamins are incredibly important to maintaining all sorts of enzymatic functions, not the least of which include those related to mitochondrial functioning.
In measuring the genetic alterations in enzymes involved in B-vitamin metabolism, homocysteine and actual concentrations of B vitamins, before, during and after space flight, the researchers found that higher pre-flight homocysteine (an indication of problems with the methylation pathway), along with a combination of certain SNPs (MTRR-66 and SHMT1) and lower vitamin status (folate, B6 in particular) predicted SANS and the subsequent visual deterioration. Interestingly, higher pre-flight DHEA and in-flight testosterone response was also indicative of SANS, though less significantly with different combinations of androgen response and SNPs predicting specific types of ocular damage.
You’re probably thinking, ‘now wait a minute, how the heck does this connect to hyperactive 11B-HSD, altered aldosterone and the elevated intracranial pressure observed in women?’ Well, for that we have to return to the pediatric cases and unpack a few more details. Bear with me. We’re almost there.
While the NASA studies were impressive, they were somewhat limited in scope. Ideally, a broader range of SNPs, nutrients, and hormones could have been considered. Neither aldosterone nor the other B vitamins involved in mitochondrial functioning were measured in this study. Nevertheless, they provide important clues that when added to those of pediatric cases present a fairly clear picture of disturbed mitochondrial function. These telltale signs of mitochondrial issues like elevated lactate, elevated glutamate and succinate and a disturbed tricarboxylic acid (TCA) cycle (also called the Krebs cycle), would inevitably influence one’s ability to respond to stressors. And they are all thiamine responsive.
Remember from high school chemistry (and all of our posts on mitochondria), dietary nutrients are processed through the TCA cycle, to produce the cellular energy known as adenosine triphosphate or ATP for short. ATP is required for proper cell function. Each of the enzymes within this cycle require vitamins and minerals as co-factors (22 of them in fact). Without these nutrients, the enzymes simply do not work effectively, no matter how much carbohydrate, fat, protein macronutrients are ingested. When the TCA cycle is struggling, energy output is reduced, the ability to detox is reduced, the amount of damaging reactive oxygen species (ROS) is increased and the metabolic balance is shifted.
From NASA, we know that folate and vitamin B6 deficiencies were predictive of SANS and both are indicative of defunct mitochondria. Folate deficiency often means thiamine deficiency and thiamine deficiency means reduced ATP, increased ROS and a cascade of damaging compensatory reactions. Similarly, B6 deficiency equals excess glutamate and from the pediatric paper, we find that glutamate is elevated with intracranial hypertension. Glutamate is a metabolic product of mitochondrial reactions. It is excitatory in nature, and thus, must be kept in balance lest it over- excite cells and induce what is called excitotoxicity, a particularly messy form of cell death. Glutamate just so happens to be in equilibrium with a-ketogluterate, an enzyme within the TCA that is highly thiamine dependent. Finally, when thiamine is deficient, the enzymes that modulate succinate, another product in the TCA cycle, may also be out of balance. In fact, even though the succinate enzymes are not thiamine dependent themselves, thiamine deficiency, nevertheless, derails the enzymes responsible for deactivating succinate. With elevated succinate, we get yet another link to elevated intracranial pressure and neuro-occular damage. And, as it turns out, elevated succinate leads to activation of the renin-angiotensin-aldosterone system in mice. Since succinate receptors are located in retinal ganglion, we have a direct link from vitamin deficiency (whether by genetic and/or nutritional means), the aldosterone system and ocular nerves.
Tied Up in a Bow
So there you have it: disparate populations exposed to entirely different stressors that result in elevated aldosterone concentrations by compensatory upregulation of the 11B-HSD enzymes, a shift in electrolyte balance in both the kidneys and in the brain, and because of vitamin deficiencies, mitochondrial dysfunction, which further and directly upregulate aldosterone in the ocular nerves inducing damage. A cool set of connections, if I do say so myself.
A few important points to consider. Firstly, what determines who succumbs to any given stressor and how that stressor manifests as a particular disease process rests entirely on the interplay between genes and nutrition. More specifically, adaptive capacity appears to involve the B vitamins and mitochondrial integrity. Secondly, our descriptive process of identifying diseases, while useful as one begins to identify patterns, falls short unless the core mechanisms of the disease process are identified. Arguably, many diseases we have identified as discrete entities are no more than individual manifestations of the same process. In the cases of intracranial hypertension/pseudotumor cerebri and astronaut ophthalmic syndrome/space flight associated neuro-occular syndrome or SANS, though discrete populations and disparate triggers, these conditions are likely all attributable to the same underlying mechanisms: nutrient enzyme mutations, nutrient availability and stressors that preferentially affect salt/water balance via the 11B-HSD enzyme.
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