Peter Crino, MD, PhD

Episode 1: Current Knowledge of TSC

Episode 2: Diagnosis of TSC, Challenges Associated

Episode 3: TSC Alliance's Strategic Research Plan

Episode 4: Investing in the Preclinical Consortium

Episode 5: Trends in TSC Research

Episode 6: Growing Potential of TSC Drug Pipeline 

Episode 7: Changing Disease Course Through Prenatal Diagnosis

Episode 8: Reasons for Hopeful Future 

Tuberous sclerosis complex (TSC), a genetic disorder that causes tumors to form in different organs, affects nearly 1 million people worldwide and approximately 50,000 in the United States alone. Founded in 1974, the 

 has been a leader in the rare disease community and a comprehensive resource for individuals and caregivers affected by TSC.

The Alliance has a proven track record of accelerating research, strengthening care, and empowering the community. Since 1984, it has funded more than $27.7 million in TSC research and has also leveraged $446 million in additional federal funding through the National Institutes of Health and the Department of Defense Congressionally Directed Medical Research Program. Other notable achievements include establishing the first TSC Natural History Database, the first clinical network for patient care, clinical studies and clinical trials, and sponsoring research that helped identify the 2 genes that cause TSC.

As part of continuing to help transform the lives of those affected by TSC, the organization has committed to investing $40 million over 7 years to accelerate the discovery and development of improved therapies for TSC. The TSC Alliance’s campaign priorities are divided into 4 sections, including natural history database and biosample repository, clinical research, the Preclinical Consortium, and innovative research.

To spread the word about the several ongoing campaigns and advancements within the field, 

partnered with the TSC Alliance for a roundtable discussion that featured experts Peter Crino, MD, and Steven Roberds, PhD. Crino, chairman of the Department of Neurology at the University of Maryland, and Roberds, chief executive officer of the TSC Alliance, have both been a part of the field for at least 2 decades. The duo sat down to converse about several topics within the space, including:

Diagnosis of TSC and challenges associated with this process

Changing disease course through prenatal diagnosis

The clinical pipeline of investigational TSC agents

To learn more about how the efforts of the TSC Alliance are helping shape the future, 

Videos

Peter Crino, MD, and Steven Roberds, PhD, join NeurologyLive to discuss several topics regarding the state of care for tuberous sclerosis complex, and the future of and advances in research. 

TSC Roundtable Discussion: Transforming the Future of TSC Care, Research

What else do you think about at night about TSC [tuberous sclerosis complex] before you go to sleep? 

 I spend a lot of time thinking about TS, actually. As I’ve looked back on my career and the challenges, I still think autism remains the unreachable goal in TSC, I really do. It changes the landscape and geography for patient care, for patient quality of life, independence, autonomy, and agency. It changes how we have to do surveillance screening with sedated MRIs versus nonsedated. We need to understand why it is that 40% of individuals with TSC develop autism.

In some ways, we’ve heard the concept of TSC as a linchpin disease, that it is useful to understand many other disorders [such as] diabetes, obesity, cancer, etc. I absolutely feel as though the role of the TSC1 and TSC2 genes in engendering autism is something we need to look at. Quite frankly, I think understanding that will have broad potential echoes in the greater autism community. If I think about what single disease burden over the last 25 years of care doing this has altered quality of life for patients, I have to say, I don’t think it’s epilepsy, I don’t think its kidney disease, and I don’t think it’s lung disease.

I think they’re all very serious, and they all need to be treated. But autism and TAND [TSC-associated neuropsychiatric disorders] completely changed the landscape of what a patient’s life is. I want to go after that in the next 5 to 10 years to understand, why is it that nearly 1 in 2 individuals with TSC will have something on the ASD [autism spectrum disorder] spectrum? There’s got to be something about the mTOR pathway. There’s lots of evidence that there may indeed be something about the mTOR pathway. I feel like that’s the next exciting thing, and we haven’t made major strides in that area. Therapeutics have not done much in that area, and so that to me is something I want to focus on.  

I completely agree. I think especially since moving to MGH [Massachusetts General Hospital] and taking care of adults as well as kids with TS, it was profoundly impactful to realize how important and what incredible impact, often very negative and profound, TAND is on people living with TS. 

I agree. And the autism, I think you and I have also always suggested that TS be a model for many things. Study autism and TS, and like you said, learn more about autism in the general population. It’s the same for infantile spasms, same for many other aspects of TS. I agree, there is a lot more to do. I agree with you that where we are now with our understanding and ability to care for TS has changed from when you and I started this. It is going to be great fun to see where things continue to go from here.  

 Well, Pete, thank you very much. I always like talking to you about TS any time, so this was a nice opportunity to touch base on many different aspects of it. I’d like to thank the audience for watching this 

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Elizabeth Thiele, MD, PhD, and Peter Crino, MD, PhD, provide closing remarks on the future treatment landscape of tuberous sclerosis complex.  

 

Final Thoughts on TSC Management 

 For community neurologists, what advice would you give them? I often will see a patient with TSC [tuberous sclerosis complex] who has been followed, as a neurologist, the focus is on the epilepsy, the behavior, the autism, etc. What’s the advice for community neurologists, not to feel that they have to have the burden of taking on all aspects of the care of an individual with TS, but what advice would you give? How would you approach taking care of either a child or an adult as a community neurologist? 

