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

"Mind Moments," a podcast from NeurologyLive, brings you an exclusive interview with Raman Malhotra, MD.

Episode 20: Taking Steps to Advance Sleep Care

As the world awaits what could be the first disease-modifying treatment for Alzheimer disease, research continues to point us in the direction of various therapeutic targets that could hold promise for prevention. No target is perhaps more promising than those embedded throughout the body—the very channels that circulate blood and oxygen to not only the brain but all other critical organs. Despite the fact that over 50% of cases of AD are attributable to a mixed pathology of vascular and Alzheimer-related factors, much of our therapeutic muscle has been thrown behind drugs that tend to target only a single AD pathology.

Although the idea of preventing such a devastating disease seems far off when we still have little grasp on our ability to actively treat it, a growing body of evidence suggests that a handful of simple “best practices”—maintaining a healthy weight, managing hypertension, staying physically active—might have a significant effect on AD risk reduction by ensuring a more healthy vascular system.

To learn more about the interaction of vascular risk factors and the shortcomings of our current clinical approach, 

® sat down with Costantino Iadecola, MD, director and chair of the Feil Family Brain and Mind Research Institute, and Anne Parrish Titzell Professor of Neurology at Weill Cornell Medicine in New York, New York.

What is our current understanding of how amyloid-β impacts vascular function in the brain? How does this affect those who are genetically predisposed versus sporadic cases?

In people who have a predisposition to Alzheimer disease, there is evidence that as amyloid is being over produced in the brain, it is being removed by 2 vascular mechanisms, either because 

the amyloid kind of goes around the blood vessels and gets out of the brain through that route, or because it goes straight to the blood vessels and gets into the blood and is then being cleared. In familial Alzheimer cases, the problem is amyloid-β overproduction; there’s too much amyloid being made for the brain to clear. It’s [as if] the drain in the sink is working properly, but the water is turned on too high. In that case, amyloid also has an effect on blood vessels as it does on the neurons, by stunning the blood vessels and making them unable to deliver the oxygen and glucose and remove this waste. It’s going to promote accumulation because, even though the vessels per se are healthy, the amyloid is making them unhealthy and unable to do what they normally do. The evidence for this is indirect, but if you measure blood flow in patients with a familial risk of Alzheimer disease way before they become cognitively impaired, you already see a reduction in blood flow. So that suggests that there is something going on with the blood vessels before the brain gets really, really sick.

People with sporadic Alzheimer disease tend to be older, [and] have diabetes, high blood pressure, and other comorbidities that come with age. In this sporadic group, the problem is not that the faucet is turned on too high, but instead the drain is clogged; the vessels and older mechanisms are unable to remove the amyloid-β that is being made. In that case, it is even more important to keep the vessels healthy because that’s really what the problem is; it is an inability to kind of drain the amyloid-β and clear it from the brain.

All these things that come with aging—hypertension, diabetes, obesity, etc—are all harming the blood vessels and making them unhealthy. That unhealthy vessel is going to be less able to supply and nourish the brain with oxygen and glucose, and to clear all the waste that is being made, including amyloid. Although these 

are 2 different conditions, in both cases, maintaining the health of the blood vessels is key. If you’re a young person who is at risk of familial Alzheimer disease, stopping smoking and taking care of your diet is going to help you, and if you’re a 55-year-old man who is hypertensive and diabetic, you really should take care of your comorbidities because you will be better off. In both scenarios, you can make the case for helping the blood vessels to work better.

I think the geriatrician is really a critical element in this brain health clinic, where the health of the brain is going to be seen in the context of the health of the other organs of the body.

Based on this knowledge and our current therapeutic targets, is clearing amyloid-β from the brain enough, or should we be tackling treatment from multiple angles?

Theoretically, it would be easier to approach treatment of the familial forms of AD because we have drugs that block the ability of enzymes to cleave amyloid-β from amyloid precursor protein— we have gamma secretase inhibitors and beta secretase inhibitors. Unfortunately, it has not been as easy as it sounds, because these enzymes do other things that we are just learning now, so if you just shut down the enzymes, you can make things worse. Now we have modulators that do not shut the enzyme down completely, but just reduce certain aspects of the enzymatic activity. Those, I think, will have the maximum advantage, particularly in the familial cases, where overproduction is the main issue. The sporadic cases are much more complex and I don’t think that a single approach is going to work because if you look at the brain of someone who died of sporadic Alzheimer disease, they often have 5 or 6 pathologies at the same time, [such as] amyloid-β, tau, TDP-43, vascular dysfunction, [and] vascular alterations. You would want, somehow, to deal with a bunch of them at the same time. Now, the vessels are easy, because by adhering to a healthy lifestyle, you can better control the vascular risk factors. Because of recent emphasis on control of these risk factors, the mortality for cardiac attacks and strokes is going down 60% to 80%. We know how to do that, but we’re not doing it in the Alzheimer populations, because the idea so far has been, "Well, it’s a disease 

of the brain." But now we know more and we should really broaden our horizons and include the health of the vessels in any treatment plan.

In terms of prevention, what could we be doing better 

from both a patient education standpoint and increasing awareness among neurology and primary care providers?

I think your question raises a very important public health issue. At the research, tertiary referral level, where these huge dementia programs exist and the people who lead these programs are at the top of their field, if this vascular prevention approach is not done in [that environment], then how can we hope to [have this knowledge] trickle down...to the general practitioner, who is going to be the first person to see someone with Alzheimer disease? Bottom line, we have a lot of work to do. We are not empowering the general practitioner with all these things that we know, yet it’s very simple. The American Heart Association has a program called Life’s Simple 7 that is a guide to help keep your vessels healthy; stop smoking, treat your diabetes, treat your blood pressure, exercise, all of those things. There would be no harm in doing those things in the context of a dementia clinic or memory disorder clinic.

