Although levodopa remains the gold standard therapy in the treatment of Parkinson disease, patients often face an unpredictable waxing and waning of treatment effect. This phenomenon, referred to as OFF time, can have a debilitating impact on quality of life.

The best methods to address OFF episodes are often hotly debated, and a therapeutic pipeline for these episodes is underway. Currently, physicians have some management options to balance these transition periods between levodopa doses, although these options do have limitations.

To add to the conversation about the management of OFF episodes, NeurologyLive® was joined by a panel of movement disorder experts led by Daniel E. Kremens, MD, JD, codirector, Parkinson’s Disease and Movement Disorders Program, and associate professor of neurology, Sidney Kimmel Medical College, Thomas Jefferson University in Philadelphia, Pennsylvania. Kremens led a discussion covering a number of topics, beginning with the goals of OFF episode management in patients with Parkinson disease.

As Stuart Isaacson, MD, director, Parkinson’s Disease and Movement Disorder Center of Boca Raton in Florida quickly pointed out, the first deter- mination made by the physician is the goals of management: defining the amount of attention OFF episodes should require, what the goal of treatment will be, and if any OFF time is acceptable.

The goal, Rajesh Pahwa, MD, the Laverne and Joyce Rider professor of neurology, chief, Parkinson’s Disease and Movement Disorder Division, and director, Parkinson’s Foundation Center of Excellence, University of Kansas Medical Center, noted, should be to get patients to no OFF time, although, he admitted the bar is set high.

“It’s like asking me or you, ‘Well, during the day, would be it OK if you couldn’t function well for an hour?,’” Pahwa explained. “We’re all going to say, ‘No, absolutely not. I want to function all day long.’ And especially if I told you the hour could happen sometime during the day, but I can’t tell you when it’s going to happen.”

One of the approaches to possibly address this phenomenon was continuous delivery of levodopa through the gastro-intestinal tract. The panel noted that although there has been some succes, data from a double-blind, placebo-controlled trial revealed that through a 3-month treatment period, OFF time was still occurring as reported in patient diaries. For patients with severe OFF periods, reduced OFF time with lower severity may come as a comparative relief. Deep brain stimulation has also been shown to allow for better function during OFF time, but not completely eliminate it.

“That’s why I go back to it’s the severity of OFF,” Pahwa said, noting that if the OFF effects are limited to a symptom such as light sleepiness, a patient may be able to overcome it with a solution as simple as a cup of coffee. However, if dopamine wears off and that causes significant impairment for the patient, the physician must address it.

“Sometimes, I try to give an analogy to patients to try to gauge the severity by thinking about driving to the store,” Isaacson said. “If the roads are open, you get there easily. But now, you have some traffic and it takes you longer. And this may be a degree of slowness. Sometimes, you get into a traffic jam and you don’t move at all, and you’re completely OFF.”

The key, Isaacson said, is getting patients to understand that there may be degrees of response to both medicine and OFF periods. This is often achieved through shared decision making with the patient. Peter LeWitt, MD, MMedSc, director, Parkinson’s Disease and Movement Disorders Program, Henry Ford Hospital, and professor of neurology, Wayne State University School of Medicine in Detroit, Michigan, explained the resulting cost-benefit ratio.

“You may have to keep up with a more compli- cated schedule,” LeWitt said. “You may have to anticipate an adverse effect like dyskinesia if you’re loading up on extra medicine. But if your goal is to get to that store and not miss the sale, that’s an important part of patient decision making.”

The decision-making process regarding how to use medications is a complex interaction, LeWitt said. The physician needs to know how much involvement the patient wants in providing feedback and how much they want their family to be observers of their life to look out for signs that might require medical attention. With limited time, clinicians must work with every tool they have, including nurse prac- titioners, home diaries, and patient portals, among others.

“It really shows the value of shared clinical decision making,” Isaacson said. “While sometimes it’s hard to share, or there’s not enough time to share fully, patients have to be involved in this decision making. We can’t always judge, by knowing OFF, whether OFF needs to be treated for that patient.”

Kremens said that the ultimate goal is to set realistic expectations “Even with optimal management, sometimes the road is closed,” Kremens said. “There are issues with the blood—brain barrier that need to be addressed with Parkinson. So even with the best therapies, optimized medicine, some patients are still going to experi- ence these episodes.”

The panelists then shifted the discussion toward different management options with adjunctive dopamine agonists. Isaacson noted that although much of the past approach has been aimed at finding the optimal dose level, spacing, and fractionating, adjunctive options have now made their way to the physician’s arsenal.

These medicines include once-per-day therapies as well as on-demand treatments, and although the decisions to use either vary, one thing is certain, as Pahwa pointed out. Adding in more levodopa, while effective, ultimately leads to more fluctuation and more OFF time.

“We have to think about all of these different ideas and then also think about the mechanisms of OFF and the value, sometimes, for patients in using a nonoral medication,” Isaacson said. “Now we have a new era that’s going to be heralded with infusion therapies, where we try to keep patients ON all the time—and management is complicated.”

Jill M. Giordano Farmer, DO, MPH, assistant professor of neurology and director, Parkinson’s Disease and Movement Disorder Program, Global Neurosciences Institute in Philadelphia, Pennsylvania, explained that one of the ways to distill the complexity is to begin with the amount of OFF time occurring. This, she said, can lead to differing decision-making paths.

“Ideally speaking, if our goal is to not necessarily eliminate OFF but to practically manage it as best as possible, the best option might not necessarily be an on-demand. It might just need to be a revamp of the scheduling of the medications that they’re already on,” Giordano Farmer said.

Isaacson and LeWitt mentioned that challenges with adherence can also come up with additional dosing, and Pahwa noted that even long-acting preparations, which can address that adherence issue, are accompanied by their own set of obstacles. There are other therapeutic classes as well, such as dopamine agonists, monoamine oxidase-B (MAO-B) inhibitors, and catechol-o-methyl transferase (COMT) inhibitors, as Giordano Farmer pointed out.

