Recent evidence suggests that the pathological process of multiple sclerosis (MS) is already underway at the time of the first episode of clinically isolated syndrome (CIS), defined as sudden neurologic dysfunction due to inflammation and demyelination that lasts 24 hours or more and does not include signs of fever, infection, or encephalopathy.

 As the range of effective treatment options for MS has expanded and the ability of magnetic resonance imaging (MRI) to track changes of pathology in response to therapies has improved, the rationale for treating CIS has grown stronger.

Although up to one-third of patients with CIS will have no further demyelinating events, a 2018 article exploring the natural course of CIS showed that more than 85% of patients diagnosed with CIS progressed to relapsing-remitting or secondary progressive MS within 20 years (

 The challenge lies with predicting which of those patients will experience future events and how to mitigate potential damage in the interim.

Although CIS has been shown to resolve with or without treatment, evidence accumulated over the past several years suggests that the implications of untreated CIS are significant to the later course of MS.

In the early period following CIS, much of the activity associated with MS remains subclinical, but it is still detectable on MRI. In fact, MRIs taken during this period show substantial axonal damage occurring despite the resolution of symptoms. A 2007 review by Ben W. Thrower, MD,

 suggested that typical demyelination patterns seen on traditional MRIs appeared as “islands” of axonal pathology surrounded by normal-appearing white matter. Newer developments in MRI technology, however, have revealed these islands to be more like icebergs, with an estimated 50% of untreated MS cases showing enhancing lesions.

 Nearly one-third of enhancing lesions will evolve into “black holes” that correlate directly with later disability, pointing to the need for treatment at the earliest point of detection—or CIS.

®, Thrower, the medical director of the Andrew C. Carlos Multiple Sclerosis Institute at the Shepherd Center in Atlanta, Georgia, explained that the main risk associated with early diagnosis of MS is that “you want to make sure you’ve gotten it right, because once a person has gotten an MS diagnosis, sometimes there’s not a lot of additional thought about the diagnosis. People just go with the flow and stay on a treatment that is maybe not appropriate for them, and whatever the correct diagnosis is, it’s not being managed at that point.

“We need to consider a balance in that you want to diagnose quickly, but also diagnose accurately,” Thrower continued. “At every [MS treatment] center, you’ll probably have a small handful of patients who have been misdiagnosed, because [they have] some- thing that mimics MS.”

Expansion of the original 2010 McDonald Criteria, which specified dissemination of lesions in time and space, now allows for much earlier diagnosis of MS.

 The 2017 update to the McDonald Criteria states that with evidence of dissemination in space (DIS), the requirement for clinical or MRI criteria for dissemination in time (DIT) can be met by the presence of oligoclonal bands in the absence of atypical cerebrospinal fluid findings; with no better explanation, this allows for a diagnosis of MS.

 Other changes to the diagnostic criteria include the recommendation that both symptomatic and asymptomatic MRI lesions can be applied to the determina- tion of DIS and DIT, and that cortical lesions can substitute for DIS.

“MS can be diagnosed with 1 MRI, if both an old and new lesion are detected at the time of CIS,” Thrower said. “Everything with multiple sclerosis always comes back to our original classic definition of dissemination of focal neurological events in time and space. And really, with 1 MRI, we can see that dissemination in time and space if we have 1 clinical event, and we have evidence of both old and new lesions on MRI. I think we’re just using technology to be able to meet that definition earlier.”

Optic neuritis (ON) and other manifestations of CIS have predictive value as well. The new criteria state that young female patients who present with unilateral ON that is painful have a higher risk of future demyelinating events, even with normal fundoscopy. Asymmetric presentation of transverse myelitis, when combined with a nonedematous spinal cord lesion, is also associated with a greater risk of MS.

“We’re now using a new blood test for myelin oligodendrocyte glycoprotein to aid in the diagnosis of MS and similar conditions,” Thrower added. “Some new [research has] looked at the morphology of MRI lesions—whether they enhance, where they’re located, and how to determine risk for clinically definite MS and disease progression.”

