Ep. 196: Is Biological Sex Important for the Development of Functional Neurological Disorders (FND)?

00:00:00: Welcome to EANcast, your weekly source for education research and updates from the European Academy of Neurology.

00:00:15: Hello!

00:00:16: And welcome today at EAN Cast Weekly Neurology.

00:00:19: My name is Primavera Españolo.

00:00:22: I'm the Interim Executive Director of the Connors Centre for Women's Health Research at the Bigham & Women Hospital Harvard Medical School in Boston.

00:00:31: I'm very pleased to welcome you here and discuss today the topic, this one topic is Functional Neurological Disorder.

00:00:41: Today we are definitely discussing about these topics using core perspective.

00:00:47: We're going talk about functional neurological disorder from the perspective of biological sex And how biological sex influence every aspect of this neuropsychiatric condition.

00:00:58: I'm very pleased to have here discussing this topic with me two amazing guests, Dr.

00:01:05: Natalia Sheiko and Dr.

00:01:06: Hanna Dunowska.

00:01:07: They both had an extensive experience in F&D And they work at the Medical University of Warsaw in Poland.

00:01:16: So welcome Dr.

00:01:17: Sheiko & Dr.

00:01:18: Dunowsika.

00:01:19: Thank you for joining us today on our podcast.

00:01:28: So, as I was mentioning... Today, we're gonna try to take a different take on functional and logical disorder for our audience.

00:01:35: And we are going to discuss the role of biological sex.

00:01:38: before asking you the first question from an audience I just want to clarify what biological sex is?

00:01:44: So what it's that were gonna be very much discussing today?

00:01:48: Biological sex refers all the biological attributes such as reproductive anatomy, sex chromosome, gonadal hormones and secondary sexual characteristics.

00:01:58: These sex-related factors influence every aspect of any disease and condition, including functional neurological disorder.

00:02:07: However you know the biological sex aspects has been very much excluded or neglected in the history, not just of FND but medicine.

00:02:17: And so today I'm very pleased to have you both here helping us understand why it's important to include biological sex in a way we study and treat patients with FND?

00:02:28: So starting with Dr.

00:02:30: Shaco Natalia if you don't mind let's keep this very informal and let's call each other on first name basis can tell our audience.

00:02:38: what are functional neurological disorders?

00:02:41: Yes,

00:02:42: yes so functional neurological disorders are generally well any kind of basically neurological symptoms that.

00:02:52: Well I'm not related to any structural change in the brain and we now know more about their clinical and you also I would say characteristics in terms of the pathophysiology.

00:03:10: So we know that it's basically related to disorders function and motor control, and interception.

00:03:18: so there is also a biological underpinning why they occur.

00:03:26: And on the other hand another important characteristic They are diagnosed on the rule in basis.

00:03:35: So it's not like, you know maybe our listeners they remember that before You had to exclude everything and at the end It was a diagnosis of exclusion.

00:03:45: Now its ruling diagnosis.

00:03:48: so there is some characteristic neurological exam for example Hoover sign That indicates indeed or some characteristic of functional seizures, for me being a tick expert.

00:04:05: Typical in the history there are more indicative of functionality like behaviors and not ticks.

00:04:10: So I would like to highlight this that it's not a diagnosis of exclusion It is a diagnosis on inclusion.

00:04:17: Rule-in is very important And also you know this aspect as Vera mentioned that as many other disorders in psychiatry especially, we now look at FND from the biopsychosocial model.

00:04:36: So there is a biological predisposition and then these important social and psychological factors could be another factor for development of FND.

00:04:51: nothing every patient also but they can occur

00:04:54: yes.

00:04:55: Thank you so much, Natalia.

00:04:56: And just a quick follow-up question and then I will turn it to Anja What about the typical patient that work in with an F&D?

00:05:07: If we think through this biological sex perspective how many of the patients do you see are females versus males?

00:05:16: Yes!

00:05:16: So this is another important feature.

00:05:21: We know from the studies at the moment that FND has

00:05:25: some other

00:05:28: neurological disorders.

00:05:29: They have female predominance, so across most studies we see about sixty-five to seventy five percent of patients with FND are females And it's also important to highlight that these patterns appear globally.

00:05:46: So in Europe, North America and increasingly some studies from Asia they show the same predominance.

