Hot Topic: Normal pressure hydrocephalus - Pathophysiology and controversies

This is the second in a hot topic series. And the topic that we're gonna be focusing on is normal pressure hydrocephalus. We've gone through the clinical aspects of NPH in a previous episode, and today we'll be [00:01:00] exploring the pathophysiology and controversies surrounding this enigmatic disease entity.

Thank you for joining us today, Dr. Fasano.

Dr. Alfonso Fasano: Thank you Sara, and thank you for the opportunity to MDS.

Dr. Sara Schaefer: So let's start with risk factors for NPH. This is something that I find very interesting because we think of it as, of course, idiopathic that's actually in the name idiopathic normal pressure hydrocephalus. But there are certain things that have shown to be associated with an increased risk for NPH.

Can you talk about those?

Dr. Alfonso Fasano: Yes, sure. And talking about risk factors we obviously need to clarify first of all that this is more of a syndrome and therefore the weight of each risk factor depends on what conditions you're talking about. An example, some cases are familial and therefore probably the contribution or the risk factors we're going to talk about right now is limited.

While in many other cases there is probably a major role. And I'm thinking in [00:02:00] particular about two risk factors. But there are many others that we can talk about. The first one is sleep apnea. Sleep apnea is very common in normal pressure hydrocephalus. So common that sometimes when I'm in doubt of whether the person in front of me has this condition or not.

The fact that they have sleep apnea makes me swing towards a positivity of the diagnosis. So it is really common. I would say more than 90% of patients have sleep apnea. And there are some reasons related to the pathophysiology of the condition. We know that the intracranial pressure tends to be elevated especially during the episodes of apnea.

And we know that a lot happens during the night in people with NPH part of the pathological process is actually occurring at night where the glymphatic system is supposed to be working better. And instead it works actually quite the opposite way. So that's one. The other one is vascular risk factors particularly hypertension.

And in fact, if you wanna create an animal model of hydrocephalus, you just need to make the rat, in this case, [00:03:00] hypertensive. So the hypertensive rat is the animal model of hydrocephalus, as well known. And not surprisingly vascular comorbidities. Very common in people with idiopathic normal pressure hydrocephalus. There are many others maybe, obviously needs to be mentioned, a ge is certain a risk factor because this condition tends to be more and more prevalent as the population ages. So clearly there is a role also for age and related problems. And then there is obviously an interplay within this many factors including genetic predisposition.

But we can talk about that later.

Dr. Sara Schaefer: Already, I'm thinking about the tangled web that we're trying to unravel a little bit here and how obstructive sleep apnea increases the risk for hypertension as well. And could that be, therefore increasing the risk for NPH or could NPH be causing OSA, we know that OSA is more common in the Parkinson's population and in any other neurodegenerative disease and where's the cause and effect.

But it sounds like the research has shown and you think that [00:04:00] OSA seems to be more the cause of NPH due to changes in CSF dynamics and things at night during episodes of apnea.

Dr. Alfonso Fasano: Yeah you're absolutely right. Maybe one thing I can add that might clarify things is that we came across a family of in particular two identical twins, both with NPH and we recently published that and they had a mutation, a pathogenic mutation of a gene that is associated with a metabolic syndrome.

So they had hypertension, heart attacks. Actually as a matter of fact they died even before we could do match to help their hydrocephalus. And so see there's maybe something even upstream. So the same genetic mutation was responsible for hypertension. So was responsible for hypertension and we assumed that the hydrocephalus we saw was related to this metabolic syndrome that they both had very severe condition so that, that's might indicate a possible direction, but your point is is also right. Maybe it's the other way around. And also vascular changes in the brain can change the structure [00:05:00] of the brain. One of the hypothesis leading to the possible causes leading to NPH, is floppy brain, so that when the brain loses the structure integrity, and this can happen also with neurodegeneration.

The fluid dynamics inside the brain itself is impaired. And an example to this will be another person I know of, and there's another case that I'm aware of with CADASIL. And as this is a genetic condition predisposing to white matter changes with a vast vascular mechanism. And this person also has NPH.