It’s a challenging disorder to follow, you have to keep juggling a bunch of balls in the air at the same time. Unfortunately, many neurologists, community neurologists in particular, end up being the point of service for patients with TS. They often do a fabulous job with the epilepsy, the behavior, and getting them connected for an IEP [individualized education plan], and all that sort of stuff. But they may not think about the evolution of kidney disease or progressive changes in terms of facial angiofibromas and cosmetic effects. In women, as they transition to adolescence, the appearance now and new burden, the new risk of potentially developing LAM [lymphangioleiomyomatosis], often is not acknowledged. The biggest thing I tell community neurologists, and I work with a lot of them, is that the surveillance criteria, the diagnostic criteria, not only are they published, they are on the website for the TSC Alliance. You can go and you can find them, and they’re pretty simple to follow.

They’re pretty straightforward. I also tell them that if they can’t find a center of excellence or a clinic center to go to, to feel free to have patients be seen by either nephrology or pulmonology or dermatology, so you get a multitude of opinions. It does take a village in a lot of ways. We as TSC specialists, we’re used to thinking about all the different organ systems. If you’re a community neurologist, you may not have thought about checking somebody’s glomerular filtration rate recently, or you haven’t thought about checking their pulmonary function test. It’s important to get other opinions to make sure you’re getting in front of the problems that evolve in TSC because that’s how you can stay on top of this disease. 

 I agree. I would promote the TSC Alliance. I can be an expert in tuberous sclerosis or maybe a few other things, but there are a lot of things I don’t know as much about and the right way to provide care for patients. I think having the TSC Alliance so easy to go to, to access information, to access advice, to be connected to peers; it’s an incredible network. I think that it not only improves the lives of people living with TS, but it supports those providing care to people living with TSC.  

We mentioned the turning point and where we need to go. But if you had to say what you consider the biggest unmet needs in TS, other than a cure, a cure would be great….

 What would be on your top 5 wish list?  

That’s a hard one. I think certainly something to get a better sense of the prognostic landscape for any individual. It’s very difficult for any one person to come in and tell them what the next 5 or 10 years hold. It is particularly relevant for kidney disease and lung disease, especially lung disease. So, being able to identify persons at risk with either biomarkers, blood biomarkers, tissue biomarkers, imaging biomarkers, but something that allows you to get a handle on what’s coming. As I said before, I try to lay the groundwork, but it’s all just a series of what-ifs. It would be nice to have some plans to say, “Look, we have this blood test, and it looks like you’re at pretty high risk of developing LAM or kidney disease, etc.” I think a prognostic biomarker would be huge. I think, as you mentioned earlier, the wholesale analysis of babies to identify those at risk for TSC, whether through a whole newborn screening program to assay the way we do for other types of genetic diseases, or in individuals at high risk.

As you mentioned, going forward, that early disease-modifying therapy, even in the first few days of life, and dare I say it, maybe even the third trimester, may have significant alterations in what the long-term outcome is in terms of neurocognitive development. I think that would be a game-changer. To take TSC, as opposed to a multisystem disorder plus autism, for example, to just a multisystem disorder with normal behavior and normal intellect. I think those are very different engagements in terms of patient care. No. 3, I think we’re going to have to look a little more at, even though we have good therapies right now for TSC, there are still some [adverse] effects that are difficult for patients, that limit their wide-scale deployment and their utility. Some people actually have to come off the medicines that we have because of [adverse] effects. 

I think we need a better sense of the next generation of medicines that have fewer [adverse] effects, are more tolerable, easier to dose. I would also include, do we really need to dose medications every day? Could we come at it from a cancer chemotherapeutics perspective, where we do maybe intermittent or periodic dosing? I think that would be fabulous. The final point, which is still largely aspirational, is at the end of the day, tuberous sclerosis complex is a genetic disease. There have been a number of advances in the last 5 years, certainly in the neurological disease space, where we have used gene editing to begin to alter the course of a neurologic disease. Some of them, in the case of spinal-bulbar muscular atrophy, are really serious pediatric diseases, and we’ve changed the course.

We have to think about how gene therapy might be a tractable option in TS to be able to either mitigate or indeed reverse the effects of the gene mutations and undo what nature has done in terms of gene mutations. I think that’s very aspirational, it’s almost a bit of science fiction. The truth of the matter is, in the last 5 years, we’ve made progress in gene editing, in altering human phenotypes and diseases, and improving lives.  

 I completely agree. I get that question a lot from patients because, gene therapy, they read about it in different disorders. There’s a lot of excitement now, like in Dravet syndrome with the ASO [antisense oligonucleotide] trial going on, and will those be possible in TS? I’ve had this discussion with some people in the gene therapy industries who view TS as a little different than spinal muscular atrophy. 

I think if you look at the burden of the possibilities, the various spectrum of involvement of TS as well as the years of surveillance, if you did have gene therapy, not only could you improve the lives of people living with TS, probably dramatically. But you could also probably end up saving health care dollars because you wouldn’t be doing all the MRI scans, necessarily, etc. I agree, it’s aspirational, and I think many of us hope that there will be a possibility for it someday. There clearly is with these other disorders that have trials in place that show promises, that the future is bright.  