00:05:54: but while this is related I think important highlights for their research That basically also FND occurs in mail.

00:06:07: it's just that females are more frequently diagnosed.

00:06:09: And I hope this is another aspect we're going to discuss later, in our podcast.

00:06:16: but yes!

00:06:17: This is the most predominantly female disorder

00:06:23: and

00:06:24: in terms of phenomenology basically... It's our functional seizures, but also functional movement disorders.

00:06:35: For example, functional tremor and now we talk more about functional cognitive disorder so any kind that it is very robust phenomenology.

00:06:48: Thank you so much Natalia for making those important points.

00:06:53: now pass to Anna, Dr.

00:06:55: Dunaska is a psychiatrist and so I think you know one of the wonderful thing about this episode today that we have truly these complementary perspective from neurologists like you Natalia and from a psychiatrist like Anna And i think thats absolutely great because FND are neuropsychiatric disorder and the diagnosis in care of those patients really, you know required this multidisciplinary approach.

00:07:23: So from a psychiatric perspective Anna I will now pass to Tell us a little bit what is, in your perspective, FND and how you think biological and hormonal factors contribute to it.

00:07:38: We just learned from Natalia that this is a female pre-nominal condition but exactly does he mean?

00:07:45: How do you see these female pre–nominal conditions so manifesting?

00:07:52: Thank You Vara!

00:07:53: I think functional neurological disorder for me as a psychiatrist is a disorder in which real neurological symptoms appear.

00:08:01: There may be different kinds of symptoms, weakness, tremor, dystonia, gait problems sensory loss and episodes that resemble epileptic seizures.

00:08:13: The key point is this system arrives from altered nervous system functioning with the damage we can see on MRI, for example.

00:08:23: So I think it's very important to remember that this is a rule in diagnosis and... And i have this in my mind when I had patient with FND.

00:08:38: When it comes the relationship between FND and sex hormones I think we need to talk about biological and hormonal contributors in F&D with precision, and with caution because there is some evidence.

00:08:55: We have evidence for biological involvement.

00:08:59: however... ...we lack evidence supporting a straightforward hormonal cause.

00:09:06: And at first I would like to say a little bit about stress systems, because i think they are very important here.

00:09:14: In general neuroscience we know that biological sex influences stress reactivity and Stradial testosterone can modulate cortisol release, amygdala reactivity, and refrontal control in the system our central in current models of FND particularly those focusing on arousal and predictive processing.

00:09:38: So, when we look specifically at FND findings are mixed.

00:09:44: a few cohorts show at the peak-occurred little patterns particularly in trauma exposed patients.

00:09:50: But other studies failed to replicate this findings.

00:09:54: Some autonomic study showed that patients with FND, specifically functional seizures have also reduced heart rate variability and increased sympathetic arousal.

00:10:09: but these findings are still not universal.

00:10:12: So the current position is stress system.

00:10:16: dysregulation is possible.

00:10:19: It is partially supported, but sex-stratified biological evidence in FND remains limited.

00:10:27: And a few words about hormonal transitions because I think it's especially important part here Because that's where biology becomes clinically relevant.

00:10:37: We can see the incidence of FND rises during early adolescence and overlaps with puberty which is major neuroendocrine transition.

00:10:48: We do not have dialogue studies, which would measure pubertal hormones in FND cohorts.

00:10:55: So this association for now is epidemiological –not mechanistic– when it comes to pregnancy you can see that most women with established FND remain stable during these times but still a meaningful subgroup of women experience onset or worsening in the peripartum period.

00:11:18: So this hormonal shift deprivation and psychosocial stress likely interact here, we'd not really have evidence that postpartum FND is directly hormone driven.

00:11:34: so I think it's mostly a multifactorial vulnerability.

00:11:39: We should still remember that perimenopause is another major transition then fluctuating estradiol levels which can affect sleep, pain modulation mood and autonomic balance.

00:11:53: Here I find the specific longitudinal data as sparse.

00:11:58: but in general these changes mostly amplify symptoms in vulnerable individuals And this hormonal transition state vulnerability windows.

00:12:11: This causation remains unproven But I think it's worth knowing about that and having this in our mind when we have our patients at the clinic, in a consultation room.

00:12:28: Thank you Anna!