Hard to really find direction of causality in these cases. But at least acknowledging that this is a complex interplay is a good starting point because that can be used for different research avenues in the future, particularly epidemiological studies might be useful in this case.

Dr. Sara Schaefer: So we're already moving to my next question, which is a basic one, but definitely not a simple question. What causes NPH? There are all kinds of theories, some of which you have touched on in CSF [00:06:00] flow dynamics theories of impaired CSF resorption impairment of glymphatic drainage. That this may be a decompensated congenital hydrocephalus, especially related to, the risk factor of increased head circumference in the literature, increased venous pressure.

I could, I just, I could just keep going really. What do you think are the more compelling theories versus potentially less compelling and why?

Dr. Alfonso Fasano: Yeah, that's a $1 million question. I think starting with saying that, like I said before, this is a syndrome. And therefore we just described something that happens. There is a dynamic alteration of the CSF pathway in the brain as a starting point. And we can say that because usually MRI or CAT scans, abnormalities come before the signs of the disease years and years before. So I think we can assume that there is something that causes a problem with absorption of CSF. And this something can vary and and sometimes it's a combination of different factors. For example we now [00:07:00] have a pretty long list of genes that are associated with NPH.

And sometimes in a very clear way talking about autosomal dominant mutation causing a MPH in a family with an autosomal dominant vertical transmission, with no question that there is really a role for these genes. And these are genes involved in ciliary function, either structure or regulation of the cilia.

And that's an interesting observation. I remember the first time I read about this, it was a family described in Neurology. And I was talking to a friend of mine who happens to be a biologist working on primary ciliary dyskinesia. So the this is a condition known in humans to affect kids usually with respiratory problems.

And he looked at me surprised because I was surprised because he told me, look, any animal model of primary dyskinesia that we use in biology to, to study this condition in children is known to have hydrocephalus as an end result. And maybe because people living with primary dyskinesia, [00:08:00] ciliary dyskinesias.

Have so many respiratory problems that they don't live long enough and therefore you only when you have milder mutation of the genes or just more polymorphism affecting the ciliary function that you can see this later in life. So it takes really many years before this becomes a problem because we know the ciliary and the edema have a role in regulating the flow of the CSF.

And if this flow exists, but it's just a little bit impaired over time you see a buildup of fluid and then becomes a structure, a problem that leads to frontal radial dysfunction. So that's just an example of how complex things can be. There are many genes, like I said, associated with disruption of the structure of the cilia.

That's not enough. There are some drugs that can affect the cilia and for example, there is a case report of a woman who develop hydrocephalus after being exposed to a chemotherapy agent known to disrupt the ciliary function because the effect on tubulin which are part of the cilia structure. And that's part of the reason as we know chemotherapy agents often cause neuropathy.[00:09:00] 

Now, why don't we see this all the time? Probably this is in conjunction with additional risk factor that people might have. And, I can mention many other things. You alluded to the head size and actually this is a kind of a joke in my clinic, anytime I see NPH patients, I go around with a measuring tape to see what's their head size.

And we are not talking about microcephalic findings of people have a normal head. Or normal looking head. But if you measure in a consistent fashion the head size of your patients, you will realize there are a group of people in your clinic with a head size that is 60, 61 centimeters for men.

Maybe a couple of centimeters less for women, which is a little on the high end abnormality. No majorly different. And this is because one of the hypothesis is that people have been exposed to some sort of insult early in life that caused hydrocephalus, but it was minor, didn't create an increase of ICP.

The person was okay overall, no big headache or need to be admitted to the hospital. And because [00:10:00] it was early in life first year of life the skull grew together with the hydrocephalus. That's why the brain compensated and then compensation got lost with aging processes. And this is why you only see this later in life.

It's a common scenario. We all I'm sure I've seen this, people that get an MRI or a CAT scan for a random reason, maybe just one day they fell. And they're found to have ventriculomegaly and then they refer for hydrocephalus. These patients don't have NPH, but they need to be monitored because maybe one day they will have it.