Pahwa noted 2 major challenges with dopamine agonists: hallucination issues with older patients and compulsive disorders in younger ones. He explained that the literature suggests up to 20% of patients on dopamine agonists can have gambling, shopping, sexual, and other compulsions, which often go unmentioned—a generalization, for sure, but a possibility, the panel declared.

“But there isn’t evidence that they protect against motor fluctua- tions or dyskinesias, as was the past marketing-driven hope, which tells us that they are adjunctive therapies that are quite useful,” LeWitt said. “They clearly have a much longer duration of action, even in oral forms. But they join the COMT and MAO-B inhibitors as other ways to stretch out the effects of levodopa. This is the bottom line that comes from studies. Another thing that many clinicians may not be aware of is, probably sometime in the next year or 2 in the United States, we may have another COMT inhibitor as well as a once-a-day therapy that could also help us treat OFF time.”

Kremens raised the use of nondopaminergic agents, which include those such as the adenosine A2A receptor antagonist istradefyl-line, which has been shown to improve ON time for patients who are taking multiple medications. This is coupled by the fact that it is better tolerated than the MAO-B inhibitors, there are no drug inter- actions, and the effect appears to be fairly rapid in onset. As LeWitt puts it, it offers a sort of an “all-or-none” effect.

The 1 downside that is obvious, the group pointed out, is the possible enhancement of dyskinesia throughout treatment. “And of course, what do you do with dyskinesias? You lower the levodopa dose,” LeWitt said.

In addition, amantadine, in both immediate-release and extended-release formulations (along with a bedtime high dose), is available for physicians to prescribe. Isaacson pointed out that glutamatergic mechanisms are also a rational way of thinking about treatment.

“The fascinating thing, to me, is it improves OFF time in patients who are on all these other medications in the studies,” LeWitt said. “It’s a unique additive effect, or synergistic effect—it isn’t this choice or the other. Going back to the notion of polypharmacy sort of makes sense if you read into the studies and look at what patients have been tested with. They’ve been on a lot of different drugs, but they do better.”

Amantadine’s extended-release formulation was shown in bedtime studies to decrease OFF time and dyskinesia and is the only medication to do so.

“The other interesting part is, when we looked at studies for which we started drugs for OFF time, patients have 6 hours of OFF time, but when we look at a drug for dyskinesias, patients only had 3 hours of OFF time,” Pahwa pointed out. “In spite of 3 hours, we

were able to reduce it by 1 hour. Now whether that is because these patients were more optimally treated or whether the drug had unique nondopaminergic effects, we don’t know. But it brings up an interesting point, that every patient out there doesn’t have 6 hours of OFF time when they get put in a clinical trial. I think those are the ones who are really undertreated. If we are treating them adequately and the dyskinesia is an issue, their OFF time is also less.”

This is all part of the balancing act, Isaacson noted. Those with OFF time will also invariably have dyskinesia at a certain levodopa dose, and likewise, patients with dyskinesia, at a lower dose, will have OFF time. The positive, Kremens said, is that the nondopa- minergic therapies and infusion therapies give physicians another way of addressing the symptoms.

To view the entire Peer Exchange, “Managing OFF Episodes in Parkinson Disease,” 

Articles

NeurologyLive Insights

An overview on the Peer Exchange series, "Managing OFF Episodes in Parkinson disease."

Addressing OFF Episodes in Parkinson Disease Management

According to the World Health Organization, the estimated global prevalence of dementia is currently 50 million, and approximately 15 million strokes occur worldwide each year.

 The incidence of both conditions has increased substantially in recent decades, and further increases are expected as the elderly population continues to expand.

Ongoing research highlights the significant role of cerebral small vessel disease (CSVD) in the pathogenesis of dementia and stroke, with some findings showing that CSVD accounts for up to 45% and 25% of cases, respectively.

 “There is very strong evidence that CSVD, when present, contributes to cognitive decline and dementia. CSVD also results in worse cognitive impairment and slower recovery in people with stroke,” Argye Elizabeth Hillis, MD, professor of neurology, executive vice chair of neurology, and director of the cerebrovascular division at Johns Hopkins University School of Medicine, told NeurologyLive®.

In a study published in 2018 in Stroke, researchers examined links between a CSVD sum score and dementia, stroke, and mortality in 1651 individuals (mean age, 73.3 years; 54.5% women) with no history of stroke or dementia at baseline.

0 to 4 based on the presence or absence of 4 magnetic resonance imaging (MRI) markers: white matter hyperintensities, lacunae, cere- bral microbleeds (CMs), and perivascular spaces.

After undergoing brain MRI in 2005 through 2011, participants were followed until 2016 and 2017, for a mean follow-up period of 7.2 years. The results showed that a higher CSVD sum score on MRI was associated with an elevated risk of stroke, dementia, and death after adjusting for age, sex, and Framingham Stroke Risk Profile predictors such as coronary heart disease, atrial fibrillation, diabetes, and smoking. For each 1-point increase in the CSVD sum score, the adjusted hazard ratios were 1.54 (95% CI, 1.16-2.03) for stroke, 1.25 (95% CI, 0.95-1.64) for dementia, and 1.15 (95% CI, 1.01-1.31) for mortality, suggesting that the score reflects global vascular brain injury.

CSVD “poses a risk for both cerebrovascular disease and cognitive impairment via effects on arterial stiffness, presenting as microvessel arteriosclerosis with vascular endothelial dysfunction,” Naoki Saji, MD, PhD, and colleagues wrote in a 2016 article.