00:12:30: You raised so many important points.

00:12:33: It seems listening to you and Natalia We really are facing sort of paradox here.

00:12:40: Two out three if not more than the patient who will work into our rule with an affinity diagnosis are females, you know and being female they will go through those hormonal transition but still we don't know why the majority of them are females.

00:12:54: And we do not know why female specific factors such as those reproductive transitions shape of FND.

00:13:05: I will say this is not an isolated paradox, unfortunately if i think about neurology and psychiatry...I can think about many examples.

00:13:13: we keep studying Alzheimer's disorder as a neutral you know neither female or male predominant condition.

00:13:19: on the contrary it's very much a female predominant again as a condition that affect men and women, which is absolutely true with whoever in epidemiology there shows the two out of three patients are females.

00:13:35: And so they bring me to the next question Natalia that yes how much here we're looking at biology or were looking also at gender bias?

00:13:48: Again I'm gonna take a second hereto tell our audience you know, biological sex but it would be really great if you can start introducing us into this topic of a gender bias.

00:14:03: Potential gender biases in the diagnosis.

00:14:05: telling as little bit about what is a gender biased?

00:14:11: Yes exactly so I think its extremely important to highlight also these factors here.

00:14:18: and basically there's difference that sometimes Exactly, even in the literature we see that there is not a clear distinction between sex and gender biases.

00:14:32: So basically you know gender-related factors are obviously more related to social constructs.

00:14:41: so for example... Especially, of course it's a relevant topic in many disorders but especially an FND.

00:14:50: We are learning more and more than is very important.

00:14:54: for example preliminary studies indicate that gender diverse population is gender diversity.

00:15:03: It's more frequently found in the FND population But you know its preliminary and we do not really know why.

00:15:12: Basically, what we know or are learning is that gender roles and social experiences they likely play a significant role in FND risk.

00:15:21: So there's several important topics here.

00:15:25: so first Anja mentioned the role of stress related factors and trauma is a very important factor in development of FND, and women globally.

00:15:39: And I know that Vera is an expert in this field.

00:15:42: they are more likely to experience chronic stress, trauma caregiving burden and social strolls strain.

00:15:49: So these experiences they can affect brain systems involved in emotion regulation, threat processing and bodily awareness And therefore maybe females also develop more frequently FND.

00:16:02: But we have to remember that on the other hand FND is not caused by trauma alone.

00:16:07: so it's an important stereotype That needs to be explained.

00:16:12: Not every FND patient has a trauma, many but not every.

00:16:17: But we know that also adverse life experience can increase vulnerability especially in combination with biological factors.

00:16:24: and again females they experience more this adverse life experiences.

00:16:34: And it's important to emphasize that FND symptoms are real of course brain based and that therefore they have this relation with these different factors.

00:16:47: And finally, I think it's very important to also mention the gender norms can influence how symptoms are expressed and interpreted so women may be more likely to seek medical care for certain symptoms which can increase also diagnosis rates.

00:17:06: And at the same time, historically even if we come back to Charcot as you know... We shouldn't be using this name anymore but there was a very unfortunate name of hysteria and obviously I feel that unfortunately doctors are biased so they tend to diagnose more frequently females with FND because of these factors, so just historical factors.

00:17:38: But on the other hand you know and this is an important I think research gap that we don't really know a lot about men with FND.

00:17:48: maybe they have experienced in diagnosis delay topic to discuss and investigate.

00:18:06: So, to summarize I think that this gender influences not only biology but also help seeking diagnosis.

00:18:12: And like I said, another important topic that actually as Vera knows we want to highlight in another podcast is exactly this FND in gender diverse population and here.

00:18:28: I'm really looking forward for contribution again from our... We will come back maybe to our FNDS special interest group and Z who's an expert on these topics.

00:18:39: so it's very complex.

00:18:42: all these different factors and really we are learning more to help our patients.

00:18:51: Absolutely, thank you so much for making this invaluable point.

00:18:54: I completely agree with that.

00:18:56: when talking about gender collection of basically social culture norms they really shape an interact biological sex in shaping, you know the vulnerability of a condition and they also shape how we interact about as patients and providers with healthcare system.

00:19:15: And those are important aspects that we should not forget.

00:19:20: now moving to um The next step right?