And this is when I actually stress the importance of sleep quality, checking for sleep apnea, controlling hypertension, and all the things we discussed earlier. This is not evidence-based. No study has shown that this is the case. That you can actually prevent the occurrence of NPH in these populations.

But why not? These are things that are going to be good to health anyways. So obviously not everybody has a large head size, and this is maybe some something else that happened later in life. So when the skull could not be adapting, and in this case [00:11:00] I'm talking in particular about people with concussion or mild traumatic brain injury.

And I'm talking about people that maybe went to the hospital just to be checked and then they left. They had a car accident. Nothing major, but we just completed a study at Toronto Western where we looked at people with mild traumatic brain injury are obviously common, but if you compare people with the body, NPH with Parkinson's or healthy control. We see that the rate of minor accidents, like the ones I reported, is significantly higher in people with idiopathic normal pressure or hydrocephalus, which once again goes back to this multifactorial process. And overall questions. The term idiopathic. We know that in medicine anytime we use idiopathic, it's just because we don't know what we're talking about.

So we hope that little by little all these idiopathic cases will be clarified.

Dr. Sara Schaefer: A lot of fascinating points there. You really stress the importance of interdisciplinary discussions, right? Across the aisle to the, pulmonary basic researcher [00:12:00] otherwise you wouldn't have known about that connection. It makes me wonder whether people with NPH have higher rates of respiratory disease pneumonias difficulty clearing their airways and things like that.

Has that been shown?

Dr. Alfonso Fasano: No, that hasn't been shown systematically, but one of the few pe families that I think the first big family with convincing evidence that was found the case I was telling you about, the one published by Japanese colleagues in neurology a few years back. They were all found to have some sort of respiratory problem, mainly sinusitis.

And the, in theory, these people should also have problems with fertility because of the role of obviously cilia in especially the male gamet. Unfortunately in this family, for one reason or another, the affected member were married. They were actively seeking to have children.

But it's also quite strange that these people were in this situation. And another avenue of research is looking into their fertility. But I will not say that overall people with NPH might have respiratory problems or problem with fertility, but I would say this is particularly relevant and [00:13:00] that subset of people with a clear, strong mutation affecting the ciliary function which is obviously just a matter of your people.

Dr. Sara Schaefer: Yeah. At the end of the day, once we understand this a bit more, we might. Get into a splitting rather than a lumping situation, right? Where there's a ciliary version of NPH, repeated traumatic brain injury version of NPH, et cetera.

Dr. Alfonso Fasano: Correct. Yeah, I agree.

Dr. Sara Schaefer: So the elephant in the room of neurodegenerative disease in general right now is co pathology, right?

We're finding that in Alzheimer's, Lewy body, PSP, really any kind of neurodegenerative disease, the existence of other pathological markers besides the hall markers of that disease, whether that's tau or amyloid or synuclein, seems to be almost the rule rather than the exception, that there's multiple things going on and this doesn't spare the NPH literature.

What do we know about co pathology in the NPH population?

Dr. Alfonso Fasano: Yeah, that's a [00:14:00] great question. So a while back, it would've been difficult for me to answer this question because a while back we knew that all pathology studies, I'm talking about autopsy studies done in NPH had shown that these people had. Alzheimer's, PSP, any sort of neurodegenerative disease.

And back then the assumption is, okay, they have found to have something when they die, their brain is showing sign of neurodegenerations. Hence, NPH doesn't exist. They didn't have MPH, they had PSP, they had Alzheimer's. Now it's easier because we know the co pathology, as you said, is the rule.

It's not the exception. So it's more it's easier for me to just say that this is co pathology. But then the question is why do we have so much co pathology in NPH? And I try to answer this question identifying four different scenarios. First thing that I also need to emphasize is that MPH doesn't have pathological hallmarks.

So all that you see when you examine the brain in these [00:15:00] people is indeed this pathologist that we're talking about right in a second, including vascular pathologist. It is not that you have something else that will tell you, okay, this person had NPH and something else. You only see this something else.

