The latest news and research presented in multiple sclerosis and related disorders.

Live Coverage of MS Virtual 2020: The 8th Joint ECTRIMS-ACTRIMS Meeting

The latest research and news from the International Congress on Parkinson's Disease and Movement Disorders.

Live Coverage of the 2020 MDS Virtual Congress

The vice president of Clinical Research at Eisai provides updates on the MOMENTUM trials which will examine lorcaserin as a potential treatment for patients with Dravet syndrome.

NeuroVoices: Michael Irazarry, PhD, on Lorcaserin for Dravet Syndrome

"Mind Moments," a podcast from NeurologyLive, brings you an exclusive interview with Paul Fisher, MD, and Gerald Grant, MD, FACS.

Episode 22: Capitalizing on Collaboration in Neurology Care

 by Michael Okun, MD, and James Giordano, PhD, highlighted some of the major flaws with the process in which deep brain stimulation and neurotechnological devices are approved for patients with rare diseases. While the process for requesting orphan drug designation for the use of specific drugs may be more straightforward, neurotechnological devices that are developed and/or can be used for rare diseases do not benefit from the same approval process.

Humanitarian device exemptions (HDEs) have been used as a regulatory pathway for device availability in rare diseases but are slowly being phased out due to industry partner concerns over the costs required to develop and maintain the HDE, as well as limitations of profit, tax exclusivity, lack of incentives, and legal liability. Okun and Giordano touch upon multiple issues within the system, including the barriers set by insurance companies which force patients who seek this selective type of care to pay out-of-pocket costs.

Okun, the executive director of the Norman Fixel Institute for Neurological Diseases, and Adelaid Lackner Professor and chair of neurology at the University of Florida, also serves as the medical director of the Parkinson’s Foundation. He calls for major reform throughout the paper, with an emphasized use of disease-based registries and modifications to the preexisting condition clause of the Patient Protection and Affordable Care Acts.

As part of the NeuroVoices series, Okun sat down to provide in-depth explanation of the flaws of approval system for neurotechnological devices for patients with rare diseases, and why they do not receive the same standardized process that clinical drugs have as they go through the pipeline. He also touched on the issues that stem from insurance companies and why change is only attainable if all levels are engaged at the discussion table.

: Why do neurotechnological devices that are developed for rare diseases not receive the same benefit as other drugs that may receive orphan drug status? Where is the disconnect?

: I would back up first and say that we’re dealing with a system that’s decades old in place, even before the advent of all these new devices and precision medicine. I don’t know that when it was first constructed but people saw these devices, particularly brain and spinal cord, not the way they see them as such transformational therapeutics. You’re dealing with a system that was designed for drug development, which is sometimes way easier. You take a pill, you document what happens with the pill, and decide yes or no. Same way vaccines were developed as well. When you implant a device, there are bumps in the road. When you implant that device in a human, there’s no blood supply, so the device can get infected. Even if you take an antibiotic, you may not be able to clear that section, and the device may have to come out. This can be anything from a pacemaker for the brain, to a spinal cord stimulator. Anything that you can put in has the potential to get infected and come out. There are hardware issues, things can break, there can be fractures, and pieces that need to be replaced. Additionally, there can be updates, software issues, all of which are not seen by pharmaceuticals in general.

The pharmaceutical industry has a heavy lobby, with a lot more money in it. I don’t think we should kid ourselves with that. If you lift the hood of the car, you’ll see that this is a very strong lobby group. I’m not judging that; I’m just stating the facts. But the device industry is expanding. Now you have a situation that nobody really anticipated. Let’s be fair, I don’t think even the smartest among us anticipated a situation where we might have a precision medicine for devices.

What do I mean by precision medicine? You could have a rare or a common disease, like Parkinson disease (PD), with a rare symptom. In that case, you can actually target a specific circuit in the brain and treat that symptom. The brain has added a level of complexity to the conversation. If you’re talking about the gallbladder, not that there’s anything wrong with the gallbladder, but the distributed network of the nervous system is amenable to being targeted by neuromodulation techniques. We can change the way the different areas communicate with each other and thereby, change individual symptoms.

Now we can change the paradigm. Normally, we get a drug, have it approved, and watch it treat the disease to the best it can. Now we have a situation where a device can be applied to a circuit as well which is very different. We have to appreciate the upside of that. The problem is that if we continue to have a process that is streamlined in the same direction as every drug, that leaves rare diseases out of the picture, or lessens their chance of moving forward. We mentioned in the report that if you’re involved in the drug development of rare diseases, you incentivize people to stay in the game. Those aspects don’t exist on the device side. In fact, what happens is that the cost to the manufacturer can be so high and the legal exposure can be at a level that creates an impossibility for a business to want to do business and get involved.

The example I’ve been involved with for many years stems from a grant from the Tourette Association of America. We have a publicly available database that has tracked 320 cases around the world for many years. Tourette still has no approval, but yet we know that our database works. We know that people with Tourette can have these head snapping tics where they can fracture their neck and become quadriplegic. They can have self-injurious behavior, which can lead to severe consequences to school, social isolation, and acceptance. We have a treatment that can suppress the motor and vocal aspects of Tourette by 40% to 50% better in most series with multiple targets, but we can’t apply it.