In an ideal world, we would have brain health clinics in which you’re going to have a cardiologist, a geriatrician, a neurologist, dietary specialists, etc, that work together on each case. I like to stress the role of the geriatrician because treating older people is not like treating a young person who has become old. Everything changes: Drugs have different interactions [and] dosages, the approaches are completely different, but that approach hasn’t really [arrived] there yet. I think the geriatrician is really a critical element in this brain health clinic, where the health of the brain is going to be seen in the context of the health of the other organs of the body. It could be that the person is going to need to pay more attention to the heart, for example, because maybe the reason why they are having memory problems is because the heart is not pumping enough blood. We have to better identify ourselves with this concept of multidisciplinarity and move away from parcellation of care. You should not hesitate to talk to your colleagues in other disciplines, and you should be aware that the brain is not really an isolated organ—it’s all part of the same thing.

Articles

Constantino Iadecola, MD, discusses the interaction of vascular risk factors and the shortcomings of our current clinical approach to Alzheimer disease. 

Alzheimer Disease Crossroads: Why a One-Way Approach to Treatment, Prevention May Be Futile

Theranica Biotherapeutics has announced that its Nerivio medical device has received clearance from the FDA for an expansion on its treatment indication to include the acute treatment of chronic migraine in patients aged 18 years and older.

This new indication means the device is now cleared to use in the acute treatment of migraine with or without aura in individuals aged 18 years or older, regardless of episodic or chronic migraine classification. The FDA’s decision was made based on the results of 2 clinical studies in chronic migraine.

“The updated Nerivio indication is an important development for patients with chronic migraine,” said Stephen Silberstein, MD, director, Headache Center, Jefferson University Hospital, in a statement. “When chronic patients find an effective treatment, they must limit its use every month to avoid loss of effectiveness and a risk of medication overuse headache. [The] availability of an additional treatment option such as Nerivio provides an important additional tool to address this patient population.

“With over 1000 treatments by 130 chronic migraine patients across 2 open-label studies with Nerivio, the data is clinically relevant,” Silberstein added.

Each Nerivio device is good to use for 12 treatments, after which a newly dispensed device can be given to fill prescriptions. The device can be recycled upon the need to discard it. It is a smartphone-controlled electroceutical device that uses non-invasive neuromodulation to create a conditioned pain modulation response. The prescription device is self-applied to the upper-arm and is used in the home environment at the onset of migraine headache or aura. It gained 

 after it was named to TIME Magazine’s annual list of top 100 best inventions.

Telemedicine: An Opportunity to Bring Better Care to All

“With this indication expansion, Theranica is now broadening market access of Nerivio in the USA, including health insurance reimbursement. It’s time to provide physicians and patients affordable access to a safe non-pharmacological acute treatment,” said Alon Ironi, chief executive officer, Theranica, in a statement.

Nerivio was granted de novo clearance by the FDA in May 2019 for the acute treatment of migraine with or without aura in adults who do not have chronic migraine. In April, Theranica announced that the device was becoming available in the United States on UpScript’s direct-to-patient telemedicine platform. Now, patients across all 50 states will have the opportunity to remotely connect with doctors to assess the need for a prescription and order Nerivio directly to their homes.

Patients who have already been prescribed Nerivio by their doctors can save time and money with the partnership with UpScript, Theranica noted. Those who feel they may be a good candidate can begin the process by going to the UpScript website, 

The user-friendly app for the device offers personalized treatments and includes a diary to track treatment sessions and migraine headaches. Clinical trial results showed a 66.7% response rate in the Nerivio group versus 38.8% in the placebo group at 2 hours post-treatment (

 <.0001), ultimately supporting the FDA’s authorization.

The same trial showed 46.3% of patients in the Nerivio group experienced relief of the most bothersome symptom compared to 22.2% of patients in the placebo group (

 <.0001). Additionally, relief of both pain and most bothersome symptom at 2 hours was found in 40% and 15.2% of Nerivio and placebo groups, respectively.

Additionally, real-world data published in September 2020 suggest that patients treated with the remote electrical neuromodulation (REN) device derive meaningful clinical benefits with minimal adverse effects. All told, that data stratified patients based on the type of visit and provider they received treatment from, including headache specialists (HS; n = 1123) or virtual visits with nonheadache specialists (NHS; n = 31).

The data revealed that 58.9% (n = 662) and 74.2% (n = 23) of the HS and NHS groups reported pain relief at 2 hours for ≥50% of their treated attacks. Additionally, 20% (n = 268) and 35.6% (n = 16) of the groups, respectively, experienced pain freedom at 2 hours in ≥50% of treated attacks. The effects of the device on associated symptoms and improvement in function were also consistent in both groups.

REFERENCES
1. Nerivio receives clearance of expanded indication to cover chronic migraine patients. News release. Montclair, NJ. Theranica Biotherapeutics. Published October 26, 2020. Accessed October 26, 2020. prnewswire.com/news-releases/nerivio-receives-clearance-of-expanded-indication-to-cover-chronic-migraine-patients-301159445.html
2. Theranica expands access to prescribed migraine wearable Nerivio through partnership with UpScript health telemedicine platform. News release. Scottsdale, AZ. Theranica Biotherapeutics. Published April 6, 2020. Accessed October 26, 2020. prnewswire.com/news-releases/theranica-expands-access-to-prescribed-migraine-wearable-nerivio-through-partnership-with-upscript-health-telemedicine-platform-301035804.html
3. Theranica Announces Results from Pivotal Study of Device for Treating Acute Migraine. News release. Scottsdale, Arizona. Theranica Biotherapeutics. Published November 15, 2018. Accessed October 26, 2020. prnewswire.com/news-releases/theranica-announces-results-from-pivotal-study-of-device-for-treating-acute-migraine-832012898.html
4. Tepper SJ, Lin T, Montal T, Ironi A, Dougherty C. Real-world Experience with Remote Electrical Neuromodulation in the Acute Treatment of Migraine. 

. Published September 16, 2020. doi: 10.1093/pm/pnaa299.