But as per the four scenarios I was talking about we need to acknowledge that NPH is common in older age and with age more problems accumulate in the brain. So you may simply be in a situation where you have a coincidental dual pathology that is possible. And I think this is for most part, common in people with Parkinson's disease.

Now NPH can have Parkinson's, but it's a mild bradykinesia. No response to levodopa, no fluctuating, no rest tremor, no upper limb involvement. But sometimes you deal with people with Parkinson's, really with levodopa responsiveness and NPH which is also shunned, responsive. And then you are left with this question.

Is this related? What doesn't help here are the studies that use DAT scan in NPH patients. And in a study, for example, we've shown that 62% [00:16:00] of NPH patients had a normal DAT scan. But a normal death scan doesn't mean degeneration like Parkinson's disease, because if that was the case you'll not see what we have later published, that if you treat them with shunt, the uptake in the dopaminergic terminals increases, which is not compatible with a degenerative hypothesis.

But even more important is the ability to use RT-QuIC. So we recently did a study and also other people have done similar studies running basically this CSF of NPH in our labs for RT-QuIC seeding alpha synuclein. And we have found that about 14 to 20% of NPH patients have a positive seeding assay which is way less than the 62% that's normal, just mentioned. And also we recently published a study when we looked at nigrosome in NPH, which unlike Parkinson's disease was normal. So overall pointing to the fact that yes, you may have a degeneration starting for the niagara of these people, but it's not common. [00:17:00] It is maybe compatible with what you will expect in terms of incidentally with body pathology in people with an age within 70 and 80.

So this might be the reason why you might have Parkinson's disease co pathology in NPH, but I think most important because Parkinson's not really common in this population. You can see it, you can see it at the autopsy, but really the most common is Alzheimer's. Alzheimer's pathology, with amyloid plaques and tauopathy. Here it's more difficult to really combine things, but this is too common to be just coincidental. And here, I think this is where the glymphatic system theory helps because there's no question that sleep apnea impairs the glymphatic system. There's poor sleep impairs the glymphatic system, and it is obviously I would say o obvious that in someone with a CSF buildup, you have an slowing down or a source of a traffic jam of the glymphatic system, which is then known to be associated with an accumulation of amyloid. Now we know there are people that arguing that [00:18:00] proteinopathy is not the culprit or in neurodegeneration.

But regardless of whether you believe the amyloid is toxic or not, if you have an impairment of the glymphatic system that we have for a reason, the neurons are exposed to more of a toxic environment for longer. Clearly metabolically, this is disruptive to the physiology of the neurons, so that alone might explain why you have a high rate of neuropathology.

Particularly of the Alzheimer's type. The other scenario is when you have neurodegeneration that per se, predisposes to NPH, this is what some people have called ventriculomegaly presentation of neurodegeneration. And this is particularly relevant in my opinion for PSP. There are several reports of PSP cases with also NPH and the reason why we think they have NPH because they are a clear ventriculomegaly.

They have other signs like dash, and then you do shunt surgery and they improve and they don't improve just for a few months like you were expect in placebo. They improve for years. Meanwhile, the signs of PSP become more and more clear, like supranuclear palsy and [00:19:00] the classical marks backwards falling and so forth.

And here there are a number of reasons this might be the case, but these are very speculative at the moment. One is what I mentioned earlier, the floppy brain. So brain that is per se, degenerating and not keeping the structural integrity that you're supposed to have, Might have folds in different parts of the CSF flow, and that contributes to the accumulation without a clear obstruction.

But even more important, and this is still neglected, is the role of tau in tubular function. Maybe here, there is a common threds. And there's something that at the same time cause tauopathy and also impairs the ciliary function. This is yet to be proven though. And this leads to my fourth scenario, which is when you have something upstream that contributes to creating neurodegeneration and NPH at the same time, and this is to me, the mutation of those genes involved in ciliary functions or ciliary regulation, or even a ciliary genesis. The [00:20:00] ciliary machinery is very complex. It involves hundreds of genes. So it is possible that some of these genes are contributing to causing the ciliary dysfunction and therefore NPH.