Although the underlying mechanisms are not yet fully understood, it is believed that there is “decreased caliber of the small perforating vessel leading to hypoperfusion and degeneration and death of the myelinated white matter fibers, causing neuronal dysfunction and cell death,” according to May Anne Kim-Tenser, MD, associate professor of clinical neurology at the Keck School of Medicine and medical director of the Neuro Intensive Care Unit at the Keck Medical Center of the University of California.

Some experts have also proposed that damage to the blood—brain barrier and local inflammation may be factors in the pathogenesis of CSVD and its association with stroke and cognitive decline.

 “Eventually, there are multiple ischemic events, some with symptoms and some clinically silent,” she said in an interview with NeurologyLive®. Additionally, results of animal research indicate that “even very small infarcts seem to ‘trigger’ or potentiate accumulation of amyloid plaques,” Hillis added.

Other evidence highlights the role of oxidative stress—with the Nox2-NADPH oxidase isoforms implicated as a key mediator&mdash;as a “contributor to some of the features of arteriopathy associated with both nonamyloid and amyloid forms of cerebral SVD and its risk factors” including hypertension and as a contributing factor to CSVD-related brain injury and cognitive impairment, according to De Silva and colleagues.

“Other considerations include the ‘hammer effect,’ with long-standing hypertension and lack of aortic distensibility. This may play a role in the genesis of lipohyalinosis or arterial wall stiffening particularly in the large and small vessels, as the distensibility characteristics of the arterial walls are lost between systole and diastole with profound hypertension,” Albert S. Favate, MD, clinical associate professor in the department of neurology, and director of the division of vascular neurology at NYU Langone, told NeurologyLive®.

“This results in stiffening of the aorta, the carotid and vertebral artery system, basilar arteries in the circle of Willis, and that ‘hammer effect’ causes the deposition of a hiatal and light material in the vessel walls. The patient must maintain a high cerebral perfusion pressure in this setting—further placing them at risk for development of small vessel strokes.”

cardiovascular and cerebrovascular diseases, with even mild hypertension showing a connection to CSVD.

In a study published in Hypertension in April 2019, researchers investigated the relationship between hypertension and CSVD lesions in 2460 healthy participants (54% men; mean age, 56 years).

 They found that that both stage 1 (β = .158; 95% CI, 0.046-0.269; P = .006) and stage 2 hypertension (β = .267; 95% CI, 0.171-0.362; P <.001) were closely associated with WMH volumes after adjustment for confounders.

Stage 1 (adjusted odds ratio [aOR], 1.66; 95% CI, 1.00-2.73; P = .048) and stage 2 hypertension (aOR, 1.76; 95% CI, 1.15-2.70; P = .009) were also associated with the presence of lacunae, as well as deep CMs (aOR, 2.50; 95% CI, 1.08-5.79; P = .033) for stage 1 and for stage 2 (aOR, 3.35; 95% CI, 1.61-6.98). An independent association was observed between stage 2 hypertension and moderate to severe enlarged perivascular spaces (aOR, 1.73; 95% CI, 1.36-2.20; P <.001).

There is very strong evidence that CSVD [cerebral small vessel disease], when present, contributes to cognitive decline and dementia. CSVD also results in worse cognitive impairment and slower recovery in people with stroke," said Argyle Elizabeth Hillis, MD. 

These findings suggest a dose-response effect of hypertension on the development of CSVD lesions. “Because CSVDs are well-known risk factors for symptomatic stroke or dementia, our findings would indicate that new, stricter [blood pressure] guidelines [per the 2017 American College of Cardiology/American Heart Association recommendations on hypertension] are plausible in terms of preventing diverse CSVDs before symptomatic events,” the authors concluded.

Diabetes, hyperlipidemia, and smoking are additional modifiable factors, whereas other non-modifiable factors aside from age include sex, race, and significant family history. “There are also genetic conditions and diseases that predispose a patient to CVSD, such as CADASIL and Fabry disease,” Kim-Tenser said.

Clinicians should screen for risk factors, cognitive impairment, and depression, and “eliminate or reduce risk factors and treat depres- sion when present,” Hillis said. An observational study presented at the American Heart Association’s Hypertension 2019 Scientific Sessions showed that patients with high blood pressure had a faster rate of cognitive decline versus those receiving hypertension treatment and those with normal blood pressure.

 A similar rate of cognitive decline was observed between patients being treated for high blood pressure and those with normal blood pressure.

Along with close blood pressure and glucose control and treat- ment of elevated non-HDL cholesterol as appropriate, clinicians should encourage patients to quit smoking, engage in daily aerobic exercise, and adhere to a healthy diet low in saturated fats, sugars, and red meat. Hillis also recommends that patients engage in enjoyable, cognitively stimulating activities—such as a book club, music lessons, and classes.

Thomas Hemmen, MD, PhD, vascular neurologist, director of the stroke center, and professor of neurosciences at the University of California, San Diego, said he is “struck by the data showing the need to remain mentally and physically engaged to prevent cognitive decline. Staying active, engaging socially, and maintaining one’s hobbies and interests later in life are very important to reduce dementia progression.”

A longitudinal study described in the November 2019 issue of the American Journal of Geriatric Psychiatry examined links between social engagement and cognitive decline in 217 community-dwelling, cognitively normal adults aged 63 to 89 years.

 Participants were assessed at baseline and at 3 years with the Community Healthy Activities Model Program for Seniors questionnaire, the Preclinical Alzheimer Cognitive Composite (PACC), and Pittsburgh compound B-PET to measure amyloid-β (Aβ).

Lower “baseline social engagement was associated with greater amyloid-β—related PACC decline, while higher baseline social engagement was associated with relative preservation of PACC scores (β = .05; P = .03),” the investigators reported. “Low social engagement may be a marker of neurocognitive vulnerability in older adults who are cognitively normal but have evidence of AD [Alzheimer disease] pathophysiologic change.”

