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

Clinical Viewpoint

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

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.

Features

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

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/

Letter From the Editor

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

Telemedicine: An Opportunity to Bring Better Care to All

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.

 Several types of phospholipids, such as structural glycerophospholipids and sphingolipids, were also increased in the brains of these mice.

 However, knockout mice lacking cholesterol 24-hydroxylase from birth maintained normal levels of cholesterol in the brain despite decreased efflux by reducing cholesterol synthesis.

 A reduction in cholesterol 24-hydroxylase levels modulates brain NMDA receptors to reduce downstream glutamate signaling pathway activity, consequently reducing the number and severity of seizures. Cholesterol 24-hydroxylase inhibition may therefore be useful for treatment of patients with rare DEEs.

Soticlestat (TAK-935/OV935; Takeda Pharmaceuticals, Ovid Therapeutics) is a potent, highly selective, first-in-class inhibitor of cholesterol 24-hydroxylase that is currently in phase 2 studies for treatment of rare DEEs. Results from the phase 2, multicenter, open- label ARCADE study (NCT03694275) and the phase 2, prospective, interventional, open-label, multicenter extension ENDYMION study (NCT03635073) in patients with CDKL5 deficiency disorder (CDD) and Dup15q syndrome were recently announced,

 showing seizure reduction over time. In patients with CDD (n = 12), median motor seizure frequency was reduced by 24% during the 12-week maintenance treatment period in ARCADE, which increased to a 50% reduction in ENDYMION in the 5 patients who completed 9 months of continuous treatment. Notably, patients with Dup15q syndrome (n = 8) recorded an increase in median motor seizure frequency during the ARCADE study; however, after 9 months of continuous treatment through the ENDYMION study (n = 4), a 74% reduction in median motor seizure frequency was recorded. Notably, all patients who completed the ARCADE study elected to roll over into ENDYMION, with a consistent safety and tolerability profile observed throughout both studies.

In addition, topline results from the phase 2, multicenter, randomized, double-blind, placebo-controlled ELEKTRA clinical trial (NCT03650452), which assessed soticlestat treatment
in patients age 2 to 17 with Dravet syndrome or Lennox-Gastaut syndrome, showed that the study met its primary end point, demonstrating a statistically significant reduction in seizures from baseline compared with placebo (P = .0007) in Dravet syndrome and numeric, but not statistically significant reductions in patients with Lennox-Gastaut syndrome.

 Specifically, a 27.8% median reduction from baseline in convulsive and drop seizure frequency compared with a 3.1% median increase in the placebo group was recorded during the 12-week maintenance period, with a 29.8% reduction recorded for the full 20-week treatment period. Results in the Dravet syndrome cohort, which showed a 33.8% median reduction in convulsive seizures compared with a 7.0% median increase in the placebo group, have propelled Ovid to pursue initiation of a phase 3 registrational program for the drug in this patient population.17 Incidence of treatment-emergent adverse events was similar between the treatment and placebo groups, with lethargy and constipation reported most frequently in those treated with the study drug. Notably, all patients who completed ELEKTRA elected to roll over to the ENDYMION extension study, early results from which indicate that treatment effect in patients originally randomized to receive soticlestat have been maintained over 6 months, with similar seizure frequency reductions observed in those originally assigned to placebo.

Based on these results, cholesterol 24-hydroxylase inhibition as epilepsy treatment appears promising, so long as preci- sion dosing and efficacy duration are well understood. The results of the ENDYMION study will reveal the tolerability of soticlestat and its effects on seizure frequency reduction after long-term use. Meanwhile, other classes of epilepsy drugs, including cannabidiol (Epidiolex; GW Pharmaceuticals), have already been approved for treatment of severe DEEs.

 Going forward, an assessment of the implication of cholesterol accumulation resulting from cholesterol 24-hydroxylase inhibition, in terms of neuronal death in humans, is also warranted due to observations that inhibiting this enzyme resulted in epileptic behavior, including seizures, paralleled by neuronal loss in the mouse hippocampus

 Overall, cholesterol 24-hydroxylase remains justified as a therapeutic target, so long as investigators are cognizant of the full effects of cholesterol 24-hydroxylase inhibition on brain cholesterol metabolism in cell types, specific brain regions, and the whole brain.