The Theranica Biotherapeutics remote electrical neuromodulation device is now cleared for the acute treatment of migraine with or without aura in adults, without limitation to episodic migraine.

Nerivio Device Granted Clearance for Acute Treatment of Chronic Migraine

Zosano Pharma announced that it has received a complete response letter (CRL) from the FDA for its zolmitriptan transdermal microneedle system (Qtrypta) in correlation with the new drug application (NDA) it had submitted.

Inconsistent zolmitriptan exposure levels observed across clinical pharmacology studies which had been previously identified in the 

FDA’s discipline review letter (DRL) in September

, were among the main reasons cited for the CRL.

The CRL also noted differences in the exposure levels of zolmitriptan observed between subjects who received different lots of the drug in the company’s trials as well as inadequate pharmacokinetic bridging between the lots that made the interpretation of some safety data unclear.

“We are working diligently to address the deficiencies identified by the FDA and look forward to the possibility of resubmitting our NDA,” said Steven Lo, president and chief executive officer, Zosano, in a statement.

Zolmitriptan, a treatment for acute migraine also known as its adhesive dermally applied microarray (ADAM) platform, had its NDA accepted by the FDA in March 2020 with an original Prescription Drug User Fee Act (PDUFA) action date of October 20, 2020, which since then has been rescheduled.

READ MORE: Telemedicine: An Opportunity to Bring Better Care to All

High plasma concentrations of zolmitriptan unexpectedly observed in 5 study subjects enrolled in the company’s pharmacokinetic studies were also among the reasons cited for the CRL. As a result, the FDA recommended that Zosano conduct a repeat bioequivalence study between 3 of the lots used during development.

Additional product quality validation data, which were planned to be submitted following approval, if received, was noted within the CRL as a requirement if the company planned to submit an application. Additionally, the CRL mentioned that inspections of Zosano’s contract manufacturing facilities were not able to be conducted due to the US government and/or agency-wide restrictions on travel but would be required before the application may be approved.

Zosano also noted that it plans on requesting a Type A meeting with the FDA to discuss strategies to address the comments in the CRL. Lo stated, “We expect that the Type A meeting with the FDA will provide clarity on the next steps for the program, which we will communicate once solidified. There are thousands of people suffering from migraine attacks that are not adequately addressed with available drugs, and we continue to believe that Qtrypta, if approved, could offer a much-needed new therapy for these patients.”

new post-hoc efficiency analyses of the adhesive dermally applied microarray (ADAM) zolmitriptan

 from its open-label, long-term study were presented virtually at the 2020 American Headache Society (AHS) Annual Meeting, which suggest that the results were consistent with what was previously observed in the phase 2/3 study results.

The data suggested that across all 6 efficacy measurements—pain freedom at 2 hours, pain relief at 2 hours, sustained pain freedom for 2 to 24 hours, sustained pain freedom for 2 to 48 hours, sustained pain relief for 2 to 24 hours, and sustained pain relief for 2 to 48 hours—the migraine headaches treated with 3.8-mg ADAM zolmitriptan displayed meaningful clinical improvements compared to those treated with placebo.

1. Zosano Pharma receives complete response letter from the FDA for Qtrypta. News release. Zosano Pharma. Published October 21, 2020. Accessed October 26, 2020. 

https://ir.zosanopharma.com/news-releases/news-release-details/zosano-pharma-receives-complete-response-letter-fda-qtryptatm

2. Zosano Pharma Receives Preliminary FDA Communication on Qtrypta™ NDA. News release. Fremont, CA. Zosano. Published September 30, 2020. Accessed October 26, 2020. https://finance.yahoo.com/news/zosano-pharma-receives-preliminary-fda-214000619.html

3. Zosano Pharma to showcase new post-hoc analyses of Qtrypta’s (M207) clinical trial data comparing key efficacy results from the pivotal study and the open-label long term safety study on the 2020 American Headache Society’s Virtual Annual Scientific Meeting Platform. News release. Zosano Pharma. Published June 13, 2020. Accessed October 26, 2020. ir.zosanopharma.com/news-releases/news-release-details/zosano-pharma-showcase-new-post-hoc-analyses-qtryptas-m207

Zosano plans to request a Type A meeting with the FDA to discuss strategies to address the FDA’s comments regarding the new drug application.

FDA Issues Complete Response Letter for Zolmitriptan

Sleep-disordered breathing (SDB) refers to any disorder in which the patient has difficulty breathing while asleep, including obstructive sleep apnea (OSA) and central sleep apnea (CSA). OSA, which occurs because of upper airway obstruction during sleep, is far more common, with estimates of approximately 936 million people worldwide suffering from the condition.

“With OSA, snoring and breathing pauses and reduced airflow during the night leads to sleep fragmentation and unrefreshing sleep, which in turn impairs daytime functioning,” said Stuart MacKay, BSc(Med), MBBS(Hons), FRACS, associate professor at Illawarra ENT Head and Neck Clinic in Australia. 

“Patients can feel groggy, tired, [and] sleepy and have a higher rate of motor vehicle collisions and workplace accidents. In addition, via a variety of pathophysiological pathways, but especially due to repetitive oxygen desaturation, patients with more significant sleep apnea are at risk of hypertension, arrhythmias, ischemic events, and other cardiometabolic consequences.”

A small subset of patients may have CSA, when the brain fails to send signals to breathe. CSA is less common in the general population, but there are increased rates in people with specific conditions, such as heart failure and chronic opioid use.

Although OSA and CSA have different causes, both contribute to reduced quality of life and have been linked to decreased cognition, increased cardiovascular risk, and increased mortality.

Continuous positive airway pressure therapy: Not suitable for all

Most sleep experts recommend continuous positive airway pressure (CPAP) as the first-line treatment for SDB, regardless of the severity of apnea. The CPAP device continuously delivers pressurized air into the upper airway, which helps keep the air passages open. Results from studies have shown that using CPAP therapy can significantly reduce the severity and morbidity associated with sleep apnea.