Results from a 2019 longitudinal observational study revealed that greater physical activity levels were associated with slower Aβ-related cognitive decline (β = .03; 95% CI, 0.02-0.05; P <.001) and volume loss (β = 482.07; 95% CI, 189.40-774.74; P = .002) in a sample of 182 clinically normal participants from the Harvard Aging Brain Study (mean age, 73.4 years; 56.6% women), even after adjustment for vascular risk.

 Independent associations were observed between vascular risk and slower Aβ-related PACC decline (β = —0.04; 95% CI, –.06 to –.02; P <.001) and volume loss (β = –483.41; 95% CI, –855.63 to –111.20; P = .01).

“These findings suggest that engaging in physical activity and lowering vascular risk may have additive protective effects on delaying the progression of Alzheimer disease,” the investigators concluded.

Hillis further emphasized the role of adequate sleep in preventing cognitive decline and the importance of screening for sleep problems and referral to specialists if needed, especially when sleep apnea is suspected.

 A systematic review and meta-analysis published in 2017 in JAMA Neurology examined research involving a total of 4,288,419 participants.

 The pooled results of 6 prospective studies demonstrated a 26% greater risk (risk ratio, 1.26; 95% CI, 1.05-1.50) of developing cognitive impairment among individuals with sleep-disordered breathing.

Favate added that “obstructive sleep apnea can cause hypertension, and effective sleep management with a CPAP device will also reduce the patient’s blood pressure and stroke risk.”

When describing the connection between CSVD and aging and dementia, Hemmen recommended that clinicians focus on brain health and the “Life’s Simple 7” from the American Heart Association.

 These include many of the previously mentioned strategies to improve cere-brovascular health, such as blood pressure and glucose control as well as lifestyle modifications. “Many clinical providers do not fully value the magnitude of benefit these simple prevention strategies can have,” he said in an interview with NeurologyLive®.

“Once CSVD is discovered, aggressive treatment of modifiable risk factors is essential,” Kim-Tenser said. “One of the biggest challenges with these patients is that much of the early damage is clinically silent and is only discovered when a patient has a larger stroke or on scans for evaluation of other diseases. It is often discovered at later stages, which may make treatment more difficult.”

Multiple studies are currently investigating advanced imaging techniques that would enable identification of mild CSVD to allow for early aggressive treatment. Other ongoing trials are focusing on the development of “new substances and medications to treat the underlying risk factors and prevent progression of CVSD, as well as neuroprotectant medications to slow or prevent neuronal cell death,” Kim-Tenser said. “There are also studies evaluating substances to treat genetic conditions, such as enzyme replacement therapy in Fabry disease.”

Hillis added that there is a need for research exploring potential interventions to reverse CSVD pathology, such as demyelination of white matter tracts, while Hemmen cited the need to elucidate the etiology of white matter disease and pointed to a review by Joanna Wardlaw that discussed the lack of understanding in this area.

 “We know the correlations with diabetes, high blood pressure, and inac- tivity, but better understanding of the actual mechanisms may better help to prevent the condition,” he said.

Favate noted that one particularly worthy focus is the connection between cerebrovascular ischemic disease and activation of the APOE allele. “In addition to the presence of small vessel infarcts and large vessel infarcts causing decline due to neuronal loss, there is a further consideration that in many cases, the production of neuro-fibrillary tangles and amyloid deposition may be accelerated in the setting of multi-infarct state whether it is small or large vessel disease,” he said.

“Studies investigating interventions in this area to promote the downregulation of the production of neurofibrillary tangles, tau, and even amyloid is, in my opinion, an important area for future research and intervention.”

1. World Health Organization. 10 facts on dementia. https://www.who.int/features/factfiles/dementia/en/. Accessed December 13, 2019.

2. Shrivastava SR, Shrivastava PS, Ramasamy JD. Reduction in global burden of stroke in underserved areas. 

 2013;4(4):475-476. doi:10.4103/0976-3147.120194.

3. Nam KW, Kwon HM, Jeong HY, Park JH, Kwon H, Jeong SM. Cerebral small vessel disease and stage 1 hypertension defined by the 2017 American College of Cardiology/American Heart Association guidelines. 

. 2019;73(6):1210-1216. doi: 10.1161/HYPERTENSIONAHA.119.12830.

4. Yilmaz P, Ikram MK, Niessen WJ, Ikram MA, Vernooij MW. Practical small vessel disease score relates to stroke, dementia, and death. 

 2018;49(12):2857-2865. doi: 10.1161/STROKEAHA.118.022485.

5. Saji N, Toba K, Sakurai T. Cerebral small vessel disease and arterial stiffness: tsunami effect in the brain? 

 (Basel). 2016;3(3-4):182-189. doi: 10.1159/000443614.

6. De Silva TM, Miller AA. Cerebral small vessel disease: targeting oxidative stress as a novel therapeutic strategy? 

. 2016;7:61. doi: 10.3389/fphar.2016.00061.

7. Han F, Zhai FF, Wang Q, et al. Prevalence and risk factors of cerebral small vessel disease in a Chinese population-based sample. 

 2018;20(2):239-246. doi: 10.5853/jos.2017.02110.

8. High blood pressure treatment may slow cognitive decline [news release]. New Orleans, LA: American Heart Association. September 5, 2019. https://www.newsroom.heart.org/news/high-blood-pressure-treatment-may-slow-cognitive-decline. Accessed December 13, 2019.

9. Biddle KD, d'Oleire Uquillas F, Jacobs HIL, et al. Social engagement and amyloid-β-related cognitive decline in cognitively normal older adults. 

 2019;27(11):1247-1256. doi: 10.1016/j.jagp.2019.05.005.

10. Rabin JS, Klein H, Kirn DR, et al. Associations of physical activity and β-amyloid with longitudinal cognition and neurodegeneration in clinically normal older adults. 

2019;76(10):1203-1210. doi: 10.1001/jamaneurol.2019.1879.

