Melanie: Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole, and I invite you to listen as we discuss the neurological management of Von Hippel-Lindau disease.

Joining me is Dr. Rimas Lukas. He's an associate professor in the Ken & Ruth Davee Department of Neurology in the Division of Neuro-oncology at Northwestern Medicine. Dr. Lukas, it's a pleasure to have you join us today. What an interesting topic we have. Tell us what is Von Hippel-Lindau disease. What's the prevalence of it?

Dr Rimas Lukas: Von Hippel-Lindau disease is a rare genetic disorder that is inherited in an autosomal dominant fashion in which patients have the potential to develop a wide range of neurologic and other systemic problems. It is not a common disorder, but because of its autosomal dominant inheritance pattern, when one family member has it, there's approximately 50% chance that the next generation of individuals may have it as well too.

Melanie: Well then, speak a little bit about the pathophysiology of it and its nervous system manifestations. Tell us about the neurological complications and some visceral manifestations that you've seen.

Dr Rimas Lukas: So Von Hippel-Lindau disease is due to a mutation at the Von Hippel-Lindau gene, which leads to a lack of the product, the Von Hippel-Lindau protein. So that plays a role in removing a break on one of the angiogenic pathways. And in turn, when that break is removed, you have the propensity to develop very vascular tumors. And these can occur throughout the body. One of the locations is in the nervous system where it manifests as hemangioblastomas, which are low-grade tumors, most oftentimes in the posterior fossa, the spinal cord or the cauda equina. You can have similar looking tumors within the retina, so retinal angiomas. And you can have wide range of tumors elsewhere in the body, including renal cell carcinoma, which is another highly vascular tumor type.

With regards to the neurologic manifestations of the disease, as I said before, patients can develop hemangioblastomas. These can be solid and/or cystic, and they cause problems by occupying space in the nervous system and compressing the underlying structures. At times, it's going to happen rapidly with the rapid cystic accumulation. It can also occur rapidly within the context of a hemorrhage within these very vascular tumors.

Melanie: Does it present with symptoms?

Dr Rimas Lukas: The typical symptoms that patients present with when they have the hemangioblastomas depend on the location of the tumors. And so when I think about them, I divide them into two big areas, the things that are intracranial and those that are spinal or spinal nerve root related. So those that are going to be intracranial are going to be space-occupying lesions predominantly in the posterior fossa. And what we can see is either localizable symptoms that are due to dysfunctions of the structures being involved. So the cerebellum, for example, and people can have ataxia, unsteadiness of gait, et cetera.

Or they can be non-localizable due to blockage of cerebral spinal fluid flow and space-occupying lesion within the intracranium and that can lead to increased intercranial pressure. So increased intracranial pressure headaches that are worse when you're lying down, may wake you from sleep. They could be associated with nausea and vomiting with double vision due to compression of the cranial nerves at the base of the skull.

In the spinal cord, what we can end up seeing is symptomatology related to whatever is below that cord level. So weakness and numbness at whatever that level of the cord is and distal to that. And if it's involving the nerve roots, particularly those with the cauda equina, what we can end up seeing is radicular pain. So this is pain that shoots down a dermatomal distribution, just like sciatica for example. And, we can also see bowel and bladder symptomatology as well as the motor weakness.

Melanie: Well then Dr. Lukas, you mentioned family history. If there is not a family history present, what's the clinical diagnostic criteria for VHL? How and when would it be diagnosed? And should physicians be on the lookout for certain things? It seems to be that if there is no family history, why would you be looking for it? And how important is early diagnosis in improving outcomes?

Dr Rimas Lukas: So that's an excellent question. The diagnosis of VHL can be quite difficult. The definitive diagnosis is established by genetic testing that reveals a specific mutation in that VHL gene. Now to be able to get to that point, what typically happens is either, A, the patient has a family history and then they meet with cancer genetics counseling, and then have other family members screened in the appropriate fashion. Or B, they present with one of the symptoms associated with VHL and that can be manifestation of any of the tumor types. And so somebody might have a newly diagnosed renal cancer, and there may be some alarms that are wrong in the sense that they might be younger than one would anticipate, or maybe somebody else in the family had renal cancer or something along those lines. They might present with a hemangioblastoma. They might present with more than one hemangioblastoma, which would be atypical for sporadic disease, but it would be fairly common for VHL-related hemangioblastoma. They might have visual symptoms related to retinal angiomas.