The main limiting factor in the use of CPAP for OSA is the lack of compliance to therapy. The device delivers air under moderate to high pressure, which can cause a certain level of discomfort for patients. “Although it is minimally invasive, not everyone can tolerate CPAP,” said Peter M. Baptista, MD, PhD, a senior clinical consultant at the Otorhinolaryngology Unit at Clínica Universidad 

de Navarra in Spain. “In addition, CPAP can cause nasal obstruction and feelings of claustrophobia.”

One cohort study estimated that only 37% to 41% of patients adhered to CPAP therapy in the long term,

 which ultimately hinders the achievement of good treatment outcomes. A recent meta-analysis showed that the cardiovascular risk associated with OSA was reduced only when patients wore the device for longer than 4 hours per day.

For patients with CSA, it is more than just the discomfort of CPAP that can raise problems. “With central sleep apnea, there is an interruption in the neural drive to breathe,” Sanjaya K. Gupta, MD, assistant professor of medicine at the University of Missouri-Kansas City School of Medicine, told 

®. “There is no movement of the diaphragm, so using CPAP does not work unless the patient is making an effort to breathe.”

Clinicians have used a wide range of surgical procedures in OSA, including palatopharyngoplasty, tonsillectomy, and maxillomandibular advancement.

 However, each surgery targets only
1 anatomical area. Results from sonographic studies have shown that OSA presents with multilevel airway collapse, which means that a single surgery may fail to resolve the complete issue.

Surgery is not an option for patients with CSA. Apart from oxygen ventilation, the only other ways to manage CSA include treating the underlying heart condition that is present and cutting back
on opioid use.

Nerve stimulation for the management of sleep apnea

The search for newer, better alternatives to CPAP has resulted in 1 promising solution––nerve stimulation. By stimulating selected nerves, specific muscles that aid in airway relaxation or breathing can be made to contract. This addresses the problem of sleep apnea at a physiological level, which would reasonably be more effective and have fewer adverse effects.

For OSA, clinicians choose the hypoglossal nerve as a target for stimulation. “Hypoglossal nerve stimulation [HGNS] provides an opening of the airway at the level of both the tongue and palate,” said Baptista. Nerve stimulation causes the genioglossus muscle to contract, which moves the tongue forward. According to research by MacKay and colleagues, it is important to only stimulate the genioglossus. “Selective stimulation of the nerve fibers to the genioglossus, the main dilator of the airway, allows [the] avoidance of stimulating retrusor muscles that can compromise airway opening,” he said. “Results of such implantation are likely to improve patient and polysomnographic outcomes.”

Research results have shown that there is also palatoglossal coupling, which increases the airway space at the retropalatal level.

 This dilates and stabilizes the airway at multiple levels. In a recent systematic review, Baptista and colleagues reviewed 12 studies that used HGNS for OSA.

 They found the procedure reduced the number of apneic and hypopnea events per hour by 18 points, measured via the apnea-hypopnea index (AHI). There was also a reduction of 14.6 points in the number of oxygen desaturations measured via the oxygen desaturation index (ODI). According to MacKay, “The advantages of HGNS include the ability to avoid devices worn on the face and in the mouth, and avoidance of painful intra-oral/pharyngeal surgeries. Disadvantages include the requirement for commitment to titrations, follow-up, and ongoing device use.”

There are different types of HGNS, namely unilateral and bilateral. “Bilateral HGNS allows a higher likelihood of symmetrical tongue and, in cases of ‘coupling,’ palatal movement to improve airway patency in sleep,” MacKay told 

®. “Advantages over currently available unilateral stimulation include [fewer] components to implant, and external stimulation rather than an implanted ‘pacemaker.’ The incision is small and relatively painless.”

In CSA, stimulation of the phrenic nerve can be just as effective. This eliminates periodic respiration by causing consistent, regular diaphragmatic contractions, which generates negative intrathoracic pressure and restores a regular breathing pattern. Last year, investigators reported the results of using a phrenic nerve stimulator over a 3-year period.

 The result was sustained improvement across a wide range of sleep metrics, including the AHI, ODI, central apnea index, and arousal index. More recently, a pooled meta-analysis of 5 different studies showed that phrenic nerve stimulation could effectively reduce AHI scores by approximately 26.7 events per hour, as well as reduce the ODI scores by approximately 24.

The nerve stimulator needs to be implanted into the patient’s body to function. Several different devices are available to treat OSA through HGNS. In general, the device consists of a sensor electrode, a pulse generator, and a stimulation electrode.

 The sensor electrode is usually implanted into the intercostal muscles, or just below the ribs. During inspiration, it gives off an electric signal that is picked up by an implantable pulse generator (IPG). The IPG is usually placed in a pocket below the clavicle, medial to the delto-pectoral groove. After receiving an electric signal, it generates a pulse that is transmitted to the stimulation electrode, which is implanted around the medial branches of the hypoglossal nerve.

The device used in CSA has a slightly different design; a sensing lead is placed in the azygous vein, behind the heart, to the level of the diaphragm to detect breathing. A pacing electrode is placed in a vein adjacent to the phrenic nerve. “The device works 

automatically and in concert with patients’ normal respiratory cycle,” said Gupta. “The pacing and sensing leads are plugged
into a device that looks and functions similar to a cardiac pacemaker. Once connected, the device and leads are surgically placed under the skin in the right upper chest, just below the collarbone. The device is programmed to sense the patient’s breathing and the moment when the breathing stops, the device will deliver electricity through the pacing lead to the phrenic nerve, which will stimulate the diaphragm to contract.” All this happens automatically and seamlessly, in concert with the patient’s normal respiratory cycle. No intervention is necessary on behalf of the patient to initiate therapy, they don’t have to wear a CPAP mask, and the device turns off when they get up in the morning.