Now that a diagnosis of MS can be made earlier, the question becomes whether it should be treated.

“Yes,” Thrower stated simply. “And the driving force behind that, if you look at our goals for treating a newly diagnosed individual, is that we would like to achieve no evidence of disease activity (NEDA). No evidence, meaning they have no relapse, no increased disability, and no MRI lesions.” He noted that setting the bar that high may not really be targeting the patient’s whole condition at the time. There may still be damage occurring that is at a level below what is visible given the resolution of standard MRI techniques, and those possibilities should be considered. “A patient on interferon may look like they are achieving NEDA, but really a level of damage is occurring beneath the surface. We may see them paying for that 10 or 15 years down the line,” he said.

Treatment approaches to CIS generally follow the same standards as those for treatment of clinically defined MS, with disease modifying therapies (DMTs) as the first-line treatment preferred by most clinicians. The growing understanding of how early demy-elinating processes may already be at work at the time of CIS has been a driving force behind more aggressive treatment strategies. It becomes important, Thrower said, to confirm the diagnosis early and to at least put more effective therapies on the table for discussion with the patient and their family as first-line options.

“We have 19 FDA-approved treatment options. They all have a certain safety profile and efficacy profile, and some drugs are more effective than others,” said Thrower. But, he explained, a para- digm shift has occurred in how existing DMTs are being utilized in MS, and especially at the time of CIS, that encompass 2 different schools of thought: escalation therapy versus induction therapy.

The more traditional approach to MS treatment that is frequently applied to patients with CIS is escalation therapy. This involves initiating treatment in a newly diagnosed individual with one of the safer drugs. Such a drug may show only modest efficacy, and the patient is escalated to more aggressive therapies if and when treatment failure occurs.

 Glatiramer acetate and interferon beta are considered first-line therapies for this approach, with immunosup-pressants as second-line treatments.

Alternatively, many MS providers are shifting to an induction strategy, which focuses on using the most effective therapies that can be used safely from the initial onset of CIS. Over time, numerous drugs, including mitoxantrone, natalizumab, and alemtuzumab, have been investigated for induction therapy in MS, all with success.

Today, however, the main choices for induction therapy are natalizumab and ocrelizumab, followed by fingolimod and siponimod, Thrower said. “If you ask providers at different MS centers, you may get some variations in the answers, but I would say natalizumab, ocrelizumab, and alemtuzumab are probably our 3 most effective therapies,” noted Thrower, referring to his experience at the Shepherd Center. “For most [clinicians], the safety profile of alemtuzumab is not going to make it an acceptable first-line therapy. However, ocrelizumab and natalizumab are acceptable first-line therapies. With natalizumab, it really hinges on the JC virus (JCV) antibody index to determine whether someone is a good candidate. If someone is JCV antibody—negative or has a low index value, natalizumab may be a great first-line option.”

Use of these more aggressive therapies presents additional risks, particularly to newly diagnosed patients, but the risks are increasingly being outweighed by the benefits. Thrower believes that when appropriate intervention is delivered early enough, the underlying damage that was often historically present at the typical point of MS diagnosis can be averted so that progression doesn’t occur. “We have individuals on some of these more effective therapies who are just stable for years,” he said.

While MRI in MS has largely been used for diagnosis and to monitor progression and treatment efficacy, novel techniques developed only recently have significantly enhanced the detec- tion of lesions and new pathology that could not be discerned on conventional MRI.

 This new degree of sensitivity vastly expands its utility in therapeutic strategy.

“We were using MRI in the initial diagnosis to confirm MS and to rule out other conditions,” Thrower said. “Again, the goal is NEDA, and one-third of NEDA is no new or active enhancing lesions on MRI. So, the average person is now going to get an MRI of the brain and spine on a yearly basis.”