 What you said about prognostication, I think that also would be huge. If I was counseling a young man or a young woman about family planning, who had TS, that’s a very difficult aspect of what we do. If I had TS and was mildly affected, right now no one would be able to promise me my child would be as well. Maybe, if we can do preventive therapy if we know a baby’s going to have TS, and we modify, but I think that’s also difficult. As we know, to date, the genotype-phenotype correlations we’ve all tried to hunt down and pick up so far haven’t been that clear and helpful, other than TSC2 [mutations] often being more severe than TSC1.

I’d like to thank the audience for watching this 

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Advice to community neurologists for the optimal care of patients with tuberous sclerosis complex and future directions for TSC.  

Future of TSC Management 

The other thing you and I think about, especially you, is transition. It’s a hot topic in neurology and all medical fields, as people with disorders are transitioning into adulthood. For a disorder like tuberous sclerosis [TS] which is not just the brain, not just treating epilepsy, but many different things, how do you approach that? You say you transition people from adolescence into adulthood. What are your recommendations for the optimum way to do that for an individual with tuberous sclerosis? 

 That’s a really important question. I have been doing this for a lot of years. Whether I was ahead of the curve, I don’t know. Maybe it just worked out that way. There are a couple of fundamental points to acknowledge. No. 1 is that transition is not an event; it’s a process. It takes time to transition people. When you talk to families, you have to realize that many of them have had superlative care by pediatric neurologists, primary care pediatricians, and other pediatric specialists in a family-centered way with lots of infrastructure and support systems and resources. That’s been a wonderful experience for them, and they’ve had lots of great care.

During the transition to adulthood, adult medicine by its nature is less family oriented and more patient oriented. The idea that the individual will gain some more autonomy for their care in terms of responsibility, medications, making appointments if they’re able. If they have intellectual challenges or autism, then that’s still going to be figured out. The third issue is understanding that you’re going to have to gain the trust of the family and that you’re a new person. I have a lot of time where I just sit, and I explain, “I know this is a transition. You don’t know who I am or what I’m going to, so we’ll work together. I’ll show you that I can do this and get you through the process.” Fourth, becoming an adult means that there are other comorbid diseases that just happen in human beings that have nothing to do with tuberous sclerosis. High blood pressure, diabetes, cancer, and heart disease just happen to people, so being aware that not everything is tuberous sclerosis and that you will still need surveillance for other things.

The fifth point is the ability to understand that a critical part of this is that the caregivers are aging out. Many caregivers who were younger, enthusiastic, and energetic, as they age into their sixth, seventh and eighth decades of life, don’t have the ability anymore to care for a 40-, or 50-, or 60-year-old adult with TSC [tuberous sclerosis complex]. Other things come in, such as advanced directives, estate planning, moving to group home settings, and getting in-home health aids. 

Those are the things we talk about because a common question I get from parents about their child is, “What’s going happen to them when I’m gone? Who’s going watch out for them?” It’s a very poignant question. It’s a very important question. In my TSC center in Maryland, we have a fabulous social worker who does a lot of these engagements with patients and has these conversations. It’s a transition. We stress that it’s not, “You’re changed now.” It’s not a day thing. It takes some time. Acknowledging that we’re taking care of an adult, not a child. A 27-year-old is an adult, and they have autonomy and agency and want to be independent. I have to recognize that and acknowledge that, and then work together to get the long view of what the care is going to look like. 

 This is something that’s changed while you and I have been doing this. I remember many years ago, at an adult TSC family conference, talking to many families whose children had been followed when they were children through TSC centers. Then they aged out, and 1 woman spent 3 years trying to find a care provider for their child because these are not easy patients, with multisystem disorder, etc. With the efforts of the TS Alliance, in part, is the strength. That’s the voice of the patient community, and we have more centers in the United States with experts in the care for adults with TSC. 

That’s very important. It must be very frightening, and not only for my patients with TS but also my other patients with pediatric epilepsy. As they age, it’s a different center of family-based care. In pediatrics, it’s the parents, the patient, and the physician. But in the adult world, for some of our patients with TS, it continues to be that, depending on if they have disabilities. For others, it’s a different adult-to-adult care-provider relationship.

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Expert neurologists and epileptologists share best practices for transitioning a patient with TSC from adolescence into adulthood. 

TSC: Transitioning From Pediatric to Adult 

 A frustration that all of us in the TS [tuberous sclerosis] community still have is that there is still a lack of awareness and understanding of this order in the medical community. I know we’re all working hard to try to improve that. Even if we have the most effective treatment, it’s only going to help if we know a person has TSC [tuberous sclerosis complex]. We looked at this several years ago: What leads to the diagnosis of an individual having TSC, and what were the missed symptoms? When we looked at this, epilepsy was the most often missed symptom, which was disappointing to me. I was looking at a lot of adults who were having seizures as children. There were no MRI scans, and there was no understanding about TS.

The other thing that’s been exciting over the past 20 years is the emergence of all these TSC clinics and programs. You and I several years ago discussed the role of TSC clinics and the concern if you don’t have access to a clinic? How do you view TS care? Obviously, we both direct TSC clinics. How would you advise either our colleagues who don’t have access to a clinic or patients who don’t have easy access to a clinic? What advice would you give them? 

