Neurology 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.

In the second episode of this series, Dr. Tesha Monteith and Dr. Peter Goadsby discuss the prediction of treatment responses for personalized medicine.
Show transcript:
Dr. Tesha Monteith: 
Hi, this is Tesha Monteith with The Neurology Minute. Today I'm speaking with Peter Goadsby from the Division of Biomedical Sciences at King Abdullah University of Science and Technology about key trends in headache medicine and some of the most impactful research presented at the AAN annual meeting. Can you talk a little bit about prediction of treatment response for personalized medicine?
Dr. Peter Goadsby
I hope that AI gives us some direction. I haven't seen anything yet, but I don't think we've done enough with it to make it stunning yet. I think that the AI systems ... I'd love to know, for example ... I've been using triptans for 30 years and apart from using sumatriptan first when [inaudible 00:00:51] had a triptan simply because it's the commonest triptan, which is generally what I do, that's a pretty naff rule when you think about it. I'd like to think that AI systems could work out where we should be going in terms of acute therapy, preventive therapy, whether there are particular red flags or amber flags you might say in a person's broad history. I don't think we've got there yet, but I actually think we will get there. I think we'll be surprised and we'll learn things about the biology of the disorder and about the pharmacology of these medicines, which must have subtle differences because we all see people who respond to one and don't respond to another, and you sort of scratch your head, but you're happy that it happens.
Dr. Tesha Monteith: 
I agree with you, and I think the future is really bright for headache medicine and the potential of AI to move the needle. Peter, thank you again for joining us and sharing your insights. I really appreciate you being on. This is Tesha Monteith. Thank you for listening to The Neurology Minute.

In the second episode of a four-part series on Rett syndrome, Dr. Stacey Clardy discusses the importance of early referrals, particularly during the regression phase. 
Show transcript: 
Dr. Stacey Clardy: 
This is the Neurology Minute. I'm Stacey Clardy from the Salt Lake City VA and the University of Utah. This is the second episode in a four-part series on Rett syndrome. Today, let's discuss when to refer and specifically early referral is absolutely critical in Rett syndrome, particularly during the regression phase. Any child, most often a girl with previously acquired developmental milestones who begins to lose language or lose purposeful hand use or develops stereotyped hand movements should prompt urgent neurologic evaluation. This would be referral to pediatric neurology, of course, and this should not wait for genetic confirmation. Early involvement of pediatric neurology allows for diagnostic clarification, anticipatory guidance, and coordination of care across systems. The genetic testing, typically with MECP2 sequencing and deletion or duplication analysis, this should be pursued early and if initial testing is negative but suspicion remains high, expanding that genetic evaluation is warranted. And beyond neurology, early engagement with developmental services, speech, occupational, and physical therapy should start before even a definitive diagnosis is necessarily established.
Rett syndrome is a multi-system disorder. So a care team is going to monitor for common comorbidities. This is not just epilepsy, but also gastrointestinal dysfunction, breathing abnormalities, and orthopedic complications. When delayed referrals occur, it's often due to attribution of regression to more common developmental conditions. Be sure to listen to the other Neurology Minute episodes in this series. We'll be back next time for our third episode, and we'll cover treatment options and ongoing management.