Monogenic Mimics of Neuroinflammatory Phenotypes in Children and Young Adults - Part 2

In the second installment of this two-part series, Drs. Stacey Clardy, Ayush Gupta, and Kuntal Sen discuss the most practical testing approach to minimize both under‑ and over‑testing for these disorders. Show citation: Gupta A, Sahjwani D, Kahn I, Gombolay GY, Sen K. Monogenic Mimics of Neuroinflammatory Phenotypes in Children and Young Adults: An Evolving Landscape. Neurol Genet. 2025;11(6):e200326. Published 2025 Nov 25. doi:10.1212/NXG.0000000000200326 Show transcript:  Dr. Stacey Clardy: Hi, this is Stacey Clardy from the Salt Lake City VA in the University of Utah. For a two-part podcast series this week, I've been speaking with Ayush Gupta, from the University of Nebraska Medical Center, and Kuntal Sen, from Children's National Hospital in Washington, DC about monogenic disorders that mimic neuroinflammatory disease. There are a lot of them, and they are no doubt sitting in our clinics waiting to be recognized. Ayush, for the minute, once a neurologist starts suspecting one of these disorders, what's the most practical testing strategy to avoid both under and over-testing for these disorders? Dr. Ayush Gupta: I think the most practical strategy is to write down all the phenotypic symptoms that you think could be related, put that exact information into a genetic testing panel that will be suitable. Or, if possible, try to do a broader genetic testing such as whole genome sequencing, and make yourself equipped to be able to analyze the results that you get from the testing. Dr. Stacey Clardy: I hear you saying, at least when you're thinking about this, be a bit of a lumper. As we covered in the podcast, if we are going to pursue that genetic testing, it is absolutely critical that we share that list with the interpreting geneticist because that determines how they score variants and how they rate them as related or not. Please take a listen to that two-part podcast series, where we get into all these details. I walked away with a great framework on how to do better in terms of picking these disorders out. Again, the paper that accompanies the two-part podcast series is in Neurology Genetics. It's a comprehensive review and called Monogenic Mimics of Neuroinflammatory Phenotypes in Children and Young Adults in Evolving Landscape. Thank you, Ayush. Dr. Ayush Gupta: Thank you so much.

In the second installment of this two-part series, Drs. Stacey Clardy, Ayush Gupta, and Kuntal Sen discuss the most practical testing approach to minimize both under‑ and over‑testing for these disorders. Show citation: Gupta A, Sahjwani D, Kahn I, Gombolay GY, Sen K. Monogenic Mimics of Neuroinflammatory Phenotypes in Children and Young Adults: An Evolving Landscape. Neurol Genet. 2025;11(6):e200326. Published 2025 Nov 25. doi:10.1212/NXG.0000000000200326 Show transcript:  Dr. Stacey Clardy: Hi, this is Stacey Clardy from the Salt Lake City VA in the University of Utah. For a two-part podcast series this week, I've been speaking with Ayush Gupta, from the University of Nebraska Medical Center, and Kuntal Sen, from Children's National Hospital in Washington, DC about monogenic disorders that mimic neuroinflammatory disease. There are a lot of them, and they are no doubt sitting in our clinics waiting to be recognized. Ayush, for the minute, once a neurologist starts suspecting one of these disorders, what's the most practical testing strategy to avoid both under and over-testing for these disorders? Dr. Ayush Gupta: I think the most practical strategy is to write down all the phenotypic symptoms that you think could be related, put that exact information into a genetic testing panel that will be suitable. Or, if possible, try to do a broader genetic testing such as whole genome sequencing, and make yourself equipped to be able to analyze the results that you get from the testing. Dr. Stacey Clardy: I hear you saying, at least when you're thinking about this, be a bit of a lumper. As we covered in the podcast, if we are going to pursue that genetic testing, it is absolutely critical that we share that list with the interpreting geneticist because that determines how they score variants and how they rate them as related or not. Please take a listen to that two-part podcast series, where we get into all these details. I walked away with a great framework on how to do better in terms of picking these disorders out. Again, the paper that accompanies the two-part podcast series is in Neurology Genetics. It's a comprehensive review and called Monogenic Mimics of Neuroinflammatory Phenotypes in Children and Young Adults in Evolving Landscape. Thank you, Ayush. Dr. Ayush Gupta: Thank you so much.