It’s a very challenging question. It comes down to access to health care. That applies to both urban and rural areas. Lots of individuals have been evaluated for seizures, and TSC has never even been on the differential diagnosis. Sadly, I’ve seen more patients than I care to who have been evaluated. I even had scans of their organs and never had a diagnosis made. No one closed the loop. It’s a sad thing. We really have to push the awareness. The Tuberous Sclerosis Alliance has done a huge job to build awareness. For patients, it’s important to be your own advocate and realize that knowledge is power. The ability to explain to your physician, “I have this genetic disease, and these are the features.” Go to the website, print the diagnostic criteria, print the surveillance criteria, and say, “This is what I need to have done.

At the end of the day, that’s very important. The nice thing about the TS Alliance is that if you’re a patient in the United States, Canada, or even worldwide, you can access the alliance and say, “I need some help. Is there anyone who can help me?” You and I and a lot of our colleagues do tele-evaluations and review records for patients. That’s the other way to do this. Finally, figuring out a network now that the pandemic has taught us all how to do telemedicine visits. The future of a telenetwork to connect people from around the globe with TSC is going to be the way of the future. That’s the way we’re going to get in underserved areas around the world. That’s the way we’re going to get the message out. Even in the United States, lots of people in designated rural areas are never evaluated for TSC. It’s unfortunate because it leads to patient morbidity. 

You and I have been very involved with the TS Alliance, and now you’re chairman of the board. Working with that organization—I was on the board for 12 years—taught me how important that type of that organization is for patients and families living with these disorders. TS Alliance is also very important for our colleagues in the medical field because it is a source of information. Not everyone can be an expert about everything, and there might be a neurologist who has 1 or 2 patients with TS, and that’s a resource to easily go to. With your role with the TS Alliance, where do you view it leading to further research and further awareness of TSC?

We’re at an inflection point, for sure. In TSC, we’ve done what many rare-disease organizations have not been able to do but still aspire to. We’ve gone from a group of patients that this diagnosis was around in the late 1800s. We have a century’s worth of clinical experience. In rapid fire over several years, we identified the causative genes for this disorder. In a bedside-to-bench strategy, we immediately did lots of funded research—some by the National Institutes of Health, some by the Department of Defense, some by the TS Alliance—and tried to understand what these genes do. What pathways do they function in? Amazingly, we were able to come up with actionable areas that we could treat with existing medications and rapidly proceeded to clinical trials. And then wow, here we are with FDA approval. 

That’s a remarkable story of bedside to bench and back to bedside. That’s all great, but we haven’t cured tuberous sclerosis. This disease is still here, and people still are suffering with epilepsy in tandem kidney disease. The next generation, the inflection point, is taking where we are, expanding on our knowledge, looking at more patients through a natural-history database, looking at tissue samples from patients in a biorepository, and using a preclinical consortium, which has existing mouse models to test in a very high throughput way different compounds that might affect the features of TSC with an eye toward eliminating autism, tuberous sclerosis, epilepsy, and lung disease in 5 to 10 years. Those are the goals in the next 10 years that we need to be aiming for. 

 I completely agree. You and I have known each other for over 20 years, and I’m thinking of the journey and the things we’ve learned. I’m thinking about how there are still unmet needs, there’s still a lot going on, and there’s a lot of more work to do. 

Elizabeth Thiele, MD, PhD, and Peter Crino, MD, PhD, comment on unmet needs and challenges in treating tuberous sclerosis complex. 

Unmet Needs in TSC Management 

There have been other exciting developments. In addition to the standard antiepileptic drugs, we have the appearance on the scene of everolimus, which in many ways is a disease-modifying therapy. It’s a class of the drugs of the mTOR inhibitor drugs. There’s good evidence that some individuals, when dosed appropriately with this medicine, will get a reduction or even seizure freedom. That’s very heartening, quite frankly. That’s an exciting option. There’s the recent appearance of cannabidiol on the scene as a potential therapeutic modality. Obviously, your research has shown that this modality is a novel strategy. It’s not 1 of the conventional antiepileptic drugs, and it clearly has a role and benefit in the treatment of seizures in TSC [tuberous sclerosis complex]. From the perspective of nonmedical therapies, there is standard epilepsy surgery, where we remove a part of the brain that’s causing seizures.

There has recently been the appearance of so-called neuromodulation, which is the use of something known as responsive neurostimulation—an implantable device in the brain that lets us countermand seizures by simply delivering electrical stimulus to the part of the brain where seizures are coming from. That technology has been completely new on the scene since you and I were in training, for sure. It’s a new avenue of therapy. We’ve got multiple medicines, we’ve got some new types of medicines, we have standard epilepsy surgery, and we have neuromodulation. There are lots of choices for practitioners to consider and evaluate.

 To your point about the medications, I approach the initial treatment of seizures in TS [tuberous sclerosis] other than infantile spasms as I would anyone coming in with focal seizure using the same antiseizure medications. I don’t think there’s any evidence. We all have our own personal experiences: “Well, this drug might be particularly effective here, or that drug might be particularly effective there.” But there haven’t been any real comparisons with either the traditional or new antiseizure medications, or the 2 that have FDA approval for treatment of seizures in TSC: Afinitor or cannabidiol, GW Pharmaceutical or Epidiolex. 