Can all patients with SDB receive nerve stimulation therapy? According to most experts, the answer is no. The type of patient selected can greatly influence treatment outcomes, and establishing which sleep apnea the patient has is a key priority. HGNS will not work if the patient has CSA. Conversely, phrenic nerve stimulation only benefits those with CSA; it is not indicated for those with primarily OSA. There is a third type of sleep apnea called “treatment emergent” CSA

 This is primarily OSA in which a central component emerges following the use of CPAP therapy. Uncertainty remains about whether nerve stimulation can benefit this subset of patients.

An obvious indication for HGNS is for patients who are unable to tolerate CPAP. However, before clinicians consider this procedure, the patient must be evaluated for other factors. “Patients should see credentialed sleep surgeons for a thorough assessment and discussion of treatment options if they cannot tolerate or adhere to CPAP or other devices long-term,” advised MacKay.

In a recent review study, Baptista highlighted 3 key factors that must be considered during patient selection.

 These include the severity of OSA, body mass index (BMI), and the severity of airway collapse at the palatal level. “If patients have [a] very high BMI (> 35) or concentric palatal collapse, HGNS is best avoided,” said Baptista. Obesity is a predictor for poor OSA treatment outcomes regardless of the type of treatment. In terms of severity of airway collapse at the palatal level, HGNS relaxes the palatal and retrolingual musculature, but if there is concomitant collapse in the posterior or lateral pharynx, this technique may not be effective. To ascertain the exact area of collapse, drug-induced sleep endoscopy can serve as a valuable diagnostic tool.

Nerve stimulation is a relatively expensive technique compared to CPAP and may not be financially feasible for patients with mild OSA. The FDA recommends using this technique for patients with moderate to severe apnea with an AHI score between 15 and 65.

For phrenic nerve stimulation, the severity of apnea and the proportion of central events are the main considerations. “We generally target patients with moderate to severe sleep apnea where at least 80% of the events are central in nature,” says Gupta.

Implantable nerve stimulation seems to be a reasonably safe method of treatment. In their meta-analysis, Baptista’s team analyzed the number of adverse events related to HGNS. Serious events were documented in 6% of all patients, for whom there was a requirement for surgical repositioning of the device or the replacement of electrodes.

 Minor adverse effects were reported by almost 60% of all patients, including discomfort from electrical stimulation and tongue abrasion due to constant movement. Although these effects were common during the first year of treatment, they reduced in subsequent years.

The meta-analysis for phrenic nerve stimulation showed serious adverse events in 3.9% of all patients. These included hematoma, migraine, and atypical chest pain, which necessitated the removal of the device. Minor adverse effects were reported in about 5.3% of all patients, including device discomfort, dislocation of leads, and lead failure.

 The more severe adverse effects may be avoided by refinements in surgical technique, whereas discomfort mostly resolves with time as the patient gets used to the device.

As the use of nerve stimulators continues to rise, the onus is now on making these devices more efficient and increasing their capabilities. Baptista believes that future research must focus on finding ways to circumvent lateral airway collapse at the palatal level. “We are just at the very beginning,” he said. “In a few years, there will be devices that are much smaller and perhaps capable of stimulating a specific group of fibers that allow airway opening.”

Research into nerve stimulation therapy still has a long way to go. Although prospective studies have illustrated the therapy’s standalone efficacy, there is no research comparing the use of this therapy to CPAP, which is still the gold standard for OSA. Longitudinal studies are also needed to assess secondary outcomes. “We still do not know if phrenic nerve stimulation can reduce morbidity and mortality rates,” Gupta pointed out.

According to Mackay, “Areas that represent the most exciting future investigation are patient preferences, combination therapies, further refinement of implantation and titration techniques, miniaturization of devices, and endophenotyping outcomes in low muscle hyporesponsive-type OSA patients.”

Most physicians are aiming for a more accurate diagnosis and evaluation, prior to wider acceptance of current treatment strategies. “For patients with an appropriate indication, the phrenic nerve pacing procedure can be life-changing,” stated Gupta. However, nerve stimulation has yet to gain wide acceptance. One main barrier, especially in the case of CSA, is the lack of a proper diagnosis. “CSA patients lack traditional symptoms such as snoring and daytime somnolence,” said Gupta, who feels that the only way to improve diagnostic accuracy is to maintain a high index of suspicion. “If you have a patient with heart failure, atrial fibrillation, or stroke who continues to complain of fatigue despite optimal medical therapy, consider the possibility of CSA,” he advised. A sleep study or polysomnogram is the best diagnostic test for sleep apnea and clinicians should recommend it to such patients.

Addressing sleep apnea at a physiological level may reasonably be more effective and have fewer adverse effects than more traditional treatment modalities that may only target one mechanism.

Stimulating the Future of Treating Sleep-Disordered Breathing

 staff prepares this preview of what to expect from our coverage. This week on 

, there are a number of hot topics that we will be posting throughout the week.

's October 2020 print issue covering the complex challenges in addressing sleep-disordered breathing, and the current alternative approaches being explored to overcome them, goes live Monday. In the piece, Nicola Davies, PhD, discusses how addressing sleep apnea at a physiological level may reasonably be more effective and have fewer adverse effects than more traditional treatment modalities that may only target one mechanism.

To read the entire October issue online, 

A new Q&A series dedicated to conversations with leaders in the neurology community, called 

 premieres with the first half of a discussion with Jennifer Frontera, MD, professor of neurology, NYU Langone Grossman School of Medicine. She discussed the results of a recent study she and colleagues conducted which revealed a number of new neurologic symptoms associated with COVID-19 infection in patients

To gain insights gleaned from Frontera in previous interviews, 

A conversation with Howard Fillit, MD, founding executive director and chief science officer, Alzheimer's Drug Discovery Foundation (ADDF), will air on 

 channel this Thursday, October 29, 2020. Fillit discussed the recent ADDF International Conference, highlighting some of the key presentations and offering insights on the state of boundary-pushing research in Alzheimer.