Dr. Aaron Zelikovich discusses the utility of neurofilament light chain as a serum biomarker in peripheral neuropathy.  Show citation: Karam C. Clinical Utility of Serum Neurofilament Light Chain in Peripheral Neuropathy. Muscle Nerve. 2026;73(1):86-92. doi:10.1002/mus.70073 Show transcript: Dr. Aaron Zelikovich: Welcome to today's neurology minute. My name is Aaron Zelikovich, a neuromuscular specialist at Lenox Hill Hospital in New York City. Today, we will discuss a recent article on the utility of neurofilament light chain as a serum biomarker in peripheral neuropathy. It has been studied in other neurological diseases like ALS and multiple sclerosis, as in the 2024 study by Robert Fox et al, which highlighted the limitations of serum neurofilament light chain in patients with multiple sclerosis, since the elevation was inconsistent and tended to occur weeks after MRI changes, and was really only found to be helpful in certain clinical situations. The study we highlight today is a single-center retrospective study that highlights the opportunities and limitations of using serum neurofilament light chain as a biomarker to monitor treatment response and peripheral neuropathy. Serum neurofilament light chain has been shown as an indicator of neuronal injury in both central and peripheral nervous system disease that has been associated with axonal injury or degeneration. It is now commercially available. The authors in this study provide a real-world single-center retrospective study that looked at various forms of peripheral neuropathy over 12 months. Patients had to be evaluated and meet criteria for peripheral neuropathy with either genetic testing, nerve conduction studies, and/or clinical exams. Neuropathies included TTR amyloid, vasculitis, CMT, CIDP, GBS, and anti-MAG neuropathy. Patients with TTR amyloid who were treatment naive and had elevated serum neurofilament light chain showed a reduction in neurofilament light chain levels with treatment. Additionally, patients with CIDP who were treatment naive with elevated serum neurofilament light chain also showed a reduction in neurofilament light chain levels with treatment. All patients with idiopathic peripheral neuropathy had normal serum neurofilament light chain levels. However, serum neurofilament light chain can vary in patients based on age, if they have diabetes, renal dysfunction, and body weight. And this makes it really challenging to interpret it in an isolated setting. Serum neurofilament light chain is a new biomarker for peripheral neuropathies. It can be a supplemental tool in the appropriate clinical context. Future studies are needed to identify its potential to be used as a treatment response biomarker in neuropathies like CADP, GBS, and TTR amyloid. Thank you so much, and have a wonderful day. 

Dr. Tesha Monteith discusses the different forms of menstrual migraines.  Show transcript:  Dr. Tesha Monteith: Hi, this is Tesha Monteith with the Neurology Minute. Welcome to our series on headache medicine and women's health. I want to start off this series with a discussion on menstrual migraine. Menstrual migraine is considered more frequent, more severe, and is associated with most migraine-associated symptoms with the exception of aura. The pathophysiology is linked to the effects of estrogen withdrawal and the impacts on the trigeminal vascular system. Do check out a recent paper by Pan and colleagues published just in neurology in November showing a robust hypothalamic activation prior to the headache phase in patients with menstrual migraine compared to controls. Now, there are two forms of menstrual migraine recognized in the International Classification of Headache Disorders III. First is menstrually related migraine which consists of attacks that occurred during the perimenstrual window. That's day one of menses plus or minus two days and at least two of three menstrual cycles and during additional times outside of the window. Perimenstrual migraine attacks occur exclusively during the perimenstrual window and is much less common than menstrually related migraine. A key point is that there's a predictable timing with each cycle, yet the condition is still very much underdiagnosed. Advise your patients to use an e-diary to improve the diagnosis and hopefully reduce disability. This is Tesha Monteith. Thank you for listening to the Neurology Minute.  