We’ve written about a bait and switch, which happens when both an insurance company agrees, their medical director agrees, and the conversation leads to confirmation about a patient having surgery. When payment time comes, they don’t pay for the device. They feel as though they aren’t obligated. We must recognize that we have shifted into a new era, and that we have to have a pathway for rare diseases and devices that can be used to treat these rare diseases or rare symptoms of common diseases.

The humanitarian device exemptions (HDEs) are beginning to fall apart as an option because insurance companies can still refuse payment on those. Device manufacturers are beginning to say, “Whoa, we don’t want this. We have legal risk. We have a million or so bucks to spend on someone patrolling this, along with all these complications and regulations. It’s not our core business anyway. Why do we want to bid?” Now I have to hold onto something that can help our kids and adults with Tourette, for example. Even if I can give it to them, the insurance company is going to bait and switch anyway. Our piece addresses the gaps. We have to have a process where we can move this in a different path. It’s reasonable to have data, but there should be a lower standard, especially if the data is done through foundations and universities and is publicly posted.

On the industry side, people should be given a legal break. Not a pass, but there should be breaks and incentives for them to make these devices available which can end up being life changing innovations for these various disorders. If we don’t do that, we’re going to be in trouble or just sitting on a lot of technology that can’t actually get out to these people with rare diseases.

How much blame is on insurance companies? Do you feel as though we are ever going to reach a point where they finally give that right-to-try?

There’s blame to go around all the way. If you give an insurance company an inch on a loophole, they’re going to take it. It’s a business, and we’ve given them a loophole out, so they’re going to exploit it. We haven’t held them accountable. My argument has been that they shouldn’t be able to loophole out of approvals from various things. They’ve loopholed out even when people have HDEs. They haven’t been paying for obsessive compulsive disorder cases, here, at the University of Florida, even with an HDE in place. In other places around the country, even though there’s an HDE, they don’t want to pay when there’s an ID or experimental IDE that’s in place.

They need to be pushed to say, “Yes, you do have that burden.” I would argue this is not necessarily a violation, but a direct conflict to the pre-existing conditions within the Affordable Care Act, because it appears to me that they’re not offering a treatment for a pre-existing condition. They would respond by saying we (clinicians) haven’t established the data and conversed with the regulatory agents, but that just leaves us stuck. You have to fix both parts of the system to get the wheel moving again. Let’s say you do allow people to post their data on public databases, and the FDA agrees there is enough evidence, then they should be held to a pre-existing standard. They shouldn’t be able to try to get out of that. This will probably reduce the long-term morbidity of the cases when its applied in the right situations as well as save these people money within their insurance systems.

There is a method to the madness, but there a few points in this wheel which make it complicated that need addressing. Industry needs to be given more of an incentive to stay in the game. Universities and foundations need to be allowed to track their own data. Remember, you’re going to need industry to submit on all the side effects and the upkeep of all of these things. The FDA is going to want to see that we’re not going to be able to provide on the device that’s being used. There has to be a way to track, and then there has to be a way within the law for us to say to insurance companies, “you can’t just say there’s a carve out or walk away from people with medical diseases.” I think there’s a few touchpoints that we get out with this piece that are very important.

Articles

Michael Okun, MD, executive director of the Normal Fixel Institute for Neurological Diseases sat down to discuss his viewpoint paper on changing the approval system for neurotechnological devices in rare diseases.

NeuroVoices: Michael Okun, MD, on Reforming the Device Approval Process

Brain imaging research in multiple sclerosis (MS) is experiencing an acceleration of technological progress. Fueled by the relentless pace of innovation in magnetic resonance imaging (MRI) and the recent outburst of artificial intelligence (AI), these advances are the crest of a new wave of scientific tools for the MS clinic.

Since its introduction nearly 3 decades ago, 2-dimensional (2D) multislice brain MRI sequences—such as proton-density, T2, fluid-attenuated inversion recovery (FLAIR), and T1 scans—have become the workhorses of any diagnostic or follow-up brain MRI exams for MS. The longevity of these scans, often referred to as conventional MRI, is explained by their high sensitivity in the detection of white matter lesions (WMLs) of the brain (represented as hyper- or hypointense focal areas) and their robust imaging on any 1.5-T and 3-T clinical scanners. However, recent advances in ultra-fast MRI sequences are about to completely transform the way these conventional brain scans are routinely acquired in hospitals and medical imaging centers.

Advances in Image Acquisition and Analysis

One of these new MRI sequences is simultaneous multislice (SMS), which collects multiple imaging slices concurrently.

 SMS can cut the scan time of conventional 2D multislice scans by a factor of 2 without degradation of image quality.

 Another technique, compressed sensing, collects and utilizes heavily undersampled data; this can reduce the scan time of any 2D or 3D anatomical scans by 20% to 50% while maintaining virtually equivalent image quality.

 Wave–controlled aliasing in parallel imaging is another technical breakthrough that combines an undersampling strategy with an efficient 3D encoding; this technique can massively accelerate any 3D T2, FLAIR, and T1 brain scan to reduce scan times to 1 to 2 minutes.