It’s exciting in the world of TS. For us, I remember when the mTOR pathway was implicated to be involved in TS. We were talking about that at the meeting in Chantilly, Virginia, and then seeing the trials of the mTOR inhibitors for the various symptoms of TS—angiomyolipoma, LAM [lymphangioleiomyomatosis]. It’s very exciting to realize that we do have therapies that can be disease modifying and are really helping a lot of individuals with TS. Clearly, a lot more needs to be done to come up with more definitive and effective treatments, but it’s been very exciting.

You’re right. My past 7 years have been focused on how effective is cannabidiol in the treatment of seizures in TS? There’s been a lot of excitement in the patient and medical community that this does appear to be an effective medication. Even to have 2 medications with FDA approval specifically for treating seizures in TS—there’s no evidence that they’re better than our traditional antiseizure medications but having them is exciting. You mentioned diet. As you know, I’m also zealous for dietary therapy. We’ve looked at this and utilized both the classic ketogenic diet as well as low glycemic index treatment in the management. There’s hope for people living with tuberous sclerosis with epilepsy that their epilepsy can be controlled. Typically, I approach thinking about refractory epilepsy and TS similarly to how I do my other patients. Wouldn’t you say? Lesional epilepsy, and if people don’t respond to the first couple of medications, then consider what other therapies—either nonpharmacological or surgery—would be an option.

 Definitely. I was just on a research roundtable about this a while ago. There’s no evidence that any of the existing commercially marketed antiepileptic drugs have any particular benefit or role in TSC epilepsy. Nothing has been shown to work for people with TSC1 vs TSC2, or complex partial and the old mode, the old terminology seizures or generalized. There’s nothing that really comes out. It is very much as you approach all focal onset epilepsies: You may have as a practitioner your own favorites that you start with, and you run through a couple of them. The data still hold up that if you have an individual who has gone through 3 medications, can tolerate them, is compliant, has therapeutic levels, and still has seizures despite those medicines, there’s no reason to delay an evaluation for epilepsy surgery in that patient. As a matter of fact, I would say the more common scenario is that people keep trying drugs and delaying an evaluation for epilepsy surgery.

After 3 medicines, that’s the time to consider whether they are a candidate for epilepsy surgery. Obviously, not everyone is a candidate, but that’s the time to think about it and get the person into the monitoring unit, so that’s pretty standard for focal onset epilepsy care. The addition of the 2 novel pharmacologies with an mTOR inhibitor and cannabidiol allows us some latitude to try some different strategies. The other is superimposing existing antiepileptic drugs on top of these new medications, which is a new world that we still have to investigate. Compared with even just a decade ago, there’s a lot more optimism and hope in terms of being able to get seizure freedom, or at least achieving a palliative reduction in daily seizure burden. 

 Over the years, a lot of the work we’ve done has been focused on looking at what impact a variable of epilepsy has on the other neurological aspects of TS, including cognitive impairment, autism, and behavior. We’ve shown, and others have shown, that clearly refractory epilepsy, infantile spasm, etc., are significant variables. When I talk to my colleagues, students, residents, and patients, we emphasize the importance of getting seizure control because it could impact many aspects for that individual, like cognition. The other exciting thing that’s been going on in the world of TS, is that we’re at the point where we ask if we could we consider prophylactic therapy. The trial going on in the United States and Europe looking at early treatment vigabatrin, could that prevent the epilepsy from developing? That’s another exciting aspect that we’re very fortunate to have because many babies are diagnosed with TS prior to the onset of seizures either from a family history, or cardiac rhabdomyomas or skin features. Could we intervene if we know a person has TS to prevent the epilepsy from happening? It could have significant impact on that individual’s life.

 Without question. The recently published EPISTOP trial that was just published provides very encouraging ideas that are keeping with the theme I suggested before, which is getting in front of things in tuberous sclerosis by being proactive and having a surveillance mode. Clearly, this is going to be the wave of the future, which is identifying babies who are at risk, and even discussion of wholesale newborn screening to try to identify in the general population babies who have TSC. And knowing that you can use EEG [electroencephalogram] as a biomarker to see if the brain is already starting to have abnormalities and how it’s wiring itself at very early stages by starting these individuals on disease-modifying therapies, whether it’s vigabatrin or an mTOR inhibitor.

The idea that you could modify the evolution of tuberous sclerosis—so that, for example, epilepsy or intellectual disability or autism spectrum disorder does not appear or appears in a lesser severity—is wholly new, wholly exciting, and the wave of the future quite frankly. We’ll be seeing that in the next 5 to 10 years.

 webinar. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming programs and other great content right in your in-box.

Peter Crino, MD, PhD, leads the discussion on exciting developments in approved therapies for managing seizures in TSC including the use of everolimus and cannabidiol. 