1. Goldenberg MM. Overview of drugs used for epilepsy and seizures: etiology, diagnosis, and treatment. P T. 2010;35(7):392-415.

2. Stafstrom CE, Carmant L. Seizures and epilepsy: an overview for neuroscientists. Cold Spring Harb Perspect Med. 2015;5(6). doi:10.1101/cshperspect.a022426

3. CDKL5 deficiency disorder. Genetics Home Reference. Accessed August 25, 2020. https://ghr.nlm.nih.gov/condition/cdkl5-deficiency-disorder

4. Ramirez DMO, Andersson S, Russell DW. Neuronal expression and subcellular localization of cholesterol 24-hydroxylase in the mouse brain. J Comp Neurol. 2008;507(5):1676-1693. doi:10.1002/cne.21605

5. Petrov AM, Pikuleva IA. Cholesterol 24-Hydroxylation by CYP46A1: Benefits of Modulation for Brain Diseases. Neurotherapeutics. 2019;16(3):635-648. doi:10.1007/s13311-019-00731-6

6. Dietschy JM, Turley SD. Thematic review series: Brain lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res. 2004;45(8):1375-1397. doi:10.1194/jlr.R400004-JLR200

7. Mast N, Norcross R, Andersson U, et al. Broad substrate specificity of human cytochrome P450 46A1 which initiates cholesterol degradation in the brain. Biochemistry. 2003;42(48):14284-14292. doi:10.1021/bi035512f

8. Lutjohann D, Breuer O, Ahlborg G, et al. Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation. Proc Natl Acad Sci. 1996;93(18):9799-9804. doi:10.1073/pnas.93.18.9799

9. Lund EG, Guileyardo JM, Russell DW. cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain. Proc Natl Acad Sci. 1999;96(13):7238-7243. doi:10.1073/pnas.96.13.7238

10. Paul SM, Doherty JJ, Robichaud AJ, et al. The major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of n-methyl-d-aspartate receptors. J Neurosci. 2013;33(44):17290-17300. doi:10.1523/JNEUROSCI.2619-13.2013

11. Djelti F, Braudeau J, Hudry E, et al. CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer’s disease. Brain. 2015;138(8):2383-2398. doi:10.1093/brain/awv166

12. Ayciriex S, Djelti F, Alves S, et al. Neuronal cholesterol accumulation induced by Cyp46a1 down-regulation in mouse hippocampus disrupts brain lipid homeostasis. Front Mol Neurosci. 2017;10. doi:10.3389/fnmol.2017.00211

13. Nóbrega C, Conceição A, Costa RG, et al. The cholesterol 24-hydroxylase activates autophagy and decreases mutant huntingtin build-up in a neuroblastoma culture model of Huntington’s disease. BMC Res Notes. 2020;13(1):210. doi:10.1186/s13104-020-05053-x

14. Burlot M-A, Braudeau J, Michaelsen-Preusse K, et al. Cholesterol 24-hydroxylase defect is implicated in memory impairments associated with Alzheimer-like tau pathology. Hum Mol Genet. 2015;24(21):5965-5976. doi:10.1093/hmg/ddv268

15. Lund EG, Xie C, Kotti T, Turley SD, Dietschy JM, Russell DW. Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover. J Biol Chem. 2003;278(25):22980-22988. doi:10.1074/jbc.M303415200

16. Ovid Therapeutics provides soticlestat (OV935/TAK-935) results from ARCADE and ENDYMION studies showing seizure reduction in rare epilepsies. News release. Ovid Therapeutics. September 30, 2020. Accessed October 2, 2020. https://www.globenewswire.com/news-release/2020/09/30/2101306/0/en/Ovid-Therapeutics-Provides-Soticlestat-OV935-TAK-935-Results-from-ARCADE-and-ENDYMION-Studies-Showing-Seizure-Reduction-in-Rare-Epilepsies.html