 Finally, AI-based image reconstruction techniques can improve the image quality of undersampled data, thus enabling shorter scans.

 This significant reduction in scan time will provide crucial benefits. First and foremost, patients will experience less discomfort as a result of a much shorter MRI exam, possibly as short as 10 minutes or even less. Second, a scan will be quickly repeated if motion affects image quality, enabling radiologists and neurologists to evaluate their patients’ images more consistently. Last, high-resolution 3D brain scans will replace conventional 2D brain scans, which produce thick-slice images, often containing large gaps between each slice. These important innovations will pave the way for widespread adoption of automated image analysis tools that provide invaluable information about MS disease activity.

Over the past decade, a multitude of image analysis techniques have been developed to automatically segment brain tissues and lesions using high-resolution 3D anatomical scans. These techniques rely on various approaches, including statistical methods (Method for Inter-Modal Segmentation Analysis

), machine-learning classifiers (Classification using DErivative-based Features

), and deep- learning algorithms (3D U-Net

). Currently, fully automated image analysis solutions powered by AI, including those from CorTechs Labs,

 Icometrix, and Quantib, are even offered as products that are approved for clinical use. Therefore, a flurry of imaging-based measures could be factored into the routine evaluation of patients with MS, including longitudinal volume changes of brain tissues, total/regional lesion load, and individual lesions.

Brain volume changes—which include whole-brain atrophy and regional brain atrophy (eg, cortical atrophy, thalamic atrophy)—are particularly useful as a measurement of brain tissue loss and have become widely accepted measures of neurodegeneration

; they are among the best predictors of physical and cognitive disability. Clinical trials evaluating new disease-modifying therapies (DMTs) for MS already incorporate brain atrophy measures as critical end points in their cohort studies. Further, ongoing efforts to improve the accuracy and reliability of these measures and build large normative reference data sets using cloud computing platforms will allow the ability to track brain atrophy routinely in individual patients. Tracking individual lesions, particularly the formation of new WMLs, is also useful to assess the biological response of a patient to DMTs targeting MS inflammatory activity. By automatically comparing a baseline 3D scan to a follow-up 3D scan, reliable detection of new lesions is now possible without using T1-enhancing lesions,

 thus preventing the repetitive use of macrocyclic and linear gadolinium-based contrast agents, a clinical practice that is being intensively debated because of possible safety concerns.

Additionally, monitoring persistent WMLs will become clinically relevant as some of the chronic lesions slowly expand over time. These slowly expanding lesions are in the spot- light of MS investigators, as they are believed to reflect the demyelination and axonal loss as a result of a smoldering inflammation behind an intact blood-brain barrier.

 Investigators suspect that this chronic inflammation drives the disease worsening observed in patients with progressive MS.

 For this reason, an ongoing race exists in the MS pharmaceutical industry to deliver the first brain-penetrant therapy that could stop this smoldering inflammation.

Other features of MS lesions may also have clinical significance. Specific lesion morphological characteristics, such as shape and surface features extracted from high-resolution 3D brain MRI scans, could help differentiate MS lesions from nonspecific WMLs.

 Additionally, lesion phenotyping based on 3D morphology may open new avenues for developing outcome measures, which would reflect the biological activity of MS lesions such as myelin repair.

Another feature, lesion intensity, is now assessed qualitatively in the clinic. As an example, chronic black holes that are known to be areas of permanent tissue destruction are defined as severely hypointense lesions on T1-weighted scans; however, depending on the type of MRI sequence and parameters of the T1 scan, the level of hypointensity can significantly change, thus hampering the proper identification of these black holes. A quantitative measure of the
T1 signal, referred to as T1 relaxation time, would provide a standardized metric of black holes, enabling their robust discrimination in the clinic.

 Initially dedicated to research, quantitative MRI techniques measuring T1 and T2 relaxation times have been significantly improved in terms of accuracy, reproducibility, and overall workflow. Some of these techniques, such as MAGnetic resonance image Compilation (MAGiC),

 2 inversion-contrast magnetization-prepared rapid gradient echo (MP2RAGE),

 are moving into the realm of clinical imaging. These techniques may even become the future workhorses of clinical MS brain protocols thanks in part to their additional capability of synthesizing multiple image contrasts simultaneously.

The advances discussed so far rely on MRI techniques that produce conventional image contrasts (eg, proton-density, T1, T2, and FLAIR). Unfortunately, these types of contrasts lack specificity regarding the underlying pathological mechanisms involved in the development of MS lesions. This poor specificity frequently complicates the evaluation of patients suffering from radiological mimics of MS, putting these patients at risk of receiving a misdiagnosis when there is an overreliance on MRI findings. Brain lesions related to comorbidities in patients with MS could be falsely interpreted as MS lesions and mislead treatment decisions. Therefore, a crucial need exists for MRI techniques to deliver biomarkers specific to MS pathology; currently, 2 extremely promising imaging biomarkers are in the research pipe- line to help address this issue of specificity (