Novel Therapies Approved for Managing Seizures in TSC 

 Think about autism in this population. Autism is more frequent in TS [tuberous sclerosis] than other disorders. When we looked at this, up to 40% of people had autism, many highly functioning. It’s still something we look for. Epilepsy has been the focus both for you and me throughout our careers. What drew me to tuberous sclerosis was the infantile spasms. We know that 85% of people with TS will develop seizures. When we looked at this—and other people have looked at this—70% had onset the first year of life, which is clearly what leads to a lot of young children being diagnosed with TS. The thing that drew me to TS was the fact that a third of children with TS will have infantile spasms. We’ve learned a lot about infantile spasms from studying it, particularly the role of vigabatrin in treating infantile spasms and then moving on. What advice do you give patients who come in? Maybe your adolescents? What do you tell them about the natural history? Do they always have epilepsy with TSC [tuberous sclerosis complex]? Are those questions that the parents of young children want to know? Are those questions adolescents want to know? What advice do you give your patients on that? 

 It’s a great question. I usually start with the disclaimer that my crystal ball is officially busted, so I don’t know what the future is going to hold. I see multiple trajectories. One is that basically nothing changes: a pattern of seizures that are recurrent—maybe recalcitrant—to medicines, which may be evaluated for epilepsy surgery. That’s 1 trajectory. The other is that I’ve seen individuals who’ve had modest epilepsy burden when they were younger, and unfortunately their epilepsy got worse as they get into teenage years and then into their 20s. In fairness, I have seen the opposite of that, which is that people had pretty hefty epilepsy burden as children and teens. Then they get to their 20s and 30s, and things quiet down a lot. 

I prepare people for the possible trajectory, so they know what’s coming. As a broad observation in the care of patients with TS, as a practitioner, the most important thing you can do is prepare them for all the options, so there are no surprises. That goes a long way, so that people understand, first, why are we doing the test? Why do we get MRIs of the kidneys and of the brain? Why do we look at the lungs? The reason for surveillance is to stay in front of TSC and to always be proactive about it. Prudence would dictate, and the literature would dictate, that if you stay in front of TSC, the outcomes for patients in terms of morbidity is much improved. I try to give people a sense of the landscape, that this is a team effort, it takes a village to get them through this. Things might get worse, but things might also get better. Either way, we’re here no matter which way it goes. 

It’s really important. Parents of children or individuals living with TSC need to understand that there’s a spectrum. I completely agree with you about the epilepsy. When we looked at this, about two-thirds of the patients we follow had refractory epilepsy, or seizures that aren’t easily treated or controlled with medication. Even if you look at outcomes with those 40% of our patients—when we looked at this several years ago—they develop remission from their epilepsy, and many were able to come off treatment. I’ve met several people over the years who see me for a second opinion, who come to a TSC center to see what comprehensive care would be like.

When we talk about epilepsy they have often said, “We were told that we would always have epilepsy because we have TSC.” That’s an important message as well, that there’s hope that you might not always need to be on treatment or be worried about seizures. When you think about treating seizures and TSC, we’d all agree that it’s not even disputable that vigabatrin is the first-line drug for treating infantile spasms in tuberous sclerosis complex. We know that seizures in TS are focal. If you look at focal vs generalized epilepsy, we know that it’s a focal epilepsy. How do you approach the treatment of seizures in TSC? 

 Thankfully, we have lots of choices in medications and nonmedical approaches. Within nonmedical approaches, we have surgery, we have neuromodulation, and we have dietary therapy. There are lots of opportunities to make quality of life better. It’s important to define what that quality of life will be. Is it seizure freedom? Is it a reduction in seizures by 50%? The physician’s concept of being seizure-free often isn’t commensurate with what patients want in terms of quality of life. I try to listen and say, “What do you what? What’s the goal here?” I use a pretty general strategy for people with epilepsy by going through standard antiepileptic medications and trying to pick ones that fit with the particular patients. Certain medicines work better in men than in women of childbearing age. Certain adverse-effect profiles work better with other medicines, medication interactions, and other comorbid medical conditions, trying to figure out what might fit best. If they come to the position that they’re indeed medically intractable, that’s to say that they’re still having seizure despite at least 3 medications alone or in combination, then I evaluate them in a very methodical way for the possibility of epilepsy surgery, starting with an admission to the epilepsy monitoring unit. If we need to go the route of considering epilepsy surgery, we either do it after the first phase of evaluation or, in some patients, we need EEG [electroencephalogram]—we need to put electrodes in the brain, and you explain the process to patients.

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Peter Crino, MD, PhD, and Elizabeth Thiele, MD, PhD, review the spectrum of epilepsy in patients with TSC and approaching the treatment of seizures. 

Management of Epilepsy in Tuberous Sclerosis Complex 

How do you view the role of genetic testing? It’s clearly important for prenatal family planning and for testing family members. If you see a 50-year-old with TS [tuberous sclerosis] and with no children, what’s the role of genetic testing for that person? 

 It’s nice to have genetic testing in the background. When we started doing this years ago, not only did we not have the genes, but we also didn’t have genetic testing. Now we do. It’s pretty easy to order, and it’s pretty user-friendly for patients. I hold that in the back burner if I can assemble a clinical diagnosis for a patient. The recommendation now is that if you screen a patient and you have a clearly pathogenic—meaning a clear disease-causing mutation in either TSC1 or TSC2—that is also a diagnostic criterion for tuberous sclerosis complex [TSC]. If I have someone who comes in who’s got a bunch of minor things that just can’t come together with the major thing, the genetic testing can be the capstone on that and can help me solidify the diagnosis. For the vast majority of patients, with an assiduous clinical exam and using imaging, I can usually make a diagnosis. 