17. Phase 2 ELEKTRA study of soticlestat (TAK-935/OV935) meets primary endpoint reducing seizure frequency in children with Dravet syndrome or Lennox-Gastaut syndrome. News release. Ovid Therapeutics. August 25, 2020. Accessed October 2, 2020. https://investors.ovidrx.com/news-releases/news-release-details/phase-2-elektra-study-soticlestat-tak-935ov935-meets-primary

18. FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy. News release. US Food and Drug Administration. June 25, 2018. Accessed October 2, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms

19. Chali F, Djelti F, Eugene E, et al. Inhibiting cholesterol degradation induces neuronal sclerosis and epileptic activity in mouse hippocampus. Eur J Neurosci. 2015;41(10):1345-1355. doi:10.1111/ejn.12911

NeuroPathways

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

Inhibiting Cholesterol 24-Hydroxylase for Epilepsy Treatment

Technological developments over the past decade are now leading to long-awaited advances in the management of Parkinson disease (PD). These tech-driven approaches—including exergaming, virtual reality, and the use of wearable devices—have not only helped improve rehabilitation but may also provide more accurate measures of therapeutic efficacy for new treatments undergoing clinical trials.

The role of virtual reality and exergaming in PD physiotherapy

Virtual reality has been used to drive purposeful, targeted exercise therapy for a number of progressive disorders affecting muscular function, including traumatic brain injury, cerebral palsy, stroke, and PD.

 Virtual reality–based games are available on widely available gaming systems and have demonstrated specific benefits for improving balance, gait, functional mobility, and overall quality of life for individuals with PD.

 Results of a recent study from Brazil showed that the weekly addition of Nintendo Wii exercises significantly magnified the therapeutic effects of conventional exercise therapy alone.

Exergaming, virtual reality, augmented reality, and their variants come in many shapes and sizes, said Jeffrey Hausdorff, PhD, director at the Center for the Study of Movement, Cognition, and Mobility at the Neurology Institute at the Sourasky Medical Center in Tel Aviv, Israel, who has been involved in many of the trials of digital technologies for PD. “In general, interventions based on these technologies can be very helpful as ways of enhancing and augmenting the impact of other, more conventional behavioral interventions for Parkinson disease. Engaging ‘games’ can heighten motivation and increase [adherence]; this in turn leads to a stronger impact of the therapy. They can also provide specific aspects of therapy that may be difficult to deliver otherwise,” he told 

In one multicenter, randomized, controlled study (RCT) designed to examine the added value of a relatively simple virtual reality system, Hausdorff explained that subjects walk on a treadmill with a screen attached to it that allows them to envision themselves walking through an environment with obstacles and challenging conditions where they have to learn implicitly, in a game-like fashion, how to walk and do other things at the same time, including dual tasks such as motor and cognitive challenges.

 In another study that included older adults as well as patients with PD, Hausdorff and colleagues found a significant reduction in falls among the participants who trained with a treadmill and virtual reality system compared with an active control group who performed treadmill training alone.

 “With this type of system, we can target certain aspects of cognitive function that are important to daily walking and cannot be targeted with treadmill training alone,” he said.

Managing progression in Parkinson disease

Long-term management of PD presents many clinical challenges as the status of the patient deteriorates over time. “In the early phases of the disease, typically patients respond well to pharmacotherapies,” explained Paolo Bonato, PhD, director of the Motion Analysis Laboratory at Spaulding Rehabilitation Hospital in Boston, Massachusetts, “but unfortunately, as the disease progresses, it 

becomes more difficult to control their symptoms.” Patients often report experiencing a roller coaster of parkinsonian symptoms, recognized clinically as motor fluctuations. Bradykinesia might respond well to treatment, but patients might experience severe dyskinesia as a result.