00:19:22: You know but you and Anna really discussed it so well About How Biological Sex In This Interaction With Gender Related Factors Shape The Vulnerability to FND and the probability of getting a diagnosis, the likelihood or receiving a diagnosis.

00:19:38: Let's move now into presentation right?

00:19:40: Starting with you Natalia and then moving on next question but starting picturing in mind, you know, this patient that comes through our door.

00:19:51: Right?

00:19:51: You know we have said it's going to be a female patients for all the reason why we mentioned before because of epidemiology tell us about women more in general tend to seek medical care than men but in terms of presentation what did they tell us?

00:20:10: Yeah,

00:20:12: so like I said unfortunately you know it's also under investigated area but maybe what i could say is a little bit similar to what Anna mentioned.

00:20:27: Is that there isn't a strict male versus female phenotype?

00:20:31: But there are some patterns I would say.

00:20:33: So women they more often present with functional seizures from the literature and mixed symptoms presentation also more robust symptoms presentation.

00:20:45: Whereas men, they may often present with isolated motor symptoms for example such as tremor or weakness but on the other hand there is a significant overlap and like I said these are some trends.

00:21:03: at that moment you know it's not clear distinction.

00:21:07: The other important thing is that in general, again these are some trends and here maybe Anya can also support me.

00:21:19: In the literature especially... the important feature of dissociation,

00:21:25: which

00:21:26: psychiatry uses.

00:21:29: This could be often associated with FNDs.

00:21:33: so you know this feeling being disconnected from the body or being disconnected just external factors.

00:21:42: what we call depersonalization is also more frequently described in females which I think is also interesting.

00:21:51: And maybe it could be from the psychological or psychiatric point of view, an interesting phenomena and this distinction between biological sexes that definitely needs further investigation?

00:22:07: Yes!

00:22:07: Okay thank you Nodalia so i'm going to stop here for Anna to really guide us through this aspect of FND presentation.

00:22:17: Also, if you can tell us a little bit more about the overall clinical picture when it comes to comorbidities and neuropsychiatric interfaces?

00:22:29: Yes I think its very important talk about comorbidity in FND because we know especially psychiatrists but also neurologic comorbids.

00:22:40: We know that anxiety, depression, PTSD and psychophonic association are common in FND.

00:22:49: Comorbidities is the rule not exception.

00:22:54: In most adult cohorts at least half of patients meet criteria for a current psychiatric disorder.

00:23:02: The most commonly as I said are depression, anxiety disorders or post-traumatic stress disorder And this mentioned by Natalia, the dissociative symptoms, psychopharmic dissociative are particularly prominent especially with functional seizures.

00:23:21: When we look at sex-related patterns The picture becomes more complex.

00:23:28: Women with FND more often present anxiety and PTSD.

00:23:34: They also more frequently report trauma exposure, particularly interpersonal and sexual trauma.

00:23:42: In seizure phenotypes women tend to have greater dissociation scores than psychopharm associations such as the realization of personalization, pathological absorption... And higher dissociation is also associated with greater symptom burden and poor quality of life in FND patients.

00:24:04: Men, on the other hand seem to be under-presented in most cohorts.

00:24:10: Some data sets suggest relatively high rates of substance misuse in male patients.

00:24:19: There is also concern that men may be underdiagnosed or referred later partially because of differences in help-seeking and symptom expression between women and men.

00:24:33: However, we need to be careful as sex stratifies.

00:24:36: longitudinal data is still limited.

00:24:40: We should not overgeneralize here.

00:24:44: And importantly, what Natalia said that psychiatric comorbidity is not required now for the diagnosis of FND and it's also seen in current classification systems such as DSM-V which does not require psychological stressor in FND.

00:25:03: So I think here their relationship is bidirectional depression anxiety increase physiological arousal and threat monitoring And this enhances bodily diligence and can strengthen maladaptive symptom predictions.

00:25:21: Yeah, I can say a little bit also about pain for example but...

00:25:31: No Anna of course you're raising another important point that is the high rate of comorbidity with chronic pain we see in FND patients.

00:25:42: And so yes, if you can say a few words and at this point I will also insert like second part of in my question since your mentioning chronic pain In general it seems that FND patients present with complex clinical picture So that seems to be very much shaped by biological sex and gender related factors.