To check out our latest conversations with Fillit, 

In partnership with the Consortium of Multiple Sclerosis Centers (CMSC) and the International Organization for Multiple Sclerosis Nurses (IOMSN), the final installment of a webcast program on multiple sclerosis (MS) taking place this month titled, "Cannabis and MS: Helping Patients Understand Risks and Benefits," will air this Wednesday, October 28, at 7PM EDT. This progressive webcast series features Allen C. Bowling, MD, PhD, director of the NeuroHealth Institute and clinical professor of neurology at the University of Colorado. Participants will earn 1 CE credit for each session completed.

Segment 4 of the “Rapid Readout: Expert Perspectives on Multiple Sclerosis” News Network series featuring Mark Freedman, MD, MSc, will air this week. Freedman gave an overview of the phase 3 OPTIMUM study involving ponesimod and how the reduction in MRI-based outcomes, including brain atrophy, is significant in supporting the clinical outcome of relapse rate reduction in patients with relapsing-remitting multiple sclerosis.

Here's what is coming soon to NeurologyLive.

This Week on NeurologyLive

There is little doubt that 2020 will be a year that lives in infamy. Unique to it has been the distinct politicization of medicine unfortunately to the disservice of the greater good. With political divide,
civil unrest, and the awakening of our country to discussions about inequality in regard to race, gender, and financial means, telemedicine landed at the forefront of a global pandemic as a way to forge through all barriers and provide care to patients. As quickly as telehealth was accepted by governing agencies that had put limits to its use in the past, barriers to providing patient care using this platform were made clear to practicing clinicians.

Telemedicine is an effective way to provide care to patients who cannot be present in the clinic or office,

 thus it is important that we continue to improve this offering so we can provide safe and effective care to all patients.

Current challenges and considerations for telemedicine include the following:

Barriers to internet and device use must be recognized.

Studies show that elderly patients, those with physical or mental disabilities, Black or Latinx patients, and those with lower socioeconomic status are less likely to have access to a reliable, secure internet source or a device capable of connecting to a video platform or the ability to use these resources on their own without a third party.

 To provide the best care to all patients, limits to internet and device use must be recognized and considerations should be made on how to provide telehealth services to patients with limited access. One possibility would be to have telehealth hubs centered in local communities where patients could book an appointment to connect via a telehealth platform. These hubs could be located in pharmacies and grocery stores or even local libraries. Privacy considerations would have to be taken into account, as would a way to continue to service and run these stations either by public or private grants.

Initial and annual physicals need to be conducted in person.

At this time, telemedicine exams cannot replace in-person exams. Although there are available devices that can connect to telehealth platforms to assist with collecting vital signs and performing EKGs and limited eye assessments, their cost and questionable security will likely continue to limit their use to those who can afford it. Ultimately, nothing will replace a physical exam that evaluates for nodules, lumps, edema, reflexes, papilledema, motor strength, and so on.

Patient education on telehealth platforms is vital.

If a patient is interested in using telehealth, they need to be educated on using the telehealth platform and how to prepare for a visit. Telemedicine leaves a lot for the patient to coordinate and if they are not prepared for this, it can make the visit less efficient and lead to higher rates of dissatisfaction and lower rates of adherence.

Use of ancillary staff provides a sustainable infrastructure.

In clinical practice, we rely on staff to create a smooth visit flow; this is no different with telemedicine. Using a medical assistant to start the visit and update the record can improve practice efficiency and allow clinicians to see a greater volume of patients.

Clinician training on telehealth platforms and conducting telehealth visits is essential.

We were not trained in medical school to stare at the eye of the camera rather than the image on the screen in front of us; on how 

to speak with warmth to a computer screen; and on how to provide compassion without a gentle touch. It takes a unique skill set to translate warmth and humanity over a televisit and without this, virtual visits can lead to decreased adherence to medication regimens, decreased patient satisfaction, and ultimately, difficulty in building long-lasting, trusting relationships. Telehealth skill training should be a required module for all clinicians who implement telehealth into their practice.

"Ultimately, the lessons learned from the rapid uptake of telemedicine should help us build a stronger, more sustainable future for the platform."

Telehealth platforms must be HIPAA compliant.

There is no substitute for a secure, private interaction between a clinician and their patient. Security for both parties should be a priority regardless of the nature of the visit, therefore standardized HIPAA-compliant safety measures should always be employed across telehealth platforms.

Ultimately, the lessons learned from the rapid uptake of telemedicine should help us build a stronger, more sustainable future for the platform.

1. Almathami HKY, Win KT, Vlahu-Gjorgievska E. Barriers and facilitators that influence telemedi- cine-based, real-time, online consultation at patients’ homes: systematic literature review. J Med Internet Res. 2020;22(2):e16407. doi:10.2196/16407

2. Bloem BR, Dorsey ER, Okun MS. The coronavirus disease 2019 crisis as catalyst for telemedicine for chronic neurological disorders. JAMA Neurol. 2020;77(8):927-928. doi:10.1001/jamaneurol.2020.1452

3. Lam K, Lu AD, Shi Y. Assessing telemedicine unreadiness among older adults in the United States during the COVID-19 pandemic. JAMA Intern Med. Published online August 3, 2020. doi:10.1001/ jamainternmed.2020.2671

4. Pearlstein J. Access to telemedicine is the hardest for those who need it most. Wired website. September 3, 2020. Accessed September 4, 2020. https://www.wired.com/story/ access-telemedicine-is-hardest-those-who-need-it-most/

Guest editor in chief Jessica Ailani, MD, FAHS, FAAN, provides an overview of the challenges and benefits associated with telemedicine. 

Recently, a group of investigators published findings from the Human Epilepsy Project, a prospective, observational, multicenter study that verified the significant delays to diagnosis faced by individuals with focal epilepsy who experience disease onset through nonmotor seizures. Additionally, the work pointed to the morbidity-related consequences of these delays.