I’ve had a couple of challenging cases over the years with adults who have had a single cortical dysplasia on their brain MRI. I cleverly get an abdominal MRI, and I find a couple of renal cysts, which are minor diagnostic criteria. Now I’ve got someone with cortical dysplasia, which could be a major criterion, and a couple of renal cysts, which is a minor criterion. That’s still possible TSC. If that person is of childbearing age, knowing that they have TSC is very important, in terms of family planning, follow-up, surveillance, and prognostication. In that situation, I find genetic testing is very useful. We’ve also done genetic testing and identified individuals with TSC who’ve wanted to know, and other family members, do others have this mutation? As many may know, TSC is a dominant disease, which means there’s no “carrier state.” So you either have this mutation, and therefore have this syndrome, or you do not. Other people have some soft signs on skin exam, so genetic testing looking at an individual plus sibs or something can be very useful. 

The genes are also included on different oncology panels. I’ve had a couple of people come to me who were diagnosed when a family member had renal cell carcinoma or something and they had a gene panel that showed the mutation. 

We sometimes have difficulty getting payer coverage, particularly in adults, particularly to cover genetic testing. Until now, and even now, treatment doesn’t differ between TSC1 and TSC2. But with evolving genetic therapies, not yet for TS but maybe in the future, it’s going to be more important.

Pete, you and I are both neurologists. The brain is what got us to the TS world. One of the things I still see often, and you probably do as well, is that a lot of medical professionals and people who read the internet assume that everyone with TSC must be cognitively impaired. That’s 1 of the things I’ve been very impressed by. You and I both know, and it’s important to stress, that 50% of people with TS are cognitively normal. In fact, I take care of a lot of people with TS who are much smarter than I’m ever going to be. 

 Don’t you find that there’s still an issue? Many of our colleagues even expect people with TS to have cognitive impairments.  

 Absolutely. It’s 1 of the sad bits of history that just can’t seem to go away, which is the idea that TSC is irrevocably associated with severe intellectual disability, autism, and severe epilepsy and that it’s viewed as a catastrophic syndrome. I’ve never had a child with tuberous sclerosis, but I am a father. I can imagine that a new parent, who’s told that their child has tuberous sclerosis, could go to the internet and get the wrong source, reading about intellectual disability—using old terms like mental retardation, epilepsy, and autism—must be devastating for families.

The truth is that the numbers don’t look anything like that. It’s much more like 50%. As you say, lots of individuals have normal cognitive function and have very limited TAND [TSC-associated neuropsychiatric disorder] burden. They may not have epilepsy and are living, working, functioning, going to college, and living normal lives in society. In that scenario, tuberous sclerosis complex is more of a chronic disease the way other chronic diseases might be, such as diabetes or lupus or other kinds of disorders, which require medical surveillance, for sure, but don’t have the burdens of intellectual disability or autism. It’s important to get the right information to people so they know what the data look like and what they might be able to expect over time.  

You were talking about your oldest patient with TS. My oldest patient TS now is 88. He did me a favor a couple of years ago and stopped shoveling his own snow. I was always very worried about this 88-year-old shoveling snow. Whenever I was shoveling my snow, I was thinking about him. It’s so important for people to know.

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Experts in neurology discuss recommendations for genetic testing when approaching the diagnosis of TSC and misconceptions around cognitive impairment. 

Role of Genetic Testing in Diagnosing TSC 

You mentioned the major and minor criteria that you use for diagnosis. The latest Tuberous Sclerosis [TS] Complex International Consensus conference was in 2012, and we’re working on revisions of that now. Can you briefly review what that means, major and minor criteria? 

 When we initially were assembling diagnostic criteria, we had put together in the original days definite, possible, and probable. We’ve reupped that and reevaluated, and we have come up with 2 broad diagnostic categories largely based on clinical criteria. This includes definite TS. Definite tuberous sclerosis is defined by the presence of 2 of the major diagnostic features, or 1 of the major diagnostic features plus 2 minor features, and we can talk about that. Possible tuberous sclerosis is someone who comes in who has 1 major diagnostic feature or more than a couple of minor diagnostic features. Until the advent of genetic testing, clinical diagnosis was how we made a diagnosis of tuberous sclerosis. Basically, we look across the series of organ systems, including the brain, the eyes, the lungs, the skin, and the kidneys, to look for the major diagnostic features. 

In the brain, the major diagnostic features include malformations of cortical development; subependymal giant cell nodules, which are small nodules in the ventricular system in the brain; and tumors. Not cancer tumors, but benign growths inside the brain that are not actually benign; they can cause a lot of problems for patients. Any of those, if seen on an MRI scan, would be considered a major diagnostic feature. In the skin, we have a number of features from facial angiofibromas, which are reddish lesions that can appear on the face. They are a major diagnostic feature. Subungual fibromas, which are warty lesions around the nail, are a major diagnostic criterion. The so-called shagreen patch—or collagenous fibroadenoma, which is often seen in the lumbosacral flank region—is a major feature. The classic so-called hypomelanotic macule used to be called the ash-leaf spot—many of us in medical school learned it as the ash-leaf spot. It’s an area of diminished or absent pigmentation often seen multiple in the body. 