11. Spira AP, Chen-Edinboro LP, Wu MN, Yaffe K. Impact of sleep on the risk of cognitive decline and dementia. 

 2014;27(6):478-483. doi: 10.1097/YCO.0000000000000106.

12. Leng Y, McEvoy CT, Allen IE, Yaffe K. Association of sleep-disordered breathing with cognitive function and risk of cognitive impairment: a systematic review and meta-analysis. 

 2017;74(10):1237-1245. doi: 10.1001/jamaneurol.2017.2180.

13. Konecny T, Kara T, Somers VK. Obstructive sleep apnea and hypertension: an update. 

. 2014;63(2):203-209. Konecny T, Kara T, Somers VK. Obstructive sleep apnea and hypertension: an update. Hypertension. 2014;63(2):203-209. doi:10.1161/HYPERTENSIONAHA.113.00613.

14. American Heart Association. What is brain health? http://www.heart.org/en/health-topics/brain-health. Accessed December 13, 2019. 

15. American Heart Association. My Life Check — Life’s Simple 7. http://www. heart.org/en/healthy-living/healthy-lifestyle/my-life-check--lifes-simple-7. Accessed December 13, 2019. 

16. Wardlaw JM. William M. Feinberg Award for Excellence in Clinical Stroke: small vessel disease; a big problem, but fixable. 

. 2018;49(7):1770-1775. doi: 10.1161/STROKEAHA.118.021184.

Features

Addressing risk factors early on may help curb the negative effects of cerebral small vessel disease on aging and reduce risk of neurovascular events.

Small Vessels, Big Impact: The Cerebrovascular Condition You Should Watch For

There appears to be no slow start to the new year in neurology, as the FDA has already approved new treatments for neurologic disorders, including intranasal diazepam for seizure clusters and expanded indications for vigabatrin and suvorexant in epilepsy and insomnia, respectively. In fact, neurology ranks second only to oncology in this year’s prospective drug pipeline, with nearly 30 potential drug approvals slated for 2020.

Within the headache specialty, my colleagues and I are fortunate to be on the receiving end of a steady flow of new drug development for patients with migraine and other headache subtypes. We closed out 2019 with the FDA approval of ubrogepant, a first-in-class small molecule inhibitor of calcitonin gene-related peptide for the acute treatment of migraine. We also look forward to the FDA’s upcoming decisions on another small molecule gepant, rimegepant, as well as eptinezumab, which if approved, will be the first anti-calcitonin gene-related peptide drug delivered via infusion.

In the end, an expanded armamentarium of treatments means more personalized therapeutic strategies for patients. It is truly an exciting time to be a neurologist as our ability to safely and effectively treat both common and rare diseases comes into focus, allowing us to take a step back and observe all of the facets that translate into a therapy being clinically meaningful for our patients

Clinical Insights

NeurologyLive's editor in chief Stephen D. Silberstein, MD, discussed the ways to optimizing patient care. 

Options Are Key to Optimizing Patient Care

By mid-2020, Ovid Therapeutics is expected to report topline data from its phase 3 pivotal trial of OV101, also known as gaboxadol, for the treatment of Angelman syndrome (AS).1 The NEPTUNE trial (NCT04106557) comes on the heels of a phase 2 study that showed overall improvement in patients treated with the therapy, a feat achieved for the first time in 50 years.

“We’re hoping to see that the trial is well conducted. We’re hoping to see that the drug is safe in patient populations with Angelman down to 2 years of age and whether the efficacy data supports gaboxadol as the first potential disease-modifying drug treatment for Angelman syndrome,” Christopher Keary, MD, associate program director, Autism Spectrum Disorder Fellowship, and behav- ioral director, Angelman Syndrome Clinic at Massachusetts General Hospital in Boston, told NeurologyLive®.

One of the challenges that Ovid has faced in bringing gaboxadol (and really, any treatment) forward in treating AS has been the multifaceted impact of the disease. AS affects various functions, including speech, general cognition and learning, motor function, behavior, and sleep.

In addition, the lack of treatment for the condition is coupled with a lack of good outcome measures for that many domains. Just as well, many outcome measures for behavior are designed for individuals who have expressive verbal abilities, whereas most patients with AS are minimally verbal.

“This has a way of creating a barrier to doing research in this field,” Keary explained. “If you don’t have these really great outcome measures that are designed for these rare neurodevelopmental disorders, that can have a chilling effect on doing research. That was

part of the reason as to why, in the trial design, it was thought to use the CGI-I [Clinical Global Impressions-Improvement] scale—to try and capture what clinicians who care for people with Angelman syndrome do in the office.”

NEPTUNE, which randomized its first patient in September 2019, has an estimated enrollment of 65 patients and will be quadruple masked to include the participant, care provider, investigator, and outcomes assessor (FIGURE). There are study sites in Arizona, California, Pennsylvania, and Washington, as well as Israel. The trial is expected to be complete in August 2020.

Thus far, only a single adjustment to the trial design has been made. Those who participated in STARS are eligible to participate in ELARA (NCT03882918), an open-label trial where subjects may maintain treatment with gaboxadol for a number of years. An amendment was made to allow those who complete NEPTUNE to also enroll into ELARA.

Keary explained that 1 of the notable assessments the trial will make is its examination of the pharmacokinetic (PK) properties of gaboxadol in children with AS. These data have already been collected from an adult population of individuals with AS and those who are neurotypical.

“PK data and safety data will first be analyzed in ages from 9 to 12, before moving on to recruitment for subjects between 4 and 8, and then before recruitment of subjects [aged] 2 to 3 to ensure safety and tolerability,” Keary said. “The decision was made to use actig- raphy to measure indexes of sleep, it being sort of the best way that we could do it rather than just using parental reports for sleep findings, to try and get the best data that we possibly could.”