MRI is also often utilized at the time of initiating a new treatment or changing to another drug to help confirm efficacy. “If you’re seeing evolution of enhancing lesions, you might switch to another therapy that avoids provocation of new lesions,” Thrower said.

More recently, MRI has been used to monitor subclinical activity in patients in the earliest stages of disease and to predict long-term outcomes. In a 2018 study,

 Ce&#769;line Louapre, MD, PhD, of Institut du Cerveau et de la Moelle Epinie&#768;re in Paris, France, reported that new MRI techniques “offer insights into MS pathophysiology beyond white matter lesions.” For instance, new evidence shows that emer- gence of new lesions in specific regions, such as the medullary and infratentorial areas of the brain, are highly predictive of long-term disability and higher risk of progression to secondary MS.

Thrower pointed out that while taking more frequent MRIs may provide more information, it’s important to look at the patterns over time for context. “That once-a-year MRI may change over time. If we have a patient who is just absolutely stable over 5 or 1 years—there’s no set number&mdash;then we would potentially do MRIs less frequently, similar to progressive forms of MS where the MRIs don’t change as drastically.”

Thrower also emphasized the importance of helping the patient understand what the changes—or lack of changes&mdash;to MRIs means for their disease course and treatment. “We always let patients know, too, that MRI is a great tool, but you have to put it into the context of how the patient is doing clinically. Early in MS you can have new disease activity that’s largely asymptomatic, where they come in and the MRI shows a new lesion. Later in MS ,you can see individuals whose MRIs really aren’t changing, but they’re progressing&mdash;and that’s very frustrating for the patient. When I tell a patient who is getting worse that their MRI is stable, at some level they hear that you don’t believe them. We do a lot of education around that,” he said.

“If you look at MS management prior to 1993, when we had no treatment options, some of those treatment paradigms were based on in-patient models, and it was just assumed that every- body was going to progress eventually. Now, 99.9% of MS therapy is outpatient, and I do think we’ve changed the natural history curve dramatically. I feel reasonably good about the potential of a newly diagnosed individual—if we get them on the right treatment early&mdash; that hopefully we’ll be able to put the brakes on MS and not see progression over decades,” Thrower concluded.

1. Brownlee WJ, Miller JH. Clinically isolated syndromes and the relationship to multiple sclerosis. J Clin Neurosci. 2014;21(12):2065-2071. doi: 10.1016/j.jocn.2014.02.026.

2. Thrower BW. Clinically isolated syndromes: predicting and delaying multiple sclerosis. Neurology. 2007;68(24 suppl 4):S12-S15. doi: 10.1212/01.wnl.0000277704.56189.85.

3. Kennedy P. Impact of delayed diagnosis and treatment in clinically isolated syndrome and multiple sclerosis. J Neurosci Nurs. 2013;45(6 suppl 1):S3-S13. doi: 10.1097/JNN.0000000000000021.

4. Hou Y, Jia Y, Hou J. Natural course of clinically isolated syndrome: a longitudinal analysis using a Markov model. Sci Rep. 2018;8(1):10857. doi: 10.1038/s41598-018-29206-y.

5. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of

the McDonald criteria. Lancet Neurol. 2018;17(2):162-173. doi: 10.1016/S1474-4422(17)30470-2.

6. Edan G, Le Page E. Induction therapy for patients with multiple sclerosis: why? when? how? CNS Drugs. 2013;27(6):403-409. doi: 10.1007/s40263-013-0065-y.

7. Louapre C. Conventional and advanced MRI in multiple sclerosis. Rev Neurol (Paris). 2018;174(6):391-397. doi: 10.1016/j.neurol.2018.03.009. 

Articles

Features

More aggressive strategies in the treatment of multiple sclerosis have created an opportunity for physicians to refine the way they address a first demyelinating event, and perhaps change the course of disease.