In the second part of this series, Dr. Neishay Ayub discusses levetiracetam and one of its most common side effects, irritability.  Show citations:  Abou-Khalil B. Levetiracetam in the treatment of epilepsy. Neuropsychiatr Dis Treat. 2008;4(3):507-523. doi:10.2147/ndt.s2937  Löscher W, Gillard M, Sands ZA, Kaminski RM, Klitgaard H. Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond. CNS Drugs. 2016;30(11):1055-1077. doi:10.1007/s40263-016-0384-x Rogawski MA. Brivaracetam: a rational drug discovery success story. Br J Pharmacol. 2008;154(8):1555-1557. doi:10.1038/bjp.2008.221 Ulloa CM, Towfigh A, Safdieh J. Review of levetiracetam, with a focus on the extended release formulation, as adjuvant therapy in controlling partial-onset seizures. Neuropsychiatr Dis Treat. 2009;5:467-476. doi:10.2147/ndt.s4844 Wu PP, Cao BR, Tian FY, Gao ZB. Development of SV2A Ligands for Epilepsy Treatment: A Review of Levetiracetam, Brivaracetam, and Padsevonil. Neurosci Bull. 2024;40(5):594-608. doi:10.1007/s12264-023-01138-2 Mahmoud A, Tabassum S, Al Enazi S, et al. Amelioration of Levetiracetam-Induced Behavioral Side Effects by Pyridoxine. A Randomized Double Blind Controlled Study. Pediatr Neurol. 2021;119:15-21. doi:10.1016/j.pediatrneurol.2021.02.010 Major P, Greenberg E, Khan A, Thiele EA. Pyridoxine supplementation for the treatment of levetiracetam-induced behavior side effects in children: preliminary results. Epilepsy Behav. 2008;13(3):557-559. doi:10.1016/j.yebeh.2008.07.004 Romoli M, Perucca E, Sen A. Pyridoxine supplementation for levetiracetam-related neuropsychiatric adverse events: A systematic review. Epilepsy Behav. 2020;103(Pt A):106861. doi:10.1016/j.yebeh.2019.106861 Show transcript:  Dr. Neishay Ayub: Hello, my name is Neishay Ayub, and today we will be discussing levetiracetam and one of its most common side effects, irritability. While levetiracetam can be remarkably helpful for patients, behavioral adverse effects were noted in post-marketing analysis and open-label studies in adult and pediatric patients. For this, physicians started using vitamin B6 supplementation, particularly in the pediatric populations. Why would physicians use B6? Well, low vitamin B6 has been associated with neuropsychiatric disorders, which could be related to the fact that vitamin B6 is an essential co-factor for several neurotransmitters that affect mood and behavior, such as serotonin, dopamine, and GABA. There is an epilepsy syndrome associated with vitamin B6 deficiency. And vitamin B6 deficiency is seen with enzyme-inducing anti-seizure medications, although levetiracetam is not an enzyme-inducing seizure medication. These are some of the possibilities as to why vitamin B6 supplementation was initially explored. Some initial anecdotal evidence and case reports were suggested that it was helpful in reducing behavioral side effects and the need to discontinue levetiracetam. There was a meta-analysis reviewing pyridoxine use, which included 11 case reports and retrospective studies, as well as one prospective study, case-control study, which was not placebo controlled. While evidence was suggestive of a benefit, the quality of the evidence was poor due to selection, reporting, and assessment biases. Overall, the authors recommended a larger randomized, controlled, double-blind trial with adequate statistical power, well-defined eligibility criteria and standardized assessment tools to evaluate B6 efficacy in treating levetiracetam-induced irritability. Since then, there was one small randomized, controlled, double-blind study involving 105 children for whom neuropsychiatric adverse effects were noted after levetiracetam was introduced. Children were randomized to receive a therapeutic dose of pyridoxine, which was 10 to 15 milligrams per kilogram per day, up to 200 milligrams, or a homeopathic dose of 0.5 milligrams per kilogram per day. They were scored on a behavioral checklist and monitored for up to six months. While there was a reduction in behavioral symptoms reported in the therapeutic pyridoxine group, there was no validated assessment tools used, and there was an absence of a true placebo group. Lastly, there are a few studies reporting on adverse effects of B6 toxicity, which is possible, but it's typically seen at higher daily doses, although something to keep in mind if considering B6 supplementation. In summary, while there has been a clinical practice of prescribing pyridoxine at 50 to 100 milligrams as a low-cost, well-tolerated adjunctive supplement, there may be a modest benefit for some patients, but the overall efficacy for the treatment of neuropsychiatric side effects for levetiracetam remain unclear, and more evidence is needed. 