“A significant portion of patients with Parkinson disease experience motor fluctuations, meaning their symptoms are not constant over time,” Bonato said. The severity of dyskinesia often varies within the interval between medication intakes; patients might experience episodes within the first hour of taking their medication (onset dyskinesia), at the peak of the medication’s effects, or at the end, as the effects are wearing off. These symptoms are quite disruptive to their ability to perform activities of daily living, Bonato noted, and they are a significant focus of clinical attention during the later years of the disease.

Although levodopa-induced dyskinesia is a common complication in PD, recent research indicates that dyskinesias develop as a function of disease duration rather than accumulation of levodopa. This has led to recommendations to initiate levodopa therapy without delay early in the disease course, but the problem with motor fluctuations remains once the disease progresses.

Bonato observed that as neurologists titrate the patients’ medications to better manage their symptoms, a major challenge is that patients do not have an objective perception of their motor status, in part because of the cognitive effects of their disease. Patients are simply not able to report reliably on the effects of changes in the medication regimen. But more than that, Bonato pointed out that proper assessment of the severity of symptoms is very challenging, even to clinicians. “In fact, clinical researchers undergo training to administer the MDS-UPDRS [International Parkinson and Movement Disorder Society Parkinson’s disease rating scale], which is the clinical scale to assess the severity of parkinsonian symptoms that is most commonly used,” he said. 

Wearable technology has been able to detect fluctuations occurring in increments of as little as 5 minutes compared with 

patient-reported symptoms in diaries, which monitor changes at only 30-minute intervals at best, according to Bonato, who plans to publish these data soon.

"We used to think that walking was primarily a motor ability that required intact muscle and skeletal function and sensory function for feedback. Those abilities are certainly critical components of safe ambulation. However, there’s a key ingredient that’s missing in that view, and that’s cognitive function," Hausdorff stated. 

Falling is a complex type of dysfunction that involves multiple aspects of cognition. “Safe ambulation also involves executive function, a set of higher-level cognitive functions that include the ability to walk and multitask and the ability to plan and adapt to one’s environment,” Hausdorff explained. “We used to think that walking was primarily a motor ability that required intact muscle and skeletal function and sensory function for feedback,” he said. “Those abilities are certainly critical components of safe ambulation. However, there’s a key ingredient that’s missing in that view, and that’s cognitive function.”

Some of his studies looked at the role of cognition in helping the patient maintain attention to tasks of mobility.

 “The virtual reality technology that we evaluated in the RCT mirrors many real-world walking situations, such as walking outdoors, which requires being able to do multiple things while walking, such as listening to head- sets, talking to companions, thinking about what we’re going to be doing next, and negotiating obstacles. If you just walk on a treadmill alone without that added virtual reality component, it’s training just for the motor part while not focusing at all on the cognitive aspects of walking that are needed for safe ambulation,” Hausdorff said.

Freezing gait is a significant problem in advanced PD, in which motion advancement is very small or does not occur at all. Results of recent studies have indicated that freezing is not limited to gait but can also significantly hinder upper limb movements and speech.

 Digital technologies have been extensively studied as cueing modalities to recover attention to specific motor tasks, to rescue the patient from a freezing episode.

Hausdorff and Alice Nieuwboer, PhD, of the University of Leuven in Belgium, are currently collaborating on a study funded by the Michael J. Fox Foundation for Parkinson’s Research designed to detect a freezing event. In this study, subjects wear a sensor on their shoes that measures the movement of their feet and any freezing events as they conduct their daily activities. The sensor’s information is wirelessly transmitted to a smartphone that measures walking in real time. The system is designed to detect when a freezing event occurs and then give a cue back to the user, helping the user to quickly become free from the event. “In the future, it’s hoped that it will also be able to warn of a freezing event before it occurs to further ameliorate the problem,” Hausdorff said.

One of the unique aspects of this study is that all the assessments are conducted in the patient’s home and the intervention takes place throughout the day, wherever and whenever the patient walks. “Testing and treating in the home is especially advantageous at this time, when it is often increasingly difficult for people to make their way to a clinic or hospital,” Hausdorff said.