The first and most mature biomarker is the central vein sign (CVS),

 which corresponds to the presence of a small vein running centrally through a focal lesion. The perivenular formation of MS lesions is a well-known biological phenomenon initiated by the breakdown of the blood-brain barrier, which releases inflammatory cells that radially diffuse from the inflamed vein into the surrounding brain tissue leading to focal demyelination. Advanced MRI techniques sensitive
to the magnetic properties of the brain can image these small veins thanks to the difference in magnetic susceptibility between venous blood and parenchymal tissue. One such technique is susceptibility-weighted imaging (SWI), which was initially developed to perform cerebral venograms. However, SWI scans acquire thick-slice images that do not allow adequate visualization of central veins running in a multitude of directions. For a more sensitive and robust detection of the CVS, optimized susceptibility-based techniques can be used instead. Indeed, T2*-weighted 3D echo-planar imaging (or T2*-3DEPI) and FLAIR* (a combination of FLAIR and T2*) produce high-isotropic-resolution 3D images that facilitate the identification of brain lesions with central veins.

 From a clinical perspective, CVS will be helpful for the differential diagnosis of MS. Multiple clinical studies have recently demonstrated that patients with MS have a significantly higher proportion of brain lesions with CVS than patients with migraine,

 Encouraged by these results, an ongoing multicenter study is investigating the diagnostic potential of CVS in undiagnosed patients with typical or atypical onset. By comparing the current diagnostic criteria against the prediction based on CVS detection, this large-scale prospective study could demonstrate a significant gain in speed and accuracy of MS diagnosis.

 Another potential benefit of CVS could be the detection of the disease even before its clinical manifestation. Indeed, patients with radiological findings but without any history of clinical symptoms can have a significant proportion of their brain lesions with CVS, suggestive of subclinical MS disease.

The second biomarker is the so-called paramagnetic rim lesions (PRLs). Using the susceptibility-based MRI techniques introduced above, along with advanced quantitative susceptibility mapping post-processing techniques, investigators very recently demonstrated that some MS lesions possess a paramagnetic rim located at their edges.

 This rim appears to correspond to the accumulation of iron-laden macrophages or microglia, which are thought to be the generation of the smoldering inflammation discussed previously. Although not all patients with MS have PRLs, those with PRLs clearly experience a more aggressive disease.

 These findings point to the potential value of PRLs as a prognostic biomarker. In addition, PRLs appear to be very specific to MS lesions

 and may be a complementary biomarker for MS diagnosis. To prepare for future clinical use of these biomarkers, automated solutions for the detection of CVS and PRLs are already in development using probabilistic methods,

 as well as deep-learning algorithms (CVSnet

Although imaging WMLs is the bread and butter of clinical MRI, cortical lesions are seen with increasing clinical importance and will become important radiological findings for predicting disease progression as well as evaluating new therapies for neuroprotection. Because of their specificity regarding MS pathology, cortical lesions are now part of the MRI diagnostic criteria for MS. However, in practice, these lesions remain difficult to detect reliably using conventional MRI scans. Newer techniques such as phase-sensitive inversion recovery

 and the very recent inversion-recovery susceptibility-weighted imaging with enhanced T2 weighting

 can improve the visualization of cortical lesions on 3T scanners, especially the detection of subpial lesions associated with cognitive decline and disease progression. Meanwhile, another powerful strategy for imaging cortical lesions with high sensitivity utilizes scanners with a stronger magnetic field, such as the 7-T scanner.

Seven-tesla MRI produces exquisite images of the human brain by achieving very high spatial resolution—on the order of hundreds of micrometers. This high-end imaging device has been intensively used in clinical research over the past 10 years to noninvasively investigate MS pathology developing in patients’ brains.

 This sustained research effort has brought new insights into the understanding of cortical and white matter MS lesions

 and sparked the discoveries of the CVS and PRLs. The recent FDA approval of the first 7-T MRI for clinical use is another major step forward for MS imaging, as it will enrich the clinician’s toolbox for diagnosing MS43 and speed up the clinical translation of future imaging biomarkers yet to be discovered with this cutting-edge imaging technology.

Without a doubt, MS imaging is set to undergo an exciting technological transformation. The next-generation MRI techniques discussed here will provide clinicians with an unprecedented wealth of information about this complex and multifaceted disease. By fully embracing these technological and scientific shifts on the horizon, neurologists will enhance their ability to diagnose earlier and more accurately, identify and anticipate the trajectory of the disease, and adapt treatment strategies to keep the irreversible progression of the disease at bay. Lastly, integrating rapidly innovative imaging biomarkers into the clinical trials of emerging drugs—especially those promoting neuroprotection and neurorepair—will help finally turn the tables on this debilitating disease. All in all, the future of MS imaging is very bright.

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Advanced imaging technology collides with artificial intelligence in what is shaping up to be a revolutionary period for the diagnosis and management of MS.

The Future of Multiple Sclerosis Imaging

 (SVD) MRI features do not improve stroke outcome model predictions despite being associated with patient functional, cognitive, and psychological outcomes.