But at the same time also some sort of other cascade for example, involved in tau and tau deposition that then leads to neurodegeneration. Things are clearly complex at the moment, but just recognizing that there's not just one size fits all type of scenario, it's the right starting point in my opinion.

And the other thing I haven't mentioned so far is the vascular co pathology that you see when these people are analyzed by the pathologist. We should keep in mind that the high pressure accepted towards the wall of the ventricles is per se, contributing to ischemia because we are compressing onto the vessels.

And we know that there are many vessels around the ventricles and so this alone might contribute at least to the vascular changes that we see at the autopsy in this patient. So this is more like a downstream effect.

Dr. Sara Schaefer: Let me see if I can just summarize what you just said about these four possibilities. [00:21:00] One possibility is that they're true and unrelated. We have an aging population. It puts them at risk for NPH. It puts them at risk for other neurodegeneration. A second possibility is that there's some sort of common physiology that's leading to both simultaneously, like impaired glymphatic drainage.

Vascular risk factors lead to both. A third possibility is that, something is causing the neurodegenerative disease like the Alzheimer's, for example. And that in turn is making the brain susceptible to develop NPH. And then a fourth possibility is that there's something way upstream at the genetic level that increases the risk of both.

Do I have that right?

Dr. Alfonso Fasano: Yeah, absolutely. You said it much better than I did. And in using way fewer words. And yeah that obviously you can think of many other possible explanations including say, you know, this is all in the head of Doctor Fasano that nothing is true and this disease doesn't exist.

And that may be something else [00:22:00] we need to discuss.

Dr. Sara Schaefer: Yep, that is my next question. So we would be remiss not to mention that there is a group out there who don't believe that NPH is real that it doesn't exist. And I certainly heard this in training, definitely have heard this over the years. What do you think are the fair arguments for that, and what do you think are the less fair arguments?

Are there things that still give you pause even after all of your clinical experience and your research experience with this disease entity or disorder? And has anything changed your mind over the years?

Dr. Alfonso Fasano: Yeah absolutely. I heard the same thing when I was a trainee. And if you think about the MDS for years hasn't even described the NPH to the, fellowship programs or even during the conference that we have annually. And for example, once I just for fun, I went on PubMed and I saw many publications had NPH in the title and where these publications were.

And I think in movement disorder, back then when I did this, it was five, six years ago, there was only one [00:23:00] paper that mentioned NPH in the title. While most of the papers were coming from neurosurgical journals. So absolutely we haven't been trained enough on this condition. But I think simply saying it doesn't exist doesn't give justice to this mystery.

And that's actually why I got interested in this condition. I'm a curious person, and in a way, when I talk about NPH, I always think about another disease that I like which is essential tremor. Essential tremor doesn't exist. It's a syndrome. We all know that it is not a single disease and it comes from many different things and maybe it's just, prodromal to other problems.

And now I don't wanna get into the problem or what essential tremor is, but at least everybody agrees that there's something that we label essential tremor just as a diagnostic placeholder. So I think we're in the same scenario when it comes to NPH. We clearly have people with a syndrome, with certain combination of symptoms and signs.

For example, fecal incontinence. When you see someone in your clinic in a movies or clinic, and this person has fecal incontinence, chances are this person has NPH, he's so specific. [00:24:00] 'Cause we don't really see it in our population. But they're just one of the main examples that can come with, and then you do a shunt and this person improves.

And the improvement is not just. Again, placebo. It's a sustained, improved that you see for years, and I've seen this over and over, I've been doing this for seven, eight years now. So I've been following people long enough to see that they have improved. And yes, over time they didn't do well because, they had arthritis, they heart attack, they had a stroke, they had, dementia on top of everything else.

But their mobility, the problem that brought them to me, which was freezing of gait, poor balance, has never come back. The other thing that I can see because I'm the one adjusting the settings of the valve, we use programmable valve. I can actually see that. And obviously the patient has no really awareness of what I'm doing.