00:26:06: So discussing chronic pain Can you tell us?

00:26:10: after listening to what you and Natalia shared from a diagnostic treatment point of view, how we can insert that saxolence in the way we convey diagnosis to our patients.

00:26:27: And also think about their treatment options?

00:26:31: Yeah so just few words for pain because it's highly relevant I think here because chronic pain is present in roughly half of patients with FND.

00:26:41: And migraine, for example, it's very common... more common than the general population and pain also associated with worse disability and higher psychiatric comorbidity.

00:26:57: Here women when it comes to biological sex which reflects broader epidemiology show higher rates of chronic pain and migraine, which may further interact with FND vulnerability and maintenance mechanisms.

00:27:14: So a few words about pain here... And when it comes to the gender-informed perspective how should influence or change clinical picture presence?

00:27:30: practice, the perspective has very practical implications because it does not mean that we treat women and men differently in a simplistic way but sex and gender informed care can change your formulation.

00:27:45: So this diagnosis remains the foundation.

00:27:50: We make positive ruling diagnoses based on clinical science.

00:27:56: We should name the signs, explain them to our patients state that symptoms are real and involuntary because it improves acceptance.

00:28:05: And creates a shared perspective which can lead us in our patient's therapeutic approaches.

00:28:15: but I think its important to integrate life stage into assessment of the patient.

00:28:23: In adolescents, incidence arises around puberty.

00:28:27: So we should ask about sleep, school stress, peer context family dynamics developmental transitions because all of these can influence and cause or intensify FND symptoms in women of reproductive age.

00:28:43: We should talk about pregnancy postpartum Symptoms like sleep deprivation breastfeeding stress or whether symptoms began around delivery, medical procedures.

00:28:58: So evidence for direct hormonal causation remains limited but the clinical context is highly relevant.

00:29:07: In mid-life we should ask about peregrinal pausal symptoms insomnia hot flashes mood instability even though when these specific hormonal data are sparse.

00:29:17: it's well known neuroendocrine transition and this transition seems to be vulnerable in those four FND symptoms.

00:29:30: When it comes to treatment, it remains phenolide-driven and evidence based.

00:29:34: maybe Natalia can tell a little bit about that and share her insight thoughts on the role of these genders.

00:29:47: Thank you Anna, I think we made so many important points Natalia.

00:29:50: We're almost at the end So can you leave our audience?

00:29:54: You know with some...I would say words of encouragement in terms like how this field Can be moved forward and help patients with appendectomy.

00:30:05: Yes first thing that i'd like to invite Our audience join functional neurological disorders society And especially your warm warmly welcome, if you're interested also in sex and gender topics to join our special interest group that is chaired by Vera and co-chaired by me and Zee.

00:30:29: And of course generally joined another special interests group of this society and the European Academy of Neurology panel on FND.

00:30:40: Well first of all I would like It's a new topic as you know, FND overall but this one on biological and gender differences.

00:30:51: But it is extremely important.

00:30:53: I think we all know how underrepresented females wear and are in many fields so i'm really looking forward for longitudinal and mechanistic studies that need to be done and really to understand how these biological, psychological and environmental factors interact.

00:31:19: Second I think it's very important that we conduct sex stratified research.

00:31:26: so we need more studies that specifically analyze sex differences in brain imaging autonomic function biomarkers.

00:31:35: And the third thing is generally future research should also include both men and women, gender diverse individuals.

00:31:46: And consider these important social and biological factors.

00:31:50: together us to move forward for precision medicine perspective.

00:31:56: also in FND, you know where treatment is more tailored.

00:32:00: To the individual.

00:32:01: rather too one size fit all models.

00:32:04: so For me this is the most important and thank You so much for giving me the opportunity to talk about this important topic.

00:32:13: Thank you, Natalia and Anna for your great insight.

00:32:19: And sharing with us the knowledge.

00:32:21: I want to thank the audience for their attention today... ...and leave all of you with a message that I hope Natalia, Anna & myself were able convey.

00:32:32: FND as any other medical condition is complex.

00:32:35: Embracing complexity at very core what we do and why would it.

00:32:41: And so from the three of us, a call to action really include biological sex and gender related factors in that way with studying care for our patients with FND.

00:32:52: With this thank you very much again for your attention!

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