Judgment Call: Exploring Treatment Tactics in Clinically Isolated Syndrome

Vestibular migraine, a condition characterized by episodic symptoms of severe vertigo with or without headaches, can signifi- cantly interfere with patient quality of life. Not only are the symptoms disruptive when they occur, but apprehension that an episode could potentially occur can lead to patient anxiety as well. The condition is typically chronic, and individuals may experience more frequent bouts of vestibular migraine for months or years at a time, with intermittent gaps of relative improvement.

Vestibular migraine can affect individuals of all ages, although it tends to begin during the young-adult years. There is a familial propensity to developing the disorder, although it can occur sporadically as well. People may develop episodes in association with certain triggers, which often include the same triggers that elicit their nonvestibular migraines.

Even for headache specialists, vestibular migraine is not always a clear-cut diagnosis. Experts suggest that the condition is underdiagnosed clinically,

 and challenges with respect to effective and accessible treatment options remain.

The International Headache Society and the Ba&#769;ra&#769;ny Society: The International Society for Neuro-otology have developed a consensus document with diagnostic criteria for vestibular migraine. The diagnosis is based on recognizing the clinical features of vestibular migraine as well as excluding other conditions that are part of the differential diagnosis.

Traditional migraine therapies—both abortive and prophylactic&mdash;have been the mainstay of treatment for vestibular migraine. Noninvasive vagal nerve stimulation (nVNS), a self-administered procedure that has been utilized in the treatment of nonvestibular migraine, is among the new approaches being considered in the treatment armamentarium for acute episodes of vestibular migraine. Given the history of this therapy in the treatment of other central nervous system disorders, its adverse effect and safety profile has been fairly well established and reported. As nVNS therapy remains under investigation for the treatment of acute vestibular migraine, more information regarding its efficacy in managing the symptoms of this condition may continue to emerge.

Vestibular migraine is considered the most common cause of recurrent spontaneous vertigo attacks.

 The pathophysiology and etiology of the condition have been examined in a number of studies, but these generally tend to be relatively small, often including fewer than 100 patients. Structural changes, inflammatory markers, and genetic alterations have all been explored in an attempt to define the cause of vestibular migraine (

Functional magnetic resonance imaging (MRI) has been used to identify brain regions that may predispose to the condition or may be altered in association with acute attacks. The identification of genetic defects and inflammatory markers have not been as clear in the context of vestibular migraine as they have been in the study of other vestibular disorders, like Me&#769;nie&#768;re’s disease, and migraine disorders, such as CADASIL syndrome [cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy].

Studies that target the identification of the pathophysiologic features of vestibular migraine have, nevertheless, yielded a few recurrent observations. Marianne Dieterich, MD, and co-authors reported “cortical regions activated by vestibular stimulation in human functional imaging studies include those also involved in pain perception—for example, the posterior and anterior insula, the orbitofrontal cortex, and the cingulate gyrus.”

 They suggest that “migraine-related vestibular disorders like vestibular migraine may be caused by enhanced excitability occurring during the processing of sensory information. The enhanced excitation induces interactions of vestibular and pain pathways on several levels, from the inner ear to the thalamus and cortical level.” The relationship between vestibular and sensory cortical excitability, they suggest, could be rooted in a genetic susceptibility.

In fact, while genetic studies have not been firmly conclusive in terms of identifying an inheritance pattern or a specific gene (or set of genes) in the context of vestibular migraine, results of genetic studies support the idea that chromosomal alterations may play a role in the predisposition to vestibular migraines for some people.

“Familial occurrence has been reported in some patients with an autosomal dominant pattern of inheritance and decreased penetrance in men. The genetics of vestibular migraine are heterogeneous and uncertain, but several studies suggest linkage to chromosome 5q35 [47] or 22q12,” Isabel Luzeiro, MD, and colleagues wrote.

In general, an understanding of the pathophysiology of a disease is often at least partially advantageous in defining diagnostic criteria and/or for determining potentially effective therapies. In the case of vestibular migraine, the pathophysiology is not explicitly linked to the diagnostic criteria or to the mainstay and emerging therapies.