Between the 246 participants with nonmotor seizures and the 201 participants with motor seizures at epilepsy onset, those with nonmotor seizures experienced a delay in median time to diagnosis from first seizure tenfold that of those with motor seizures (

 <.001). As well, more patients with new-onset focal disease presented with initial nonmotor seizures than motor seizures (55% vs. 45%, respectively; 

For the total 447-patient study cohort, the median number of days from first seizure to diagnosis was 219 days. Those in the motor group reported a median time of 60 days compared to the drastically longer 616 days for those in the nonmotor group (

Lead investigator Jacob Pellinen, MD, assistant professor of neurology, University of Colorado School of Medicine, and colleagues noted that the possibility of overlooking the possibility of seizure, particularly during emergency department visits and after motor vehicle accidents. They observed that the majority of injuries reported by patients prior to diagnosis for those who presented initially with nonmotor seizures occurred in those who ultimately developed motor seizures (92 of 167 patients; 55.1%). Although the number of patients with injuries prior to diagnosis were similar, and the severity of those injuries not differ significantly, of 23 motor vehicle accidents reported, the vast majority (n = 19; 82.6%) occurred in patients with undiagnosed nonmotor seizures.

To find out more about the importance of the earlier identification of these patients and how physician and public education tools may be able to help bridge this large gap in treatment, 

 reached out to Pellinen for his perspective on what challenges remain.

: How important is it to educate physicians and patients on the signs of focal epilepsy to prevent situations such as these assessed in the study?

 Improving recognition of focal epilepsy, particularly when it manifests as non-motor seizures, will be critical in closing the treatment gap highlighted in our study. A major takeaway from our study is that there is substantial under-recognition of non-motor seizures by patients, family, and healthcare providers. Educational initiatives for the public, healthcare trainees, and healthcare professionals, would undoubtedly improve the lives of many people with new-onset focal epilepsy.

Are there challenges that stand in the way of that education?

There are a couple of barriers to improving education. One is related to research, and that is simply improving our understanding of what is happening and what can be done about it. This is what we are tackling in our work. The other barrier is obtaining support for educational initiatives, which requires time and resources to achieve at each level – for the public, healthcare trainees, and healthcare professionals. We are hoping that through our research, we can not only identify problems, but find solutions, and that this will help garner support for educational initiatives.

REFERENCE
Pellinen J, Tafuro E, Yang A, et al. Focal nonmotor versus motor seizures: The impact on diagnostic delay in focal epilepsy. 

. Published online October 20, 2020. doi: 10.1111/epi.16707

The lead investigator of the study and assistant professor of neurology at University of Colorado School of Medicine, Jacob Pellinen, MD, spoke to the importance of identifying nonmotor seizures.

Improving Education on Nonmotor Focal Seizure Identification

New data published at the Child Neurology Society and International Child Neurology Congress (CNS/ICNA) 2020 meeting suggest that treatment with fenfluramine (Fintepla; Zogenix) represents an important new treatment option for patients with Dravet syndrome and offers a favorable percentage of patients an opportunity to reduce monthly convulsive seizure frequency.

The first poster presentation explored fenfluramine’s efficacy and durability in treating Dravet syndrome in an open-label extensions (OLE) study, the findings of which demonstrated a median reduction in monthly convulsive seizures of 63% (

 The second poster’s results suggest that for every 2–3 patients treated with fenfluramine, 1 achieved a reduction in monthly convulsive seizure frequency of ≥50% or ≥75% compared with placebo (Cohen’s 

“In addition to the significant convulsive seizure reductions seen in all three multi-national phase 3 studies of Fintepla in Dravet syndrome, we are proud to collaborate with expert clinician investigators to show the durability of the clinically meaningful seizure reduction that FINTEPLA provided for patients treated for up to 2 years,” said Bradley S. Galer, MD, executive vice president and chief medical officer, Zogenix, in a statement.

 “Furthermore, new post-hoc data analysis from our studies demonstrated that for every 2 to 3 patients treated with Fintepla, 1 patient achieved ≥75% (profound) convulsive seizure reduction compared with placebo. We believe these new data analyses further showcase the clinical value that Fintepla provides for many Dravet syndrome patients and their families.”

The ongoing OLE assessment, known as Study 1503 (NCT02823145), included 330 patients with a mean age of 9 years (standard deviation [SD], 4.6) and a median treatment duration of 445 days. In total, 8% (n = 26) of patients received a mean daily dose of up to 0.2 mg/kg per day, while 27% (n = 90) received >0.2 mg/kg to <0.3 mg/kg, 37% (n = 123) received 0.3 mg/kg to 0.5 mg/kg, and 28% (n = 91) received >0.5 mg/kg to 0.7 mg/kg.

In total, 61.7% (n = 204) and 37.1% (n = 123) of patients reported a ≥50% and a ≥75% reduction in monthly convulsive seizure frequency, respectively, during the entire 2-year OLE period. Additionally, 1.9% (n = 6) patients reported complete seizure freedom, with a mean duration of 285 days (median, 193 days).

Additionally, fenfluramine was deemed generally well-tolerated, with the most common treatment-emergent adverse events (AEs) being nasopharyngitis (23.3%; n = 77), pyrexia (23%; n = 76), decreased appetite (21.2%; n = 70), and diarrhea (15.2%; n = 50). In total, 93.3% (n = 308) of patients reported an AE. No cases of valvular heart disease or pulmonary arterial hypertension were reported.

Anticonvulsants to Treat Epilepsy and Alternatives

The second poster featured a post hoc analysis that took data from phase 3 and long-term extension studies of fenfluramine for the treatment of Dravet syndrome in pediatric patients (NCT02682927/NCT02826863, NCT02926898, NCT02823145). The patient population included 119 total patients from Study 1 with monthly convulsive seizure frequency data at Visit 12 (roughly Week 14), and the corresponding Clinical Global Impression of Improvement (CGI-I) data for 112 caregivers and 114 investigators. Additionally, there were 53 patients in the OLE who completed ≥1 year of treatment and had both pre-randomization baseline and Year 1 Behavior Rating Inventory of Executive Function (BRIEF 2) data available. Patients were treated with 0.2 mg/kg per day, 0.7 mg/kg per day, or placebo.

