Neurology Minute

In part one of this series, Dr. Andy Southerland and Dr. Dan Ackerman discuss what stands out in the latest thrombolysis guidelines, how these decisions are applied in stroke center practice, and how to educate residents and fellows on incorporating new evidence into treatment choices.
Show transcript:
Dr. Andy Southerland:
Hi. This is Andy Southerland from the University of Virginia, and for today's Neurology Minute, I'm speaking with my friend and colleague, Dan Ackerman, Chief of Neurology and Director of Stroke at St. Luke's University Health System. I've been speaking with Dan on the main neurology podcast regarding updates to acute stroke treatment related to the 2026 American Heart Association guidelines that came out in late January of this year on the early management of patients with acute ischemic stroke.
For our episode today, we might focus our discussion around thrombolytic therapy thrombolysis, which is at the core of what we do as acute stroke neurologists when it comes to treatment decision-making. So maybe as a first prompt, Dan, when you look at these guidelines, what stands out to you as you're thinking about how you practice, how you all are practicing at your stroke center, and then specifically how we educate our residents, our fellows on what they need to know, particularly the newness of it when it comes to making thrombolysis treatment decisions?
Dr. Dan Ackerman:
With all the discussions we've had in the past, there have been a lot of specifics about certain studies and how they might affect practice, but this guideline really opened up a lot and gave us an opportunity to do things in a way that makes really good clinical sense and really brings a lot of practices that have now become common at some centers into the fore so that we can get that information out to everyone and make sure everyone has that same really high level of stroke care everywhere they go.
I think the first thing that stands out to me is what did not change. And want to reinforce that, particularly for people who are just getting into this, stroke alert is a screening tool, not a severity score. It's not like an MI alert where you do an EKG and you see the tombstone wave and you say, "Oh, there's an MI and we're taking them to treatment." This is a screening tool, so it is meant to be highly sensitive at the cost of being specific.
At our shop for a long time now, we have initiated stroke alert for anyone who presents either within 24 hours of acute onset of neurologic symptoms or has an unknown onset of acute neurologic symptoms and they are still symptomatic to some degree at the time of their presentation, and that's it. We don't make any other statements about how severe something is or what kinds of symptoms someone necessarily has to have. We purposely keep it as broad as possible, again, because we're trying to screen.
And the other thing that has not changed, time is still brain. So with all of these different nuances on how we can treat patients and who might be candidates for intervention, it is still a matter of understanding these guidelines, applying our best evidence, but doing it as quickly as possible to make sure that we are rescuing as much of that ischemic penumbra as we possibly can.
Now, aside from that, in terms of what stands out that is different, I think one of the early things for me are the recommendations for extended time window for IV thrombolysis. So when you look at the original studies, we understand that when you get out beyond four and a half hours, if you just take all-comers, the risk is going to start to outweigh the benefit. But that doesn't mean there's zero benefit or that no one would receive benefit, but it's a question of, well, how do we cherry-pick those patients who may still receive benefit? And there are a few real specifics in the guideline that help us figure that out.
One is for patients who have an unknown time of onset, but they're within four and a half hours of symptom discovery. And for those patients, they would suggest that doing a stat MRI and comparing a DWI lesion with the corresponding area flare to determine if you see DWI hyper-intensity and the flare image is nice and normal, that would suggest that stroke is young enough that it may still be appropriate to treat that patient.
But we would also say for folks who have salvageable ischemic penumbra, so again, brain at risk that is not core yet, who either awoke with stroke symptoms within nine hours from the midpoint of sleep or, and this is the kicker, are within four and a half to nine hours from last known well. So in other words, they may have been symptomatic already for more than four and a half hours. If those patients have an appropriate ischemic penumbra, it may be reasonable to treat them with IV thrombolysis to improve functional outcomes.
Dr. Andy Southerland:
Well, that's all for this Neurology Minute. We hope this vibrant conversation will help all those who are out looking to make the best treatment decisions for their patients, both based on established evidence and most recent evidence in our new guidelines.