The clinical presentation of vestibular migraine is not considered consistent or straightforward. Patients often present to their primary care physi- cians with complaints of episodes that may involve a combination of dizziness, lightheadedness, vertigo, nausea, vomiting, and/or head pain.

“Vestibular symptoms include both a sense of false internal or external motion, visual motion sensitivity, positional vertigo, and head motion vertigo,” Jennifer Kriegler, MD, a headache specialist with the Center for Neurological Restoration at Cleveland Clinic in Ohio, told 

®. Yet, as David Watson, MD, chair and director of West Virginia University Headache Center, explained, not every patient who experiences migraines and vestibular symptoms is necessarily afflicted by vestibular migraine. “Vestibular symptoms are common, and migraine is common. They often occur in the same person. Sometimes they are part of the same process, such as in vestibular migraine,” Watson said.

These patients are eventually referred to a number of consulting physicians, including neurologists, cardiologists, and/or ear, nose, and throat specialists, often based on their predominant symptoms. Even after referral to a specialist, it can take months or years for these patients to receive a definitive diagnosis. Concerns about potentially disabling conditions frequently arise based on the clinical presentation. Gayle Rebovich, MD, division director of neurology at Roger Williams Medical Center in Providence, Rhode Island, told 

® that “with regular migraine, we can usually proceed directly to treatment based on history and exam alone. The difficulty is that the symptoms of vestibular migraine can appear to represent posterior circulation stroke, transient ischemic attack, or peripheral vestibulopathy.”

Clinical Evaluation and Diagnostic Criteria

Diagnostic criteria have been established only relatively recently, in 2012.

 While neurologists and other specialists have been diagnosing and treating vestibular migraine prior to the formulation of these guidelines, these parameters offer a more standardized approach

that can be used across multiple specialties and disciplines.

Despite the existence of formal criteria, however, a number of hurdles exist when it comes to diagnosis of this disorder. “The challenges related to diagnosis of vestibular migraine lie in its relatively broad spectrum of manifestations, the absence of typical migraine headaches with vestibular symptoms, and its very recent definition as a distinct entity,” Huang and colleagues wrote.

In real-world practice, the differential diagnosis can vary based on an individual patient’s presentation. Therefore, the methods used to exclude other potential entities require careful clinical consideration. Neurologists who are referred patients with symptoms of vestibular migraine must rule out other, more precarious disease processes in the initial workup phase, which can involve a variety of specialized tests. “Diagnosis is often delayed because these patients require a more extensive diagnostic workup to rule out other issues. I will therefore get an MRI of the brain and internal auditory canals with and without gadolinium and usually vascular imaging of the head and neck—either computed tomography angiography or magnetic resonance angiog- raphy&mdash;to visualize the posterior vasculature,” Rebovich said. Once other conditions in the differential diagnosis are ruled out, however, no testing mechanism exists for formally confirming a diagnosis of vestibular migraine. “Clinical tests of vestibular function are typically normal, or difficult to interpret based on inconsistent results reported in earlier studies,” Huang et al wrote.

"With regular migraine, we can usually proceed directly to treatment based on history and exam alone. The difficulty is that the symptoms of vestibular migraine can appear to represent posterior circulation stroke, transient ischemic attack, or peripheral vestibulopathy," said Gayle Rebovich, MD. 

It is important to note that even when vascular events are ruled out, the features of vestibular migraine can be mistaken for those of other types of migraine. “Vestibular migraine should not be confused with migraine with brainstem aura when the vertigo occurs as an aura, which occurs 5 to 60 minutes preceding the migraine headache. Migraine with brainstem aura requires at least 2 brainstem symptoms. Vertigo occurs in up to 60% of patients in addition to visual, sensory, or dysphasia aura symptoms,” Kriegler said.