The first model developed in the study (model 1), based on age, baseline National Institute of Health Stroke Scale (NIHSS) score, and infarct volume, performed well at discriminating poor vs. good functional outcomes (area under the curve [AUC], 0.915) and performed fairly at identifying cognitively impaired (AUC, 0.750) and cognitively distressed (AUC, 0.688) patients. Model 2 (created by adding the total SVD score to model 1) and model 3 (adding individual SVD MRI features to model 1) did not perform significantly better than model 1, despite higher SVD scores associating with poorer outcomes for patients (odds ratio [OR], 1.30; 95% CI, 1.07–1.58; 

Senior author Thomas Tourdias, MD, PhD, professor, medical imaging, Bordeaux University, Bordeaux University Hospital, and colleagues stated that this “’negative’ result is of substantial value because [the] study included a large dataset of patients, prospectively and longitudinally followed over time, with applications of all major methodological requirements for prognostic research design and analysis.”

Tourdias and colleagues looked at 2 datasets of patient information. Of the 348 patients from the “Brain before Stroke” cohort, the mean age was 67.5 years (SD, 14.1) and the median NIHSS score was 4 (interquartile range [IQR], 2–8). Of the 137 patients from the “Strokedem” cohort, the mean age was 64.8 (SD, 12.6) and the median NIHSS score was 1 (IQR, 0–2). Both cohorts were around 60% male.

The biggest driving factor in model 1’s prediction success was NIHSS score, which was significantly associated with a poor modified Rankin score (mRS) at 3 months (odds ratio [OR] for log-transformed NIHSS, 10.56; 95% CI, 5.83–19.14) and depression. Higher age was also significantly associated with mRS and depression at 3 months. 

Machine Learning Models Accurately Predict Outcomes in Subarachnoid Hemorrhages

Tourdias and colleagues found a significant association between SVD score and functional outcome (OR, 1.30; 95% CI, 1.07–1.58; 

 = .009), and cognitive outcome (OR, 1.23; 95% CI, 1.00–1.5; 

 = .05) and an insignificant association between SVD score and psychological outcome (OR, 1.16; 95% CI, 0.92–1.45; 

 = .2077). However, when added to the multivariate analyses, total SVD score did not improve outcome predictions. Combined models were not statistically different from model 1, with an AUC difference of 0.003 (95% CI, -0.006 to 0.014) for functional outcome, -0.004 (95% CI, -0.018 to 0.010) for cognitive outcome, and –0.004 (95% CI, -0.030 to 0.023) for psychological outcome. 

Total SVD score alone was also investigated for its ability to predict outcomes and was found to be close to random for all outcomes, with ORs of around 0.5. Total SVD score was determined by white matter hyperintensity (WMH), lacunes, perivascular space, microbleeds and atrophy, of which WMH was consistently found to be associated with poor outcome. Tourdias and colleagues also found a significant association between brain volume loss and poor functional outcome at 3 months (OR, 1.18; 95% CI, 1.06–1.31; 

Tourdias and colleagues hypothesize that “[one] reason why cerebral SVD does not add information to the prediction might have been that age and cerebral SVA are correlated...age, which was included in our models, [could have conveyed] most of the information.”

Coutureau J, Asselineau J, Perez P, et al. Cerebral small vessel disease MRI features do not improve the prediction of stroke outcome. 

. Published online November 12, 2020. doi: 10.1212/WNL.0000000000011208

Despite having independent association with a number of outcomes, SVD MRI features lacked prognostic value for patients with stroke.

Cerebral Small Vessel Disease Score Shows No Predictive Value in Stroke Models

A new multicenter study that investigated 1-year outcomes of minimally invasive surgical treatment with laser interstitial thermal therapy (LITT) found it to be a safe and effective treatment option for patients with drug resistant epilepsy (DRE), with 64% of patients free of seizures at the end of the study period. 

Additionally, the study assessed quality of life with the Quality of Life (QoL) in Epilepsy questionnaire (QOLIE-31). The median score increased by 14.1 points at 1-year follow up, driven by improvements in seizure worry and social functioning. Although this total score change was not statistically significant, it is still clinically meaningful, according to Patrick Landazuri, MD, associate professor of neurology, University of Kansas Medical Center, and colleagues. 

They examined these 1-year outcomes from patients enrolled in the multicenter, prospective LAANTERN registry (Laser Ablation of Abnormal Neurological Tissue Using Robotic NeuroBlate System; NCT02392078) specifically for epilepsy treatment. They looked at the 60 LITT procedures performed for DRE. Patients with mesial temporal lobe epilepsy/mesial temporal sclerosis (MTLE/MTS) made up the majority of procedures but other etiologies were assessed, too. 

 talked to Landazuri to learn more about the LITT procedure, the advantages of epilepsy surgery for patients, and how it compares to these other procedures.

: Could you give an overview on how the LITT procedure compares to other epilepsy surgeries?