In part one of this two-part series, Dr. Stacey Clardy and Drs. Ayush Gupta and Kuntal Sen discuss the key clinical features that should shift suspicion from autoimmune encephalitis or demyelinating disease to monogenic mimics.  Show citation: Gupta A, Sahjwani D, Kahn I, Gombolay GY, Sen K. Monogenic Mimics of Neuroinflammatory Phenotypes in Children and Young Adults: An Evolving Landscape. Neurol Genet. 2025;11(6):e200326. Published 2025 Nov 25. doi:10.1212/NXG.0000000000200326 Show transcript:  Dr. Stacey Clardy: Hi, this is Stacey Clardy from the Salt Lake City VA in the University of Utah. For a two-part podcast series, I've been speaking with Ayush Gupta from the University of Nebraska Medical Center and Kuntal Sen from Children's National Hospital in Washington DC about the monogenic disorders that mimic neuroinflammatory disease that are lurking in all of our clinics just waiting to be diagnosed. Ayush, for the minute, when you're seeing a patient with a presumed autoimmune encephalitis or demyelinating disease, what single cluster of features should instead most strongly push us to think of monogenic mimics at the top of our differential? Dr. Ayush Gupta: So when you are seeing a patient with presumed autoimmune encephalitis or a demyelinating disorder, cluster of features such as earlier onset in terms of age, developmental delays, CSF or imaging finding that's non-concordant with the diagnosis such as a non-inflammatory CSF, a symmetric white matter or deep gray matter involvement and relentless progression despite immunotherapy, these are the red flags where you should stop, seriously consider the possibility of a monogenic disorder and reach out to help from colleagues. Dr. Stacey Clardy: That's a great list, and we get into far more detail in the two-part podcast series. So please listen to both of those and take a read of the neurology genetics review titled Monogenic Mimics of Neuroinflammatory Phenotypes in Children and Young Adults: An Evolving Landscape.

Dr. Elizabeth Coon and Prof. Franziska Hopfner discuss the frequency and disease trajectory of MSA patients who do not experience dysautonomia, in comparison to those with autonomic involvement. Show citation:  Wilkens I, Bebermeier S, Heine J, et al. Multiple System Atrophy Without Dysautonomia: An Autopsy-Confirmed Study. Neurology. 2025;105(11):e214316. doi:10.1212/WNL.0000000000214316 Show transcript:  Dr. Elizabeth Coon: Welcome to the Neurology Minute. I'm Elizabeth Coon, and I'm delighted to welcome Professor Hopfner, who will give us a summary of her recently published paper in Neurology, "Multiple System Atrophy Without Dysautonomia and Autopsy Confirmed Study." Welcome, Professor Hopfner. Please tell us about this study and the key findings. Prof. Franziska Hopfner: So this work reframes how we think about MSA. So, autonomic failure is common but not universal and its absence does not rule out the diagnosis of MSA. So recognizing motor only in multiple system atrophy expands our diagnostic accuracy, improves patients consulting and broadens inclusions in future therapeutic trials. Dr. Elizabeth Coon: Excellent. Thank you. And thank you for listening to this Neurology Minute.