All told, using Receiver operator characteristic (ROC) analysis per the investigator assessment of CGI-I, 25.6% and 52.5% of the low- and high-dose groups were deemed very much improved compared to 5% of the placebo group, with a reduction in monthly convulsive seizure frequency of 68%. This group was defined as deriving “profound” benefit. Likewise, the caregiver assessment of CGI-I, a “profound” benefit was achieved by 28.2% and 60% of the treatment groups, respectively, for a reduction of 60% in monthly convulsive seizures.

Patients who achieved what was defined as a “clinically meaningful” benefit were identical for both investigator and caregiver assessment of CGI-I. Those respective figures were 46.2% and 77.5% for the treatment groups and 12.5% for the placebo group, with a 44% reduction in monthly convulsive seizure frequency.

In a pooled analysis of active and placebo subjects at Year 1, more patients (24 of 53 patients; 45%) achieved profound (≥75%) compared to minimal (<25%) levels of monthly convulsive seizure frequency reduction (11 of 53 patients; 21%).

A profound reduction in monthly convulsive seizure frequency corresponded with the number-needed-to-treat of 2 to achieve these levels for patients receiving fenfluramine 0.7 mg/kg/day. In a second randomized controlled trial (Study 2), which assessed adjunctive fenfluramine in patients taking stiripentol), the number-needed-to-treat of 3 was observed at the ≥75% responder level.

REFERENCES
1. Zogenix Presents New Data for FINTEPLA® in Dravet Syndrome at CNS 2020. News release. Emeryville, CA. Zogenix. Published October 15, 2020. Accessed October 23, 2020. zogenixinc.gcs-web.com/news-releases/news-release-details/zogenix-presents-new-data-finteplar-dravet-syndrome-cns-2020
2. Sullivan J, Auvin S, Pringshelm M, et al. Long-Term (2-Year) Safety and Efficacy of Adjunctive ZX008 (Fenfluramine HCl) for Dravet Syndrome: Interim Results of an Ongoing Open-Label Extension Study. Presented at CNS 2020. PL30.
3. Sullivan J, Dlugos D, Nabbout R, et al. Number needed to treat (NNT) with fenfluramine to achieve a clinically meaningful reduction in convulsive seizure frequency in patients with Dravet syndrome. Presented at CNS 2020. PL31.

A number of poster presentations suggest that fenfluramine (Fintepla; Zogenix) offers a high percentage of patients with Dravet syndrome an opportunity to reduce monthly convulsive seizure frequency

Fenfluramine Shows Durability in Monthly Convulsive Seizure Reduction

Epilepsy is a chronic neurologic disorder resulting in unpredictable, unprovoked, recurrent seizures that affect mental and physical functions. Antiepileptic drug therapy aims to eliminate or reduce seizure frequency, minimize adverse effects during long- term treatment, and help patients maintain a normal lifestyle.

 Existing antiepileptic drugs function by decreasing the electrical activity of the brain, either by preventing neuronal depolarization via modulation of ion channels, inhibiting excitation mediated by the neurotransmitter glutamate, or promoting inhibition mediated by γ-aminobutyric acid.

 Selecting the appropriate drug therapy for epilepsy management necessitates an understanding of the disorder’s natural history and treatment response profile.

Despite the availability of antiepileptic drugs, there are few if any approved therapies for rare developmental and epileptic encephalopathies (DEEs), which are associated with severe cognitive and developmental impairment in addition to frequent treatment-refractory seizures. For example, patients with Dravet syndrome typically present with seizures before 18 months of age that are often refractory to treatment, while those with Lennox-Gastaut syndrome experience up to hundreds of intractable seizures per day of various subtypes, often the result of hypoxic brain injury, cerebral dysgenesis, or neurocutaneous disorders, among other etiologies.

 Patients with CDKL5 deficiency disorder have reduced or altered CDKL5 protein in neurons, resulting in treatment-resistant tonic-clonic or tonic seizures that begin in infancy.

 Given the significant morbidity associated with these syndromes,

 novel therapies are necessary to address comorbidities while altering the course of the disease.

Cholesterol 24-hydroxylase, a central nervous system–specific enzyme encoded by the CYP46A1 gene and expressed in cell bodies and dendrites of neurons,

 is a promising target for treatment of brain disorders, including epilepsy. Cholesterol is particularly enriched in mammalian brains, indicating that this sterol is essential for proper brain development and function. Indeed, cholesterol is a neurosteroid precursor and key component of eukary-otic membranes, with 70% found in myelin sheaths of white matter and 30% in glial cells and subcellular membranes of neurons of gray matter.

 Due to the impermeability of the blood-brain barrier to lipoproteins, brain cholesterol is derived almost exclusively from in situ biosynthesis. Excess cholesterol is then extruded from the brain after hydroxylation by cholesterol 24-hydroxylase

 to yield the rapidly diffusible 24(S)-hydroxycholesterol (

 24(S)-hydroxycholesterol has a direct impact on synaptic plasticity by modulating N-methyl-D-aspartic acid (NMDA) receptors, implicating cholesterol 24-hydroxylase in memory and learning.

 This maintenance is crucial for neuronal cholesterol homeostasis, with abnormalities implicated in neurodegenerative disorders, including Alzheimer disease, Parkinson disease, and Huntington disease.

Both inhibition and activation of cholesterol 24-hydroxylase exhibit therapeutic potential.

 Increasing cholesterol 24-hydroxylase expression in a mouse model of Huntington disease reduced the number and size of intranuclear protein aggregates by activating autophagy, improving motor impairment.

 Downregulation of the enzyme in the adult mouse hippocampus via RNA interference conversely led to increased neuronal cholesterol concentration due to reduced efflux, although cholesterol biosynthesis was unaffected.

Despite the continual epilepsy treatment landscape growth, there are only a few if any approved therapies for rare developmental and epileptic encephalopathies. 

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