: LITT is also known as selective laser ablation or SLA. The way it's performed is, prior to the surgery itself, the epileptologist and the neurosurgeon both clearly identify the part of the brain that's epileptogenic. That can be done in multiple ways. Sometimes, a preoperative MRI will clearly show an epileptogenic cause. Other times it's more extensive and includes recording EEG from inside someone's brain, often with intracranial electrodes, one method being stereo encephalography, or sEEG. Once that area has been defined, whether by imaging or by electrographic findings, the patient's case is discussed at a surgical conference, which is the standard of care for all surgical centers. When the decision is made to offer LITT as a potential therapy, that's discussed with the patient. When the patient agrees, they are brought to surgery and LITT is done in an MRI scanner. The patient is positioned, and the surgeon will stereotactically plan how to insert essentially a probe inside someone's brain. The surgeon then verifies the probe positioning using the MRI. When the probe is appropriately placed, the neurosurgeon starts the ablation. If it's not, then the surgeon adjusts the location of the probe. Once it's in the position, then they fire the laser into the probe. The surgeon uses the MRI during that period to take real time thermography so that they know exactly what's been heated and so that they're not injuring tissue surrounding the intended target. Then they make sure that the brain tissue that they mean to ablate is ablated to a high enough temperature. Once that's seen on the thermography, the ablation is stopped. If they think they need to get any surrounding area that the initial ablation didn't cover, then they'll move the probe again to cover that region. When they're done the probe is removed. After that it's most typically one or two stitches and then the patient goes to recovery.

Could you outline some of the advantages of LITT over other kinds of epilepsy surgery?

The main advantage of LITT versus resection or open craniotomy is that it's a minimally invasive surgery. Inserting the probe typically requires just one Burr hole, or a 3-millimeter hole for the laser equipment that KU uses, and that's the only entrance into the head. MTLE ablation is the most common ablation surgery, but the most common brain surgery for epilepsy is an anterior temporal lobectomy (ATL). This involves an incision into the skull on the side of the head that is a significantly larger opening compared to the 3-millimeter Burr hole. An ATL is a typical surgery, but what's typical to the surgeons and to the neurologist is not typical to the patient who, hopefully, only does that once. It's a big decision for the patient, and that's the big difference. In our study, we actually captured pain scores. The average pain score was 1.4 out of 10, which is very minimal head pain score at discharge.

How do you think clinicians can mediate these sometimes-disproportionate fears about epilepsy surgery?

One of the main challenges in epilepsy care is the misperception of the efficacy of seizure medicines after a certain time point. So, to be clear, medicines are a very effective treatment for epilepsy — nearly 70% of people will be seizure free on medications. The challenge is that's most typically within the first three medicines that they try. After a third failed medicine, less than 1% of people are seizure free on a long-term basis with medicines alone. So, I think it has to do with the early recognition, and appropriate referral to centers that are able to discuss surgical therapy and evaluate people that would benefit from surgery. Once a patient is at one of those centers, patients can know that our study saw 97% of patients discharged to home with our median length of stay being 32.7 hours. Coupled with the low head pain score on discharge, these findings continue to suggest LITT as a form of epilepsy surgery is a safe and well tolerated procedure.

Transcript edited for clarity. NeurologyLive has previously written about Landazuri and colleagues’ investigation, which you can read more about by clicking 

Landazuri P, Shih J, Leuthardt E, et. al. A prospective multicenter study of laser ablation for drug resistant epilepsy – One year outcomes. 

. 2020; 167. doi: 10.1016/j.eplepsyres.2020.106473

In this interview, Patrick Landazuri, MD, shares an in-depth look at his investigations into the safety and efficacy of laser ablation. 

Laser Ablation for Drug Resistant Epilepsy: An Effective and Minimally Invasive Surgery

This fall at the Alzheimer’s Drug Discovery Foundation (ADDF) International Conference, Ronald G. Crystal, MD, presented to more than 800 attendees on the current state of gene therapy for 

 influenced Alzheimer disease and other neurodegenerative disorders, detailing ongoing development and the current state of a small trial in patients with Alzheimer.

Crystal, who is the chairman of the Department of Genetic Medicine at Weill Cornell Medicine, urged attendees to watch this therapeutic development closely, noting that the progress of gene therapy after decades of research reveals a promising future. With regard to Alzheimer, the plan is to provide the 

 gene—which literature has suggested may offer a protective effect against Alzheimer disease—to individuals who are 

, Crystal spoke to the takeaways for the clinical community and discussed the current state of that research. He also explained some of the challenges of developing these therapies, specifically as it relates to the differences in approach to intracellular versus extracellular targets.

: What are your thoughts are on the current state of gene therapy development?

 If you take the common neurodegenerative diseases and make a list of them, they have certain things in common despite the fact that they're very different diseases. One of the things that they have in common is that they are chronic diseases, right? They also, obviously, are in the nervous system and they have a therapeutic challenge—the blood-brain barrier. Those are 2 things that are key things that gene therapy can do. You can use gene therapy to have genes put directly into the nervous system, that bypasses the blood-brain barrier problem. Also, with gene therapy—if it works and if it's safe—there's a single administration to cure it forever. That's why so many people are interested, like us and many others.

We’re interested in gene therapy for the central nervous system. Now the issue is what's the state of the art and where are we? It started with us and some others approaching some diffuse diseases, like the lysosomal storage diseases, by taking the affected individuals to the operating room, putting Burr holes in the skull, catheters directly into the brain, and infusing the viruses that we use to carry the gene. But then the investigators start thinking, could you do this intravenously? That would obviously be a lot easier, right? Spinal muscular atrophy (SMA) was a good example of that. But the problem there was that even though it worked and it’s an approved therapy, is that it’s in infants before the blood-brain barrier is fully formed. With the blood-brain barrier fully formed, it's much tougher to use intravenous approaches because you think about how do the viruses get across the blood-brain barrier?