A primary obstacle to many clinical trials of the 1980s and 1990s that may have contributed to negative results, according to Bonato, was the inaccuracy of the self-reported data being collected from patients. He and colleagues

 published a study early in 2020 that made a strong case for the use of wearable technologies to replace patient diaries in making treatment decisions as well as in clinical trials.

"There are 2 problems with the use of patient diaries,” Bonato stated. “The first and more obvious one is that patients display poor [adherence] with the use of diaries. We know that because we track when patients log on to fill out electronic diaries, and hence we know that they are not doing that on a regular basis. The second and perhaps even more important issue is that we have discovered that motor fluctuations evolve more rapidly than we originally thought. Therefore, gathering data at intervals of 30 minutes, as we do by using patient diaries, is not enough to properly capture the characteristics of the motor fluctuations that patients experience.”

Because clinical trials have relied heavily on patient diaries as measurements for outcomes, this new finding is highly significant. Bonato observed that pharmaceutical companies have started wondering whether the negative results of past clinical trials were the by-product of not having access to the right technology to capture the effects of medications on motor fluctuations. “I anticipate that the large body of work in this area will result in important advances in the field and better treatments for patients with Parkinson disease,” he added.

A multinational task force on technology from the MDS convened in 2018 to produce a set of objectives for the use of digital technologies to obtain more usable data to inform treatment decisions.

 They reported that development of mobile digital devices has reached sufficient levels of “sophistication, versatility, and wearability” to warrant recommending their implementation in routine care for patients with PD.

 With different technologies offering opportunities to improve quality of life and outcomes for patients as they begin to develop advanced symptoms, these tools are increasingly being recognized as necessary supportive therapies over the long term.

"Clinicians, researchers, and pharmaceutical companies are very interested in using wearable technology,” Bonato said. “Clinicians are hoping that this technology may lead to significant improvements in the clinical management of symptoms experienced by patients, and researchers are adopting the technology to collect more reliable data and hence improve their ability to study the effects of new therapies.”

1. Barry G, Galna B, Rochester L. The role of exergaming in Parkinson’s disease rehabilitation: a systematic review of the evidence. J Neuroeng Rehabil. 2014;11:33. doi:10.1186/1743-0003-11-33.

2. Santos P, Machado T, Santos L, Ribeiro N, Melo A. Efficacy of the Nintendo Wii combination with conven- tional exercises in the rehabilitation of individuals with Parkinson’s disease: a randomized clinical trial. NeuroRehabilitation. 2019;45(2):255-263. doi:10.3233/NRE-192771

3. Garcia-Agundez A, Folkerts AK, Konrad R, et al. Recent advances in rehabilitation for Parkinson’s disease with exergames: a systematic review. J Neuroeng Rehabil. 2019;16(1):17. doi:10.1186/s12984-019-0492-1

4. Mirelman A, Maidan I, Herman T, Deutsch JE, Giladi N, Hausdorff JM. Virtual reality for gait training: can it induce motor learning to enhance complex walking and reduce fall risk in patients with Parkinson’s disease? J Gerontol A Biol Sci Med Sci. 2011;66(2):234-240. doi:10.1093/gerona/glq201

5. Mirelman A, Rochester L, Reelick M, et al. V-TIME: a treadmill training program augmented by virtual reality to decrease fall risk in older adults: study design of a randomized controlled trial. BMC Neurol. 2013;13:15. doi:10.1186/1471-2377-13-15

6. Espay AJ, Morgante F, Merola A, et al. Levodopa-induced dyskinesia in Parkinson disease: current and evolving concepts. Ann Neurol. 2018;84(6):797-811. doi:10.1002/ana.25364

7. Maidan I, Nieuwhof F, Bernad-Elazari H, et al. Evidence for differential effects of 2 forms of exer- cise on prefrontal plasticity during walking in Parkinson’s disease. Neurorehabil Neural Repair. 2018;32(3):200-208. doi:10.1177/1545968318763750

8. Ginis P, Nackaerts E, Nieuwboer A, Heremans E. Cueing for people with Parkinson’s disease with freezing of gait: a narrative review of the state-of-the-art and novel perspectives. Ann Phys Rehabil Med. 2018;61(6):407-413. doi:10.1016/j.rehab.2017.08.002