And then once that diagnosis is made, I do believe the clinician is astute, and can suspect VHL and then proceed down that appropriate pathway to make that genetic diagnosis. There is benefit from my perspective in comprehensive care with individuals who are very experienced in caring for the management of VHL patients. And we know that in the recent past, we've had notable improvements in survival in patients with VHL. And we think in large part, this is driven by well-coordinated care for this patient population, for whom there are a lot of different moving parts and a lot of different potential risks with regards to malignancies.

Melanie: And I'd like to get into that multidisciplinary approach that you're touching on right there. But before we do tell us about the therapeutic management and tell us any insight that you have into the type of tumors that you see for VHL.

Dr Rimas Lukas: As a medical neuro-oncologist, I end up seeing predominantly hemangioblastomas of the nervous system. And as I said earlier, these are tumors that arise almost oftentimes in the posterior fossa, in the spinal cord. These are low-grade tumors. They are WHO grade 1 tumor, but they can still have a significant amount of morbidity as well as mortality associated with them.

Oftentimes, our management is fairly conservative within the setting of VHL. And the rationale behind that is patients, one, may have multiple lesions. And so it's not practical to chase after one lesion or another lesion and then another lesion with regards to aggressive therapeutic intervention. And two, these tumors oftentimes follow what's called a saltatory growth pattern. So unlike most tumors where you see a linear growth pattern, it gets a little bit bigger, a little bit bigger, a little bit bigger, or you see a logarithmic growth pattern where things get a lot bigger, fairly quickly. These can grow, they can stop growing, they can grow again. And we don't have at this point in time, good predictors of what will lead to growth of tumor, what will lead to stoppage of growth of tumor in these patients. And so oftentimes because patients have multiple lesions in that saltatory pattern of growth, will oftentimes follow the lesions themselves and just keep a close watch on them.

If they start to become symptomatic or if the rate of growth is very high or they're causing compression of critical structures, in that situation, we would intervene. And most oftentimes the intervention would be surgical. Neurosurgeons can cut the entire lesion out, oftentimes cure the patients of that specific lesion, but it does not address the other lesions.

In some circumstances, we think about radiotherapeutic approaches. And we also do think about the potential of systemic therapies typically within the context of a clinical trial.

Melanie: And you're a member of the VHL Alliance's Clinical Advisory Council. Are there any updates you can share and latest research in the field? Speak to us a little about how recent advances have increased your understanding of the pathologies of VHL.

Dr Rimas Lukas: So the VHL Alliance has recently put out some new guidelines with regards to screening of patients with known VHL diagnosis. These are available online and are now actively being submitted to various scientific journals for formal publication within each subspecialty area. So neuro-oncology being one, for example, renal another, et cetera.

Melanie: And before we wrap up, tell us about the VHL clinic at Northwestern Medicine. What makes it unique? And what are you and your colleagues doing to advance the understanding and treatment of this disease? Tell us about that multidisciplinary approach.

Dr Rimas Lukas: So I'm quite proud of our VHL clinic at Northwestern. I think it's a well integrated group of individuals who have expertise within their specific areas of interest. And for me, the overarching infrastructure that allows patients to move quickly through the process of the appropriate imaging and other diagnostic studies, as well as being able to see the key providers, I think is, one of the most favorable aspects.

Our program is anchored by the cancer genetics counselors, who have a tremendous amount of experience with VHL. And they're able to build the overall framework for the rest of us to understand which aspects of the disease are active for a specific patient in other family members, and help guide patients through this complicated path in as efficient manner as possible.

For us, what we are interested in is not just providing exceptional care for patients, but to be able to glean a better understanding of the disease, in turn, ideally, having a favorable impact on it in the future.

Melanie: Excellent information, Dr. Lukas. Thank you so much for joining us today. That was so fascinating. And to refer your patient or for more information, you can visit us at NM.org/neuro to get connected with one of our providers. That concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians.

Please remember to subscribe, rate and review this podcast and all the other Northwestern Medicine podcasts. I'm Melanie Cole.