All those are major diagnostic features. In the lung, there is lymphangioleiomyomatosis, which is a progressive lung disease seen almost exclusively in women with tuberous sclerosis complex [TSC]. In the kidney, there are lesions known as angiomyolipomas. Angiomyolipomas can be seen in the kidney most commonly but also in other visceral organs, including the liver. The eye, which is part of the nervous system but is a little different, has characteristic lesions known as retinal hamartomas. These are basically malformations or abnormalities in the retina. All those are considered to be major diagnostic criteria. If I see a patient who’s come in with either a first-time seizure, or as I was mentioning before, the parent of a child with TSC, those are the things that I’m going to surveil for. Quite simply, you assemble a checklist of those features, and anyone who’s got more than 2 major diagnostic criteria—hypomelanotic macules and angiofibromas and a tuber the brain—by clinical criteria has definite tuberous sclerosis. For someone who has only has 1 of those and a couple of minor features, which we can discuss, we would say that it’s possible tuberous sclerosis. We’d want to do more investigation with imaging or even genetic testing to confirm that diagnosis. 

That concept of possible TSC is an important 1. As you know, these different organ involvements can occur at different times during individuals’ lives. If I have a child who might have multiple rhabdomyomas, and I know the criteria at that time, if I do genetic testing and find the disease-causing mutation, I know that child has TSC. If for some reason I can’t or if no mutation is found, it’s still important to follow that child because that person likely has TSC with multiple cardiac rhabdomyomas. To minimize the impact of TSC on an individual’s health, they should be followed closely. We follow those people, but we don’t necessarily do the recommended surveillance testing at the same intervals in the possible TSC or probable TSC. It’s important because for many of them…if you do the clinical diagnostic work-up at birth with the baby’s rhabdomyomas, probably some people with TSC were missed because they didn’t meet criteria at that time. 

I tell my patients and other people: The major criteria are things that we see very frequently in TS that can be seen in the general population but not as frequently. For example, renal angiomyolipoma [AML] is not rare, but it’s pretty unusual to have multiple bilateral AMLs outside of TSC. Regarding the minor criteria, we can go through them. We just mentioned that there are things that we see in TS but are also seen in the general population. They’re not as specific. I have diagnosed 1 person over the years by using the minor criteria. It’s pretty unusual because we know the brain and the skin affected 95% of people with TS, so it’s often possible to do then.

Peter Crino, MD, PhD, and Elizabeth Thiele, MD, PhD, review the major and minor diagnostic criteria for TSC based on the 2012 International Tuberous Sclerosis Complex Consensus Recommendations. 

Diagnostic Criteria for Tuberous Sclerosis Complex 

The other thing that’s interesting about TS [tuberous sclerosis] is when people get diagnosed. What leads to the diagnosis? As a pediatric person, I think it’s often prenatally with the cardiac rhabdomyomas or in infancy with the onset of seizures. We’re going to talk a lot about seizures. People have been diagnosed also—in adolescence, in childhood—by being referred for clinical acne or other issues. I know we see a lot of adults who were diagnosed in childhood. What about the people who walk in and are diagnosed as adults. What usually leads to that diagnosis? 

It’s been an incredible set of stories. I’ve been doing TS care since the mid-1990s, and I’ve seen all kinds of presentations. Suffice it to say, in every person, when they find out that they have a genetic disease, whether inherited or a spontaneous sporadic mutation, they’re usually pretty surprised and ask, “What’s tuberous sclerosis? I’ve never heard of that in my life.” It’s been a mixture of presentations. A common presentation, for example, is a parent who comes in with a child with known tuberous sclerosis. We have the conversation that this is a genetic disease. Then I say, “Would you like me to look at your skin or do an exam?” It turns out they have some of the major or minor diagnostic features of TSC [tuberous sclerosis complex], and I say, “You may have this as well,” which is always a fairly sobering conversation. I’ve had individuals who have come in with a first-time seizure, gotten a brain MRI, and have found abnormalities in the brain that are highly consistent with TSC. Then I do a skin exam or look at the kidneys, and I’m able to assemble a diagnosis.

We’ve had a number of individuals present primarily with very odd and rare types of cancers that are associated with tuberous sclerosis. Obviously, TSC is not a cancer syndrome. But there are a couple of very rare cancers, such as pancreatic neuroectodermal tumors. I’ve seen 2 people present with that as their initial manifestation, and they never knew they had tuberous sclerosis complex. Interestingly, they never really had seizures or much else. It’s curious that many of them, when queried about TAND [TSC-associated neuropsychiatric disorders], report that they have a lot of the things that are very compatible with TAND. It’s a broad range of presentations. My oldest new diagnosis was a man in his mid-70s who had prostate cancer unrelated to his tuberous sclerosis. As part of his work-up, he had an abdominal MRI and bilateral kidney lesions, and he told me, as you mentioned acne before, “Yeah, I’ve had lifelong acne. I never could get rid of it.” It turns out he had tuberous sclerosis complex. 

 It’s amazing. I’ve also seen many people as adults who are diagnosed who had been living with this disorder for decades and never knew. 

My oldest is also in his 70s, so it’s interesting.

Expert neurologists discuss the clinical presentation and diagnosis of tuberous sclerosis complex. 