Ruling out other entities often relies, at least partially, on diagnostic tests. But ruling in vestibular migraine is a purely clinical decision-making process that relies on confirming several symptomatic features. “Patients must have a diagnosis of current or past history of migraine with or without aura, vestibular symptoms that last between 5 minutes and 72 hours, and at least 1 of the following 3 migrainous features: photophobia and phonophobia, visual aura, and headache with at least 2 of the following 4 characteristics: unilateral location, pulsating quality, moderate or severe intensity, or aggravation by routine physical activity,” Kriegler said.

Sometimes, patients are started on empirical treatment without a definitive diagnosis, and in some cases, a treatment response may help direct diagnostic decision making. “We may try a course of vestibular therapy to see if they derive any benefit from that. If [they do] not, this supports the diagnosis of vestibular migraine,” Rebovich added.

Patients who suffer from recurrent migraine episodes may need to be provided with a treatment strategy that includes preventative care as well as a plan for abortive therapy. Neurologists generally use the same 2-pronged approach when taking care of patients who experience recurrent vestibular migraines. When patients have frequent, unpredictable, or disabling symptoms, prevention is certainly an important consideration.

“Prevention remains key, and I find antiepileptic drugs (AEDs) or venlafaxine to be most effective,” Watson said. “If the vestibular symptoms are part of migraine, the prognosis is pretty good.” However, not all preventative medications are accessible for each patient, and some treatments that are FDA-approved for migraine prophylaxis are not approved for vestibular migraine, making payer authorization for off-label use in vestibular migraine another impediment.

“I generally treat patients who have vestibular migraine prophylactically just like I do ‘regular migraine’ patients, and it depends what their insurance will approve. Options for prophylaxis include amitriptyline, propranolol, and topiramate. My preference—but often not approved up-front by insurance&mdash;would be 1 of the 3 anti—calcitonin gene-related peptide injectables: erenumab (Aimovig), fremanezumab (Ajovy), or galcanezumab (Emgality),” Rebovich said. Other treatments used for prevention of vestibular migraine include flunarizine and cinnarizine, AEDs (valproic acid, topiramate, and lamotrigine), beta blockers (propranolol and metoprolol), antidepressants (such as amitriptyline), and magnesium and clonazepam.

In addition to prophylaxis, some patients also benefit from using abortive therapies when they experience an episode of vestibular migraine. “In terms of abortive therapy, I am more likely to give benzodiazepines and not give triptans to patients who have vestibular migraine,” Rebovich said. In fact, evidence regarding efficacy of triptans as abortives in the context of acute vestibular migraine is lacking, despite several investigational studies. “Randomized and controlled studies with triptans—zolmitriptan versus placebo during vestibular migraine attacks and rizatriptan versus placebo&mdash;produced inconclusive evidence,” according to Luzeiro et al.

Implantable devices used to deliver VNS have not been successful alternatives in the treatment of vestibular migraine for a number of reasons, including a lack of proven efficacy and an inherent impracticality for patients. “I am generally not a fan of vagal nerve stimulation for vestibular migraine because the implant renders it difficult to impossible to get a future MRI if my patient were to ever need one. Most of these patients are young, so it’s likely that they would need an MRI of some sort in their future decades of life,” Rebovich said. Payers have not been convinced that an implant is cost-effective, either. “It is somewhat expensive and insurers remain skeptical,” Watson added.

However, among the newer approaches to abortive therapy in vestibular migraine, nVNS has shown some promise. It does not require a surgical procedure for implantation and it does not entail the patient commitment to an embedded device. Patients must have a prescription to obtain a nVNS device, and they can usually watch instructional videos to learn how to self-administer the treatment. While there are increasing data regarding the effects of nVNS in the treatment of acute and chronic migraine, not as many studies are available that report the effects of nVNS on the symptoms of vestibular migraine, either prophylactically or as an acute therapy.