In part one of this two-part series, Dr. Neishay Ayub discusses the history of a novel anti-epileptic drug, levetiracetam.  Show citations:  Abou-Khalil B. Levetiracetam in the treatment of epilepsy. Neuropsychiatr Dis Treat. 2008;4(3):507-523. doi:10.2147/ndt.s2937  Löscher W, Gillard M, Sands ZA, Kaminski RM, Klitgaard H. Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond. CNS Drugs. 2016;30(11):1055-1077. doi:10.1007/s40263-016-0384-x Rogawski MA. Brivaracetam: a rational drug discovery success story. Br J Pharmacol. 2008;154(8):1555-1557. doi:10.1038/bjp.2008.221 Ulloa CM, Towfigh A, Safdieh J. Review of levetiracetam, with a focus on the extended release formulation, as adjuvant therapy in controlling partial-onset seizures. Neuropsychiatr Dis Treat. 2009;5:467-476. doi:10.2147/ndt.s4844 Wu PP, Cao BR, Tian FY, Gao ZB. Development of SV2A Ligands for Epilepsy Treatment: A Review of Levetiracetam, Brivaracetam, and Padsevonil. Neurosci Bull. 2024;40(5):594-608. doi:10.1007/s12264-023-01138-2 Mahmoud A, Tabassum S, Al Enazi S, et al. Amelioration of Levetiracetam-Induced Behavioral Side Effects by Pyridoxine. A Randomized Double Blind Controlled Study. Pediatr Neurol. 2021;119:15-21. doi:10.1016/j.pediatrneurol.2021.02.010 Major P, Greenberg E, Khan A, Thiele EA. Pyridoxine supplementation for the treatment of levetiracetam-induced behavior side effects in children: preliminary results. Epilepsy Behav. 2008;13(3):557-559. doi:10.1016/j.yebeh.2008.07.004 Romoli M, Perucca E, Sen A. Pyridoxine supplementation for levetiracetam-related neuropsychiatric adverse events: A systematic review. Epilepsy Behav. 2020;103(Pt A):106861. doi:10.1016/j.yebeh.2019.106861 Show transcript:  Dr. Neishay Ayub: Hello, my name is Neishay Ayub, and today we are discussing the history of a novel anti-epileptic drug, levetiracetam. It's a story of a scientific dead end, a radical new testing method, and a mystery that took years to unravel. To set the scene, let's go back to 1974. The pharmaceutical company, UCB Pharma, was working on compounds to boost cognitive function. They were looking for a successor to their drug piracetam. During this research, levetiracetam was first synthesized, but the compound didn't show any significant brain-boosting effects. With no discernible purpose, it was filed away and largely forgotten. For nearly two decades, this medicine sat on a shelf an anonymous entry in a long list of failed drug candidates. The story could have ended there, but in the early 1990s, researchers took a different approach to drug discovery. Researchers screened their entire library of forgotten compounds against audiogenic seizure-susceptible mice. These are mice prone to seizures triggered by sound. Levetiracetam was incredibly ineffective in chronic epileptic mice. Interestingly, levetiracetam had previously failed traditional screening tests which was to prevent acute seizures in normal animals subjected to maximal electroshock or pentylenetetrazole. Levetiracetam was pushed forward to human clinical trials and was found to be efficacious in three placebo-controlled, randomized, blinded clinical trials for adults with refractory focal epilepsy. Two of the clinical trials reviewed levetiracetam three grams per day compared to placebo. They found the responder rate, i.e., 50% reduction in seizure frequency, was 39% to 42% for patients on three grams per day versus placebo at 10% to 16% when used as adjunctive therapy. One of these trials also used levetiracetam as monotherapy, noting a median percent reduction in focal seizure frequency of 73%, a responder rate of 59%, and 18% of patients achieving seizure freedom. In November 1999, the FDA gave its approval for adjunctive treatment of partial onset seizures. While levetiracetam was effective, how it worked was still unclear. It didn't affect the ion channels and neurotransmitter receptors that older, more traditional anti-epileptic drugs targeted. Eventually in 2004, scientists made another breakthrough. They identified the drug's primary molecular target, a protein called SV2A. This protein is involved in regulating the release of neurotransmitters. Instead of suppressing all neurologic activity, levetiracetam appears to bind to SV2A and selectively modulate neurotransmitter release in overactive seizing neurons. This precise mechanism is why it has such a favorable side effect profile. With the mystery solved and a novel mechanism understood, levetiracetam continues to be a popular anti-seizure medication to this day, and its use has been expanded. Further clinical trials led to FDA approvals for use in adult and pediatric patients with myoclonic epilepsy for myoclonic seizures as well as adult and pediatric patients with idiopathic generalized epilepsy for primary generalized tonic-clonic seizures. There is an off-label use for status epilepticus and seizure prophylaxis in TBI, in traumatic brain injury, subarachnoid hemorrhage, and neurosurgical cases. Formulations have also expanded to include tablets and liquid formulations for immediate release, extended-release tablets, and intravenous formulations. Today, with the original patent expired, generic versions are available, making this treatment accessible to millions. The journey of levetiracetam from an abandoned compound to a frontline treatment is a powerful reminder that in science, a failure might just be a success waiting to be tested in a different way.