In the third episode of this series, Dr. Stacey Clardy discusses treatment options and ongoing management.
Show transcript: 
Dr. Stacey Clardy:
This is The Neurology Minute. I'm Stacey Clardy from the Salt Lake City VA at the University of Utah. This is the third episode today in our four-part series on Rett syndrome, and we're going to talk about treatment options and ongoing management. There is still no curative therapy for Rett syndrome and management remains largely supportive and multidisciplinary. But there is now an FDA-approved treatment, trofinetide, for adults and children two years of age and older with Rett syndrome. Trofinetide is a synthetic analog of glypromate. It's thought to modulate neuroinflammation and synaptic function, right? Because Rett syndrome involves difficulty with synaptic function. Clinical trials demonstrated improvements in some of the core Rett symptoms, but of course, as always, treatment decisions are going to require an individualized discussion, particularly given some common adverse effects such as diarrhea and vomiting. Beyond disease-specific therapy, management remains symptom driven. Given that epilepsy is common and may be refractory, careful EEG correlations are often necessary.
Of course, the breathing abnormalities like hyperventilation and apnea are fairly characteristic and can fluctuate over time so need to be monitored, and gastrointestinal dysfunction, nutritional challenges, other sleep disturbances, and scoliosis require ongoing monitoring and intervention when relevant. Rehabilitation therapies, physical, occupational, and speech, are foundational throughout life. A key principle here is anticipatory management, right? Many of the complications, like cardiac conduction abnormalities and bone health issues, can be identified early and addressed early with better outcomes when Rett syndrome patients have coordinated care. That's it for today. Be sure to listen to the other Neurology Minute episodes in this series on Rett syndrome, and check back for our next and final episode, where we will cover care team essentials and multidisciplinary management. I'm Stacey Clardy for the minute.

Dr. Margarita Fedorova discusses the effectiveness of shunting for idiopathic normal pressure hydrocephalus. 
Show citation: 
Luciano MG, Williams MA, Hamilton MG, et al. A Randomized Trial of Shunting for Idiopathic Normal-Pressure Hydrocephalus. N Engl J Med. 2025;393(22):2198-2209. doi:10.1056/NEJMoa2503109  
Show transcript: 
Dr. Margarita Fedorova:
Welcome to Neurology Minute. My name is Margarita Fedorova and I'm a neurology resident at the Cleveland Clinic. Today we're reviewing a randomized trial that provides high quality evidence for treatment we've been using for decades, shunting for idiopathic normal pressure hydrocephalus. The PENS trial, a placebo controlled effectiveness and iNPH shunting trial was published in the New England Journal of Medicine in December 2025 by Luciano and colleagues. This international multicenter study enrolled 99 patients across the United States candidate in Sweden. While idiopathic normal pressure hydrocephalus or iNPH is characterized by triad of gait impairment, cognitive decline in urinary continence, these findings can be non-specific and we mass factor in radiological findings too. Furthermore, while CSF shunting has long been the standard treatment, its effectiveness has never been rigorously confirmed in a large well-powered randomized trial. In this trial, patients with a clinical improvement in gait velocity after temporary CSF drainage were deemed eligible for shunting and randomizing the trial.
What makes this trial particularly elegant is its blending strategy. All 99 participants underwent the same surgical procedure with the same commercially available programmable shunt valve. After surgery, the valve was set either to an open functioning position or to a high resistance placebo setting. Neither patients nor assessors knew who had a working shunt. This is about as close to a true double-blind design as neurosurgery can get. The primary outcome was changing gait velocity at three months. The open shunt group improved by 0.23 meters per second on average, while the placebo group showed essentially no change in 0.03 meters per second. That's a treatment difference of 0.21 meters per second, both statistically significant and clinically meaningful. To put that in perspective, a change of 0.10 meters per second is considered the threshold for substantial meaningful change in the elderly. 80% of the open shunt group exceeded that threshold compared to only 24% of the placebo group. 
The Tenet scale, which measures gait imbalance, also showed significant improvement in the open shunt group. However, screening measures for good condition using the MoCA scale and bladder symptoms did not reach significance at three months, though tertiary outcomes for cognitive testing, quality of life and functional independence tended in favor of shunting. Importantly, falls were more common in the placebo group at 46% compared to 25% in the open shunt group. This is a meaningful safety signal given how dangerous falls are in older adults. There were also real risks with active shunting. Subdural hematomas occurred in 12% of the open shunt group versus 2% of placebo and three even required surgical intervention. Positional headaches from low CSF pressure were more common in the open shunt group at 59% versus 28%. The good news is that the adjustable valve allowed non-invasive management of many of these complications. While this trial gives us reasons to be cautiously optimistic about shunting for appropriately selected iNPH patients, it's worth noting that we only have evidence for improvement in gait and follow-up is only three months. 
Longer-term data is still being collected so we don't know yet how durable these benefits are. If you want to read more, please find the paper by Mark G. Luciano, et al. It's titled A Randomized Trial of Shunting for Idiopathic Normal Pressure Hydrocephalus published in the New England Journal of Medicine in December 2025. That's your neurology menu for today. Keep exploring and we'll see you next time.