That when I adjust the settings, the stronger the drainage, the better their symptoms are. The symptom control. So this is giving me some sort of idea that I'm tapping into something that is real, that is not just placebo, which I don't think is really relevant to this population.

These [00:25:00] are not Parkinson's patients where we see placebo is really a problem. So these are all, I think, valid arguments that are not put pointing out here to say NPH is a thing. Just forget about who says it doesn't exist. No, it is something that at least tells us that we need to do more more research to understand what this mysterious condition is.

And obviously we're talking about idiopathic NPH because NPH coming after a meningitis , or other major traumas of the brain. Those are obviously established, they're known to exist. So it's idiopathic NPH that is a bit of an issue because happens very gradually in older people.

They also display other problems and I understand why people are skeptical. I was skeptical myself, but I was sincerely curious to understand a bit better their gait problem because gait is one of my research interests. And that's how I approached the condition. And then the more I explored this condition, the more I realized that there was actually a fascinating field that gives us a lot of research opportunities.

Exactly like essential [00:26:00] tremor is.

Dr. Sara Schaefer: Why do you think NPH has proven to be such an enigma and where do you think we should go from here to understand it better?

Dr. Alfonso Fasano: There are several reasons this is the case starting from the fact that the name itself is a problem. Normal pressure hydrocephalus. So idiopathic normal pressures hydrocephalus, idiopathic means nothing. And we should do our best to remove it from any condition we we deal with. And for example, we don't use idiopathic Parkinson's disease anymore. Actually, this is right now a proposal from the Hydrocephalus Society to change the name of this condition and call it Hackings Disease, which has pros and cons. We can talk about it if you want. The second thing is this normal pressure thing, the pressure is not really normal. It is, yes, normal-ish. If you just measure the opening pressure once.

But if you monitor these patients, especially at night, when they're sleeping, when they're sleeping and they have maybe a sleep apnea event, that the ICP is quite high. It fluctuates [00:27:00] always high, and in fact you always see it in around 20-21. It's always borderline abnormal. So that's something that many people have argued.

It's the name itself is a problem. But I think the biggest problem is this idea that this is a reversible dementia. It's not because, first of all, it's not a clear dementia in the sense of a cortical dementia. If you have a cognitive problems, it's more of a subcortical type of issue, more this executive.

And if you have a full blown dementia, either it is not NPH or it's too late, and for sure this is not reversible. This is to me a reversible gait disorder. And I think the Movement Disorder Society should approach this mindset because this way we'll capture this condition earlier and we can potentially help a lot of people much earlier when the interventions are effective.

Waiting too long because you wanna see the whole triad might mean wasting time. Another problem is that this idea that when you do a VPS or any other shunt surgery, you cure the patient is not true. You just improve them. [00:28:00] The condition remains the worsen but you improve them. And the improvement, as I mentioned before, is sustained.

But the other biggest problem is that for most part, research has been in the hands of neurosurgeons and no question, they're great colleagues and I don't wanna, necessarily be critical of what they do. As a matter of fact, I spend most of my time with neurosurgeon because of my interest in deep brain stimulation, but they have a bias towards the here and now. So they treat patients, they operate and they don't follow them over the years, some of them do, but it's not their research interest. For most neurosurgeons. In fact, neurosurgeons don't wanna deal with NPH 'cause they don't wanna deal with chronicity. It's just different mindset and we need their help with surgery.

And I think it's the role, the neurologist to select them, diagnose them, and then follow them after surgery, exactly like we do for DBS in Parkinson's.

Dr. Sara Schaefer: Yeah, absolutely. And in the third episode of this Hot Topic series, we're gonna be talking about assessing treatment and outcomes, measures, and what we know and what we still have yet to learn about outcomes in [00:29:00] shunting for these patients.

Thank you so much Dr. Fasano for this really enlightening conversation.

I learned a lot and I hope the listeners did as well. 

Dr. Alfonso Fasano: Thank you.