Dr. Tesha Monteith discusses menstrual migraine and treatment options.  Show transcript: Dr. Tesha Monteith: This is Tesha Monteith with the Neurology Minute. Welcome back to our series on headache medicine and women's health. I'm continuing our discussion on menstrual migraine, and I want to focus on treatment. We talked about increasing the yield of diagnosis for menstrual migraine, but what are the best ways to treat our patients? I think there are two broad categories we can think about: We can think about non-hormonal methods or hormonal methods. The non-hormonal methods include a combination of abortive therapies, as well as preventative therapies that can be used for a mini prophylaxis, as well as when patients have a higher burden of overall migraine, considering the general highly effective preventive therapies. Common mini prophylaxis include triptans such as Frovatriptan, Naratriptan, and Zolmitriptan when used twice per day. Nonsteroidal anti-inflammatories can be used for five to seven days around menses, such as naproxen, 550 milligrams twice per day. Magnesium, 360 milligrams daily or higher, can also be started mid-cycle, so day 15, towards menstruation. Although considered off-label, gepants, ubrogepant, as well as rimegepant, can also be used during the susceptible window. This is Tesha Monteith. Thank you for listening to the Neurology Minute. 

In the January episode of the President's Spotlight, Dr. Jason Crowell and Dr. Natalia Rost discuss AAN's plans for 2026, including a general neurology boot camp, Autoimmune Conference, and new resources for members.  Stay informed by watching the President's Spotlight video.  Show transcript: Dr. Jason Crowell: Hello, and welcome to today's Neurology Minute. This is the first installment of 2026 that we have with the president of the AAN, Natalia Rost. Natalia, thanks so much for joining us today, we look forward to our monthly chats to talk about things going on with the AAN. Before we start talking about the plans for 2026 with the American Academy of Neurology, what are the things that are on your mind? Dr. Natalia Rost: Happy new year, Jason, great to join you today. Well, first of all, I think 2026 is going to be a strong year, and as I think what's coming down our pipeline, it's our work to promote brain health and to support neuroscience research. It's the fight that we have to fulfill Medicare payments, and to protect patient access to care. Our efforts to advance physician-led neurology teams and to reduce burnout. And to always stand firmly for science and evidence-based medicine. Dr. Jason Crowell: Now, I know every year the AAN has new programming and content that they're putting out, what's going to be in store for 2026? Dr. Natalia Rost: First of all, we're launching a brand new general neurology bootcamp at the annual meeting, high impact learning, real connections, and great energy guaranteed. Also back by popular demand, the Autoimmune Conference will take place again this summer, featuring all the latest science, so I'm excited about that. For our advanced practice provider members, expect a new online toolkit to improve your neurology knowledge and patient care skills. For our residents, we are adding a new pediatric neurology option for our RITE exam lineup. And last but not least, we are fully reimagining our patient education on brainandlife.org, because as you know and as our members know, an informed public makes powerful partners in our Brain Health For All movement. Dr. Jason Crowell: Terrific. And so, are there any efforts from last year that will continue to be a focus for this coming year? Dr. Natalia Rost: Two things immediately come to mind, and our work will only grow stronger there. Number one is to continue to modernize our digital platforms and provide resources to our members to tackle AI and emerging technologies. As you know, this is a big issue. And number two is to advocate relentlessly for fair reimbursement and access to care. Our advocacy is only going to grow stronger in 2026. Dr. Jason Crowell: So, Natalia, most of us are still working to keep our New Year's resolutions intact, I'm a few days into my exercise program, we'll see how long that goes. But what would you say are the New Year's resolutions, if you will, for the AAN? Dr. Natalia Rost: Well, this year is going to be the year to fully embrace our Brain Health For All approach, I think. Neurologists are the experts in brain health, so our promise is for the AAN to continue tirelessly support our members so they can lead, care, and thrive as they do. Dr. Jason Crowell: Terrific, Natalia. Thanks so much. Happy New Year again. Dr. Natalia Rost: Happy New Year.