We and many others then started thinking about other strategies to deliver viruses to the brain. One approach was intraventricular: put a burr hole in the skull and a catheter directly into the cerebral spinal fluid in the ventricle. That's one approach. Then we started thinking about using intracisternal or intrathecal approaches, as well. That's evolving more as the favorite approach. Now, that doesn't mean it solves everything. But there's a lot of data in the field by many investigators, including us, that using intracisternal—or perhaps going down a little lower to C1, C2, or going down even lower and threading a catheter up—is another way to do it. If you can do that without toxicity, although there are some issues, you can get widespread expression throughout the brain. So that's been a part of a revolution in gene therapy for the CNS.

With regard to the viruses that are used, we think of those gene therapy terms as serotypes, and what is being used in the field is adeno-associated viruses (AAVs). There are some that are derived from humans, and some that are derived from nonhuman primates, and then there are some that are man-made in the laboratory by taking known ones and modifying the capsid. That’s done by sort of evolutionary techniques or directed techniques where you make specific changes. In the field, people are developing more capsids that may be a little better here and there, but I think in general, we have the capsids right. The strategy now is to use those capsids to choose the gene of interest and then the approach in terms of how we're going to deliver it.

Gene therapy for the CNS has really evolved over the last decade or so, and I think it's now at the point where there is obviously is an approved drug now, and I think you're going to see a number of approved drugs.

For neurodegenerative disease specifically, what are the challenges and what work are you and your colleagues doing?

In terms of the neurodegenerative diseases, the issues are with the hereditary disorders and the nonhereditary disorders and then sort of in-between disorders. The hereditary disorders like the lysosomal storage diseases, or the genetic form of ALS, or frontal temporal dementia, or Parkinson, or Huntington—you know what the target is. There becomes a delivery problem, a safety problem, an efficacy problem because you know you can deliver the gene, but can you accomplish it and do it sufficiently?

Then there's a group of disorders like we're interested in like Alzheimer, where we're taking advantage of the epidemiology that the apolipoprotein (

. Now, 85% of us are APOE3, but then if you're an 

 homozygote, you have a 15- to 20-fold increased risk for the development of Alzheimer, and if you develop it, it's more aggressive and occurs earlier as well. But if you're lucky enough to inherit from your parents 

, you have a decreased risk of Alzheimer, and if you do develop Alzheimer, it's milder and occurs later.

What got us interested in it was the heterozygotes. If you're an 

 takes away most of the risk—not entirely—for 

. APOE is made mostly by glia and astroglia, and the receptors are mostly on neurons. The particles are formed in the extracellular space. So, if you're heterozygote, your extracellular particles are 

heterozygotes. Our whole strategy is to bathe the brain of 

, so that the particles become heterozygote or even more 

. What we're doing is ignoring the pathogenesis of the disease, whether it's its amyloid, phospho-tau, inflammation, or multiple other mechanisms, all of which are being studied. We're proximal to that because we know that 

 affect multiple sites in the pathogenesis. That's the whole strategy. The way we're administering it is that we decided not to go intracisternal, we do it at C1 or C2. There is a sort of argument in the field about what's best. As you probably know, there are some blood vessels that run at the roof of the cisterna magna, so there's a little bit of a risk to going into the cisterna magna, so we decided to do C1 or C2, just below that. It's done under CT scanning, it's an outpatient procedure, and it takes about 25 to 30 minutes to place the needle, and about 5 minutes to administer. So far, we've treated 3 patients and we're looking for more, and we are actively following them.

What’s the takeaway for the clinical community from your perspective?

Gene therapy is essentially a drug delivery system. It's not an end-all, but it's a drug delivery system, just like small molecules are and monoclonal antibodies are. Gene therapy is real now. We and others have been working on it for several decades now. We now have approval for 1 drug in the field, and I think that one of the real challenges in neurodegenerative disease is the blood-brain barrier and that we can overcome that with the technology that we have. The questions are: can we do it safely, can we get enough in, and can we design the right targets?

What I'd want people to take away is to pay attention to the space. This is going to be something real, and there'll be select diseases where this will be a therapy that over the next decade will become real for you in terms of treating patients.

Ronald Crystal, MD, chairman, Department of Genetic Medicine, Weill Cornell Medicine, discussed the promise of gene therapy for patients with Alzheimer disease and related disorders.

Gene Therapy for Alzheimer and Neurogenerative Disease

The FDA has accepted the biologics license application (BLA) for avalglucosidase alfa (Sanofi) for long-term enzyme replacement therapy for the treatment of patients with Pompe disease. A prescription drug user fee act (PDUFA) date has been set for May 18, 2021.

Avalglucosidase alfa has received FDA breakthrough therapy and fast track designations for the treatment of people with Pompe disease. The basis for the BLA originates from positive data from both the phase 3 COMET trial (NCT02782741) and the phase 2 mini-COMET trial (NCT03019406), which showed improvements over standard of care.