With NEPTUNE underway, the potential of gaboxadol is becoming clearer. The phase 2 STARS data ultimately suggest that the treat- ment is tolerable, as those with AS tend to be extraordinarily sensi- tive to medications and that the levels of global improvement were different enough between treatment and placebo to suggest it was clinically meaningful.

“These are really promising data in the absence of any current disease-modifying treatments in Angelman. We’re eager to expand on research with NEPTUNE, and if the data supports it, bring it forward as a potential treatment,” Keary said.

1. Ovid Therapeutics announces first patient randomized in pivotal phase 3 NEPTUNE trial of OV101 for the treatment of Angelman syndrome [press release]. New York, NY: Ovid Therapeutics; September 12, 2019. globenewswire.com/news-release/2019/09/12/1914719/0/en/Ovid-Therapeutics-Announces-First-Patient-Randomized-in-Pivotal-Phase-3-NEPTUNE-Trial-of-OV101-for-the-Treatment-of-Angelman-Syndrome.html. Accessed January 15, 2020.

2. Bird LM, Ochoa-Lubinoff C, Tan WH, et al. STARS: results from a safety and efficacy study of OV101 (gaboxadol) in adults and adolescents with Angelman syndrome. Presented at: 2019 American Academy of Neurology Annual Meeting; May 4-10, 2019; Philadelphia, PA.

Clinical Trial in Progress

Gaboxadol is the first treatment in 50 years associated with positive change in outcomes in Angelman syndrome.

Phase 3 Trial of Gaboxadol Is Underway for Angelman Syndrome

In October 2019, we cochaired a landmark event organized by the Consortium of Multiple Sclerosis Centers (CMSC). This international effort brought together an expert panel to update the guidelines for a standardized magnetic resonance imaging (MRI) protocol for the diagnosis and follow-up of multiple sclerosis (MS). Presently, there are 2 recommended protocols: guidelines from the CMSC in North America and the Magnetic Resonance Imaging in MS group (MAGNIMS) in Europe.1-5 During this MRI Consensus Guidelines Conference, the aim was to come together to begin developing globally aligned recommendations and to promote more widespread use of a standardized MRI protocol for MS.

The CMSC guidelines for a standardized MRI protocol for the diagnosis and follow-up of patients with MS were first developed in 2001 and have been subsequently updated 5 times.

 The October 2019 consensus conference attendees consisted of neurol- ogists, radiologists, MR technologists, and imaging scientists with an expertise in MS from the United States, Canada, and Europe, including representatives from the CMSC, MAGNIMS, NAIMS (North American Imaging in Multiple Sclerosis Cooperative), the National MS Society, MS Association of America, and representatives from leading MRI manufacturers and commercial image anal- ysis companies. Prior to the meeting, the CMSC also surveyed its members regarding the use of MRI with a consistent standardized protocol, as well as for the use of gadolinium, diffusion-weighted imaging sequences in MS diagnosis and follow-up, and the central vein sign for diagnosis.

The use of MRI is invaluable in the diagnosis and follow-up of patients with MS. Experts agree that a standardized examination is key to the confident and accurate identification of new lesions and activity that facilitates an earlier diagnosis and prompts initiation and/or change in disease-modifying therapy. Annual MRIs that detect new clinically silent disease activity enable health care professionals to treat patients earlier in the disease course and to modify therapy, when needed. As part of the standardized protocol, routine monitoring of patients with MS is recommended.

Using a standardized MRI protocol is of the utmost importance in providing optimal care of patients with MS. By using the same scanner, the same facility, and the same standardized MS MRI protocol with specific core sequences (including defined scan orientation, slice thickness, and coverage) for brain and spinal cord studies, the resultant MRI can be compared with previous studies more easily, effectively, and efficiently. Having 2 scans that are as similar as possible to each other allows the health care provider to more easily detect a new lesion. In addition to improving the ease of comparing scans over time, the use of a standardized protocol will minimize the need for gadolinium. Although gadolinium is helpful in identifying disease activity, its use is not essential.

Peer Exchange: Updates to the MRI Protocol and Clinical Guidelines for MS: CMSC Working Group 

The use of yearly T2-weighted fluid-attenuated inversion recovery sequences using a well-performed standardized MR image is all that is necessary to detect new MS lesions when compared with previous standardized MR imaging studies.

The disease phenotypes as defined by Lublin et al

 include objective criteria of disease activity provided by imaging findings and disease progression. Well-performed standardized MRIs that can be followed and compared longitudinally are important in providing accurate clinical course descriptions,

 with respect to changes in MS lesion activity, lesion, and brain volumes.

In addition to improving patient care, standardizing the MRI protocol will save money. In times of excessive spending in health care, patients may not always receive an MRI that is optimal and able to provide the critical information needed for diagnosis, treatment initiation, monitoring, and follow-up. Repeating subpar MRI scans is a waste of time and money. Another concern is patient time in the scanner. If the goal is to achieve all necessary sequences as efficiently as possible, standardization of the MRI protocol becomes essential. This is an important economic consideration for health care providers, patients, and MRI vendors. With regard to insurance companies, if we provide better care for our patients with MS, it will ultimately be cost saving for patients and their insurance companies (ie, prescribing appropriate disease-modifying therapies and minimizing adverse events).

At the October consensus meeting, representatives from global MRI manufacturers expressed interest in a potential internationally aligned MRI protocol that could be preprogrammed into scanners with the appropriate core sequences for examination of patients with MS, similar to procedures for prostate cancer imaging with recommended protocols being preloaded in MRI scanners. A globally recommended MRI protocol for MS could be preloaded into scanners, and MR technologists could receive training in the use of these standard baseline MRI sequences for patients with MS, and the radiologist’s further optimization preferences could be handled at the time of the scan. Another approach would be to provide exam cards on the CMSC website that could be down- loaded and subsequently uploaded into the MR scanner.