9. Erb MK, Karlin DR, Ho BK, et al. mHealth and wearable technology should replace motor diaries to track motor fluctuations in Parkinson’s disease. NPJ Digit Med. 2020;3:6. doi:10.1038/s41746-019-0214-x

10. Espay AJ, Hausdorff JM, Sánchez-Ferro Á, et al. A roadmap for implementation of patient-centered digital outcome measures in Parkinson’s disease obtained using mobile health technologies. Mov Disord. 2019;34(5):657-663. doi:10.1002/mds.27671

Advances in wearables and virtual reality present an opportunity to maximize rehabilitative efforts and improve outcomes.

The Technology Behind Optimizing Parkinson Disease Management

The treatment landscape for Duchenne muscular dystrophy (DMD) continues to be quite lively, as the FDA recently approved viltolarsen (Viltepso; NS Pharma) for patients with DMD amenable to exon 53 skipping, marking only the second FDA-approved therapy for the DMD gene mutation that affects 8% to 10% of patients.1 Additionally, the agency recently granted orphan drug designation to Vita Therapeutics’ VTA-110, an allogeneic induced pluripotent stem cell–based therapy, as it advances to human trials

; and Catabasis’ oral small molecule NF-kB inhibitor, edasalonexent, was deemed well tolerated in the phase 2 MoveDMD trial.

Although the increased activity in the DMD drug pipeline could mean more effective disease-modifying treatments in the near future, the current approach to treatment relies on large teams of multidisciplinary physicians and other health care professionals who offer comprehensive, symptomatic disease management.

Challenges of the multisystem impact of DMD require a collaborative and mixed-specialty approach in its management. To learn more about the care that is provided by the team, several experts in DMD recently came together to share their thoughts in the 

“Management of Duchenne Muscular Dystrophy.”

Mechanistically, DMD disrupts the production of dystrophin, the lack of which impacts muscle function throughout the body. This functional deficit is at the root of the requirement for patients’ multidisciplinary management.

“We see weakness in the arms and legs, weakness of the respiratory muscles, and we see an impact, as well, to the cardiac muscles,” said

, pediatric neuromuscular neurologist at Children’s Hospital of The King’s Daughters in Norfolk, Virginia. “In addition, we can’t forget about the muscles that allow us to do things like chew and swallow, and those that impact bowel and bladder habits. So, it really requires a comprehensive team to be able to care for the patients with DMD.”

Proud noted that her institution’s DMD team includes herself as well as a physiatrist, who helps provide accommodations to patients that can improve their overall quality of life and their ability to participate in activities of daily living; these apparatuses include wheelchairs, transfer boards, back chairs, and braces.

Additionally, depending on the patient, the team can include physical and occupational therapists, a pulmonologist, a cardiologist, an orthopedist, an endocrinologist, an educational liaison, a dietician, and social workers. Occasionally, the team expands to include surgeons as well.

A patient’s physical therapy regimen often includes routine standardized testing to track progression, which helps detect any functional decline, Proud explained. Progression, in turn, can trigger changes in supportive care recommendations. The test results also allow the occupational therapist to provide guidance for patient accommodations at home or school.

Experts in the diagnosis and treatment of Duchenne muscular dystrophy share their perspectives on the complex care of this patient population in the NeurologyLive® Insights series “Management of Duchenne Muscular Dystrophy.”

October 2020

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

Stimulating the Future of Treating Sleep-Disordered Breathing

Telemedicine: An Opportunity to Bring Better Care to All

Inhibiting Cholesterol 24-Hydroxylase for Epilepsy Treatment

The Technology Behind Optimizing Parkinson Disease Management

It Takes a Village: Multidisciplinary Management of DMD

Building Your Acute Migraine Toolbox

Evobrutinib Paves the Way for BTK Inhibitors in Multiple Sclerosis

Advanced Imaging for Extended Stroke Treatment