The investigational enzyme replacement therapy was designed to improve the delivery of acid alpha-glucosidase (GAA) enzyme to muscle cells, in which patients with Pompe disease are deficient. It has approximately a 15-fold increase in mannose-6-phosphate (M6P) content, compared to standard of care alglucosidase alfa, and aims to help improve cellular enzyme uptake and enhance glycogen clearance in target tissues. Sanofi noted that the M6P receptor plays a key role in the transport of GAA.

"The hallmarks of Pompe disease are the relentless and debilitating deterioration of the muscles, which causes decreased respiratory function and mobility,” Karin Knobe, MD, PhD, head of development for rare diseases and rare blood disorders, Sanofi, said in a statement. “Avalglucosidase alfa is specifically designed to deliver more GAA enzyme into the lysosomes of the muscle cells. We have been greatly encouraged by positive clinical trial results in patients with late-onset and infantile-onset Pompe disease.”

READ MORE: Centralizing Neuromuscular Disease Data With the MDA MOVR Database

Data from the double-blind, global comparator-controlled COMET trial showed that 

avalglucosidase alfa met the primary end point

 of the study in demonstrating non-inferiority in improving respiratory function compared to the standard of care with alglucosidase alfa (Lumizyme; Sanofi) in patients with late-onset Pompe disease.

Those treated with the drug showed a 2.43-point greater improvement (95% CI, –0.13 to 4.99) in percent-predicted forced vital capacity (FVC) compared to the standard of care (

 = .0074). All told, those in the avalglucosidase alfa group reported a percent predicted FVC of 2.89 (standard deviation [SD], 0.88) compared to the reported 0.46 (SD, 0.93) with the standard of care group.

The agent, while achieving statistical significance for the primary end point, did not achieve statistical superiority (

= .0626). Due to the hierarchy of the study protocol, Sanofi noted that the formal statistical testing for all secondary end points was not conducted. Although, a key secondary end point measuring mobility was the 6-minute walk test (6MWT), and those treated with avalglucosidase alfa walked 30.01 m farther (95% CI, 1.33–58.69; distance, 32.21 m [SD, 9.93]) than the standard of care group (distance, 2.19 m [SD, 10.40]).

Also assessed were the percent-predicted Maximum Inspiratory Pressure and Maximum Expiratory Pressure. Those in the avalglucosidase alfa group reported percentages of -0.29 (SD, 3.84) and 2.39 (SD, 4.00), respectively, compared to -2.87 (SD, 4.04) and 5.00 (SD, 4.20) with standard of care. Those totaled differences of 2.58 (95% CI, -8.54 to 13.71) for Maximum Inspiratory Pressure and -2.61 (95% CI, -14.22 to 9.00) for Maximum Expiratory Pressure.

Mini-COMET is an ongoing, phase 2, open-label, ascending-dose, 3-cohort study of avalglucosidase alfa in 22 patients under 18 years of age with infantile-onset Pompe disease, who were previously treated with avalglucosidase alfa and showed incomplete treatment response in pre-specified clinical outcomes.

Presented at the WORLDSymposium in February 2020, results showed that treatment with avalglucosidase alfa was well-tolerated at 20mg/kg and 40mg/kg dose every 2 weeks at the 6-month period. The most common adverse events (AEs) reported were all mild to moderate in nature, including vomiting and pyrexia (6 patients each), upper respiratory tract infections (5 patients), and cough and rash (4 patients each). There were no serious or severe treatment-related AEs, including no AEs that resulted in permanent discontinuation or death.

1. FDA grants priority review for avalglucosidase alfa, a potential new therapy for Pompe disease. News release. Sanofi. November 18, 2020. Accessed November 19, 2020. 

http://www.news.sanofi.us/2020-11-18-FDA-grants-priority-review-for-avalglucosidase-alfa-a-potential-new-therapy-for-Pompe-disease

2. Sanofi’s investigational enzyme replacement therapy shows clinically meaningful improvement in critical manifestations of late-onset Pompe disease. News release. Sanofi. June 16, 2020. Accessed November 19, 2020. https://www.sanofi.com/en/media-room/press-releases/2020/2020-06-16-14-00-00

3. Avalglucosidase alfa showed positive exploratory efficacy and was well-tolerated in phase 2 trials in Pompe disease. News release. February 10, 2020. Accessed November 19, 2020. https://www.sanofigenzyme.com/en/about-us/newsroom/2020/2020-02-10-04-45-00

Evidence from 2 clinical trials were the basis of the biologics license application, with an FDA decision expected to be made by May 18, 2021.

FDA Accepts BLA for Avalglucosidase Alfa for Pompe Disease

"One of the biggest concerns is that it puts them at a very high risk to have refractory seizures, or seizures that do not respond to medication.”

Infantile spasms are seizures that typically begin in infants between 3 and 8 months of age, characterized by a sudden stiffening followed by knees pulling up and the body bending forward. These seizures can last for a few seconds, but usually occur close together in a series. Babies who are diagnosed with this condition often will have their development slowed, and potentially lose skills such as sitting, rolling over, or babbling.

The professor of neurology and pediatrics at the University of Alabama at Birmingham Epilepsy Center detailed challenges faced by children with infantile spasms and how the spasms evolve later in life.

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