If health care providers for MS demand standardization of an MRI protocol for their patients, the vendors indicated that such a protocol could be implemented into the manufacturers’ software. This is an important effort to explore further with MRI manufacturers and with regulators from the FDA and European Union.

Another outcome of the consensus meeting was re-emphasizing the importance of communication between the neurologist and the radiologist. The clinical question being addressed must be included in the requisition for the MRI. If the neurologist is looking for current activity, use of gadolinium may be recommended because it will indicate new activity that has occurred within the past 4 weeks. However, if the health care provider wants to determine whether any new activity has happened since the patient’s last visit a year ago, a T2-weighted fluid-attenuated scan by itself, without the need for gadolinium, is all that would be necessary. Clinical concern about possible new activity, or if switching therapy is a consideration, should appear on the requisition form so the radiologist’s report can provide the appropriate information about the MRI examination. Similarly, if a diagnosis of MS is being considered on the requisition, the report will focus on providing the necessary details concerning lesion dissemination in space and time.

This year, the CMSC and our guideline consensus group will be undertaking an ambitious plan to disseminate information about the importance and value of a standardized MRI protocol and to educate neurologists, radiologists, MR technicians, MR manufacturers, and patients with MS regarding the need for a globally aligned MRI protocol for MS. We plan to present abstracts, posters, and educational presentations at various medical meetings in 2020. Other methods for dissemination that were discussed include webinars and developing cards with the MRI protocol for distribution to clinicians, radiologists, technicians, MS and MRI centers, as well as patients.

Standardized MRI protocol and clinical guidelines for the diag- nosis and follow-up of MS have been available for over a decade. Although these guidelines are useful and useable, they are not yet widely used. The expert group convened recently by the CMSC is currently updating the MRI guidelines with the vision and action plans for the MRI protocols to be universally useful, useable, and used as the standard of care for patients with MS. In the plans for the coming year is a meeting of representatives from the CMSC, MAGNIMS, and NAIMS to bring together the updated CMSC and MAGNIMS guidelines into 1 international consensus standardized protocol, with special attention to alignment on the core sequences needed for optimal care of patients with MS and to have these guidelines endorsed and adopted internationally by various MS-related organizations, MRI vendors, and MR imaging facilities from around the world.

Lori Saslow (Great Neck, NY) a medical writing consultant on behalf of the CMSC, assisted in editorial preparation and editing.

1. Traboulsee A, Simon JH, Stone L, et al. Revised recommendations of the Consortium of MS Centers Task Force for a standardized MRI protocol and clinical guidelines for the diagnosis and follow-up of multiple sclerosis. 

. 2016;37(3):394-401. doi: 10.3174/ajnr.A4539.

2. The Consortium of MS Centers MRI Task Force. Consortium of MS Centers MRI protocol and clinical guidelines for the diagnosis and follow-up of MS. 2018 Revised guidelines. 2018. https://cdn.ymaws.com/mscare.site-ym.com/resource/collection/9C5F19B9-3489-48B0-A54B-623A1ECEE07B/2018MRIGuidelines_booklet_with_final_changes_0522.pdf. Accessed January 9, 2020.

3.  Rovira À, Wattjes MP, et al, on behalf of the MAGNIMS study group. MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis—clinical implementation in the diagnostic process. 

. 2015;11(8):471-482. doi:10.1038/nrneurol.2015.106.

4. Wattjes MP, Rovira À, et al, on behalf of the MAGNIMS study group. MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis—establishing disease prognosis and monitoring patients. 

. 2015;11(10):597-606. doi:10.1038/nrneurol.2015.157.

5. Arevalo O, Riascos R, Rabiei P, Kamali A, Nelson F. Standardizing magnetic resonance imaging protocols, requisitions, and reports in multiple sclerosis: an update for radiologist based on 2017 magnetic resonance imaging in multiple sclerosis and 2018 consortium of multiple sclerosis centers consensus guidelines. 

. 2019;43(1):1-12. doi: 10.1097/RCT.0000000000000767.

6. Simon JH, Li D, Traboulsee A, et al. Standardized MR imaging protocol for multiple sclerosis: consortium of MS centers consensus guidelines. 

7. Traboulsee A, Li D. Addressing concerns regarding the use of gadolinium in a standardized MRI protocol for the diagnosis and follow-up of multiple sclerosis 

 Published online September 1, 2016. doi:10.3174/ajnr.A4943.

8. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions.

2014;83:278-286. doi: 10.1212/WNL.0000000000000560.

Leaders of the CMSC Working Group on MRI protocols and clinical guidelines express the need for a unified approach to diagnosing and monitoring multiple sclerosis.

The Importance of a Globally Aligned, Standardized MRI Protocol for MS

Inhibition of the neonatal Fc receptor (FcRn) is currently being explored as a novel treatment approach for myasthenia gravis (MG), a disease in which immunoglobulin G (IgG) autoantibodies form against acetylcholine receptors (AChRs), muscle-specific kinase (MuSK), and lipoprotein-related protein 4 (LRP4).

The pathophysiology of MG is associated with the type of auto-antibody present. AChR MG accounts for approximately 85% of cases and is characterized by the predominant expression of IgG1 and IgG3.

 These antibodies directly bind and selectively degrade the AChRs.

 Additionally, IgG1 and IgG3 activate the complement pathway, which has been implicated as the major source of destruction of the neuromuscular end plate and has been observed in both animal and human studies.

of cases and is characterized by binding of MuSK autoantibodies to an Ig-like region of MuSK, which blocks activation of the agrin-LRP4-MuSK complex and inhibits neuromuscular transmission.

 The MuSK autoantibody primarily consists of the IgG4 subtype, which is not normally associated with complement activation.

 The transmembrane protein LRP4 functions as a receptor for agrin; after binding, these 2 proteins form a complex with MuSK, leading to MuSK activation. MuSK activation is thought to be essential for AChR clustering and formation of the neuromuscular junction.

FcRn primarily functions as either a recycling receptor, maintaining high levels of albumin and IgG in the circulation, or a transcytosis receptor, responsible for the bidirectional transport of these ligands across polarized cellular barriers (FIGURE).

Efgartigimod (ARGX-113) is an investigational monoclonal Fc fragment of IgG1 that has been modified at 5 residues, using ABDEG (antibodies that enhance the degradation of IgG) technology, to increase its affinity for FcRn.

 Molecules that harbor the ABDEG mutations (M252Y/S254T/T256E/H433K/N434F) have been shown to block the function of FcRn.

 Efgartigimod engages with and occupies FcRn, stopping its interaction with and salvage of IgG in the circulation. A multicenter, double-blind, phase 2 trial was launched to evaluate the safety, efficacy, and pharmacokinetics of efgartigimod in 24 patients with MG and generalized muscle weakness.

 The study was based on the hypothesis that patients with MG who received efgartigimod would experience therapeutic benefit if the drug reduced their levels of anti-AChR autoantibodies, similar to the total IgG decrease observed in healthy volunteers during a previous phase 1 trial of the drug.

 Participants received 4 intravenous administrations of placebo or efgartigimod over a 3-week period, followed by 8 weeks of observation.

Frequently reported adverse events in those treated with efgartigimod included headache and reduced monocyte count, which were considered mild in severity, as well as a moderately severe 16 shingles episode reported by 1 patient treated with efgartigimod. Investigators reported a rapid and sustained reduction of IgG levels which paralleled the reduction of anti-AChR autoantibodies.

Clinical improvement was assessed using the Myasthenia Gravis Activities of Daily Living (MG-ADL), Quantitative Myasthenia Gravis, and Myasthenia Gravis Composite efficacy scales, as well as the 15-item Myasthenia Gravis Quality of Life scale.

 Clinical improvement was consistent with serum IgG and anti-AChR autoantibody levels, with effects noted 7 days after the initial infusion. Whereas IgG and autoantibody levels returned to approximate baseline levels by the study’s end, clinical scores indicated a sustained improvement throughout the study. Notably, for any point reduction level, a larger proportion of patients treated with efgartigimod experienced clinical improvement compared with those who received placebo. There was a clinically meaningful improvement in MG-ADL score for at least 6 consecutive weeks in 75% of patients treated with efgar- tigimod versus 25% in the placebo group.

A phase 3, randomized, double-blind, placebo-controlled trial is currently under way to evaluate the safety, efficacy, and tolerability of the drug in patients with MG and generalized muscle weakness.

 The trial includes 167 participants and will assess the percentage of MG-ADL responders among those who are anti-AChR antibody seropositive, in addition to several secondary end points. The trial is expected to reach completion in November 2020.

1. Gable KL, Guptill JT. Antagonism of the neonatal Fc receptor as an emerging treatment for myasthenia gravis. 

 2020;10:3052. doi: 10.3389/fimmu.2019.03052.

2. Gilhus NE, Verschuuren JJ. Myasthenia gravis: subgroup classification and therapeutic strategies. 

. 2015;14(10):1023-1036. doi: 10.1016/S1474-4422(15)00145-3.

3. Verschuuren JJGM, Huijbers MG, Plomp JJ, et al. Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase and low-density lipoprotein receptor-related protein 4. 

. 2013;12(9):918-92 doi: 10.1016/j.autrev.2013.03.001.

4. Drachman DB, Angus CW, Adams RN, Kao I. Effect of myasthenic patients' immunoglobulin on acetylcholine receptor turnover: selectivity of degradation process. 

. 1978;75(7):3422-3426. doi: 10.1073/pnas.75.7.3422.

5. Chamberlain-Banoub J, Neal JW, Mizuno M, Harris CL, Morgan BP. Complement membrane attack is required for endplate damage and clinical disease in passive experimental myasthenia gravis in Lewis rats. 

. 2006;146(2):278-286. doi: 10.1111/j.1365-2249.2006.03198.x.

6. Engel AG, Arahata K. The membrane attack complex of complement at the endplate in myasthenia gravis. 

. 1987;505:326-332. doi: 10.1111/j.1749-6632.1987.tb51301.x.

7. Morgan BP, Chamberlain-Banoub J, Neal JW, Song W, Mizuno M, Harris CL. The membrane attack pathway of complement drives pathology in passively induced experimental autoimmune myasthenia gravis in mice. 

. 2006;146(2):294-302. doi: 10.1111/j.1365-2249.2006.03205.x.

8. Gilhus NE, Tzartos S, Evoli A, Palace J, Burns TM, Verschuuren JJGM. Myasthenia gravis. 

 2019;5(1):30. doi: 10.1038/s41572-019-0079-y. 

9. Phillips WD, Vincent A. Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms. 

. 2016;5: pii: F1000 Faculty Rev-1513. doi: 10.12688/f1000research.8206.1.

Understanding the pathophysiology of myasthenia gravis is still being determined to this day, but the neonatal Fc receptor is emerging as a potential treatment. 

February 2020

Addressing OFF Episodes in Parkinson Disease Management

Small Vessels, Big Impact: The Cerebrovascular Condition You Should Watch For

Options Are Key to Optimizing Patient Care

Phase 3 Trial of Gaboxadol Is Underway for Angelman Syndrome

The Importance of a Globally Aligned, Standardized MRI Protocol for MS

Targeting the Neonatal Fc Receptor in Myasthenia Gravis

Mission Control: Cleveland Clinic's Hub of Epilepsy Expertise Has Global Benefits

How an Innovative Trial Design May Change the ALS Treatment Landscape

Improving Migraine Treatment Adherence: Can Anti-CGRPs Turn the Tide?