Dr. Casandra MacLeod discusses central retinal artery occlusions, recent trials, and those anticipated in the future. 
Show citation: 
Préterre C, Gaultier A, Obadia M, et al. Intravenous alteplase versus oral aspirin for acute central retinal artery occlusion within 4·5 h of severe vision loss (THEIA): a multicentre, double-dummy, patient-blinded and assessor-blinded, randomised, controlled, phase 3 trial. Lancet Neurol. 2025;24(11):909-919. doi:10.1016/S1474-4422(25)00308-4 
Poli S, Grohmann C, Wenzel DA, et al. Early REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION): Study protocol of a phase III trial. Int J Stroke. 2024;19(7):823-829. doi:10.1177/17474930241248516 
Ryan SJ, Jørstad ØK, Skjelland M, et al. A Randomized Trial of Tenecteplase in Acute Central Retinal Artery Occlusion. N Engl J Med. 2026;394(5):442-450. doi:10.1056/NEJMoa2508515
Show transcript: 
Dr. Casandra MacLeod
Hello, this is Casandra MacLeod, a neurology resident at Cleveland Clinic with today's Neurology Minute. Today we will be discussing central retinal artery occlusions, or CRAOs, and the recent trials that have come out and even those further on the horizon. The 2026 American Heart Association and American Stroke Association guidelines for the early management of patients with acute ischemic stroke were recently published and in them highlight the uncertainty around the treatment of acute CRAOs with intravenous thrombolysis, even when the patient presents within four and a half hours and is otherwise eligible. These guidelines come after two recent trials, which we will further discuss.
The thrombolysis in patients with acute central retinal artery occlusion, or the THEIA trial, was published in the November issue of Lancet Neurology. This multicenter trial out of France randomized 70 patients with acute CRAOs presented within four and a half hours of time from last known well to either receive IV alteplase and oral placebo or IV placebo and oral aspirin.
While safety measures showed no symptomatic hemorrhage event, although they did have one asymptomatic intracerebral hemorrhage occur, the primary outcomes, which included visual acuity improvement at one month, showed some evidence for a trend of improved acuity in the IV thrombolytic group at 66% compared to 48 in the aspirin group, it did not reach significant. And now more recently, the Tenecteplase in central retinal artery occlusion study, or TenCRAOs, was published in the January 2026 issue of The New England Journal of Medicine. TenCRAOs was a six European country multicenter trial that randomized 78 patients with CRAOs all presenting within four and a half hours of time from last known well to either receive IV Tenecteplase or aspirin, both with placebo-matching as in THEIA.
The primary outcomes of TenCRAOs also included visual acuity at one month, but unfortunately this trial also did not show [inaudible 00:02:07]. They showed 20% in the IV TNK group compared to 24% in aspirin. And additionally, there was one fatal intracerebral hemorrhage in the TNK group that should be considered.
Overall, the AHA and ASA guidelines state the usefulness of treatment with intravenous thrombolysis is uncertain. And this is based largely on these studies as neither trial showed improved visual recovery. Although both of these trials are underpowered, leading many to believe that the jury is still out on the use of IV thrombolytics in CRAOs. But importantly, stay on the lookout for one last trial. The early reperfusion therapy with intravenous alteplase for recovery of vision and acute central retinal artery occlusion, or the Revision trial, is actively recruiting. Revision is similar in design as THEIA, but with a goal of up to 422 total patients for a goal of a well-powered study to guide decision making.

Dr. Gregg Day and Drs. Sonia Vallabh and Eric Minikel discuss scientific insights and the future of prion disease treatment, highlighting the importance of early diagnosis, personalized medicine, and hope for affected families. 
Learn about the clinical trial.  
Learn more about the Prion Alliance. 
Show transcript: 
Dr. Gregg Day:
This is Gregg Day with Neurology Minute. I've just been speaking with Eric Minikel and Sonia Vallabh, a husband and wife team at the heart of the PRiSM trial, a first-in-human study of a prion protein-lowering, divalent, small-interfering RNA for patients with symptomatic prion disease. Eric and Sonia, could you provide us with a brief overview of the PRiSM trial and what this first-in-human study seeks to accomplish?
Dr. Eric Minikel:
The PRiSM trial is testing a short interfering RNA designed to bind the RNA that encodes the prion protein. That is the protein that causes Prion disease. We are at the heart of what causes this disease. Through doing this, we hope to make prion disease a treatable and preventable condition. We both want to stabilize symptomatic patients and prevent the disease in people who are at genetic risk. This is a personal mission for us. Sonia is a carrier of a prion disease mutation that she inherited from her mother who died of prion disease, and we, along the way, aspire to be a different kind of sponsor. We want to create our own clinical data that are shareable learnings for the entire field.
Dr. Gregg Day:
This is Gregg Day with Neurology Minute. Thanks for listening.