Recently, Deborah Friedman, MD, and Shin C. Beh, MD, of UT Southwest Medical Center in Dallas, Texas, published a retrospective chart review in Neurology 6 to examine the effects of nVNS on acute vestibular migraine. They compared the effects of nVNS in patients with vestibular migraine with its effects in patients who had another diagnosis: persistent perceptual postural dizziness (PPPD). The study included 18 patients with vestibular migraine; 14 participants were ultimately treated for a vestibular migraine attack and 4 were treated for bothersome symptoms consistent with PPPD. Patients graded the severity of their vestibular symp- toms and headache using an 11-point visual analogue scale at baseline and 15 minutes after treatment with nVNS. The results showed a substantial improvement for patients with vestibular migraine compared with those with PPPD. The investigators reported that mean vertigo intensity before nVNS was 5.2 compared with 3.1 after stimulation, with a mean reduction in vertigo intensity of 46.9%. In terms of headache, mean severity was graded as a 6.0 prior to treatment and 2.4 after treatments, with a mean reduction in headache intensity of 63.3%. Notably, patients with suspected PPPD reported no benefit.

Friedman and Beh concluded that their study results “provide preliminary evidence that nVNS may provide rapid relief of vertigo and headache in acute vestibular migraine, and support further randomized, sham-controlled studies into nVNS in vestibular migraine.”6

Whether nVNS will prove to be a beneficial and practical treat- ment strategy for abortive or prophylactic management of vestibular migraines remains to be seen. This therapeutic approach has also been used in the prevention of nonvestibular migraine, also with promising results and a paucity of reported adverse effects.

1. Huang TC, Wang SJ, Kheradmand A. Vestibular migraine: an update on current understanding and future directions [published online August 8, 2019]. Cephalalgia. doi: 10.1177/0333102419869317.

2. Flook M, Frejo L, Gallego-Martinez A, et al. Differential proinflammatory signature in vestibular migraine and Me&#769;nie&#768;re disease. Front Immunol. 2019;10:1229. doi: 10.3389/fimmu.2019.01229.

3. Dieterich M, Obermann M, Celebisoy N. Vestibular migraine: the most frequent entity of episodic vertigo. J Neurol. 2016;263 (Suppl 1):S82-S89. doi: 10.1007/s00415-015-7905-2.

4. Luzeiro I, Lui&#769;s L, Gonc&#807;alves F, Pava&#771;o Martins I. Vestibular migraine: clinical challenges and opportuni- ties for multidisciplinarity. Behav Neurol. 2016;2016:6179805. doi: 10.1155/2016/6179805.

5. Lempert T, Olesen J, Furman J, et al. Vestibular migraine: diagnostic criteria. J Vestib Res. 2012;22(4):167-172. doi: 10.3233/VES-2012-0453.

6. Beh SC, Friedman DI. Acute vestibular migraine treatment with noninvasive vagus nerve stimulation. Neurology. 2019;93(18):e1715-e1719. doi: 10.1212/WNL.0000000000008388.

7. Silberstein SD, Calhoun AH, Lipton RB, et al; EVENT Study Group. Chronic migraine headache preven- tion with noninvasive vagus nerve stimulation: the EVENT study. Neurology. 2016;87(5):529-538. doi: 10.1212/WNL.0000000000002918. 

Cover Story

With a differential diagnosis that varies from patient to patient, identifying and treating vestibular migraine continues to challenge even the most experienced clinicians.

Managing Vestibular Migraine: Optimizing Diagnosis and Treatment

As 2019 comes to a close, I feel it’s important to reflect on breakthroughs and advances as it can help invigorate us and our practice in the new year. The past year saw dozens of drug approvals for common, well-known neurological disorders, such as headache and multiple sclerosis (MS), as well as lesser-known but serious disorders, including spinal muscular atrophy. Indeed, the neurology pipeline has been especially fruitful this year, and we have much to look forward to in 2020.

As a headache specialist, 2019 proved especially exciting as several new treatments have become available, including traditional pharmaceuticals as well as noninvasive devices. Notably, the FDA approved galcanezumab as the first drug for the treatment of episodic cluster headache, an incredibly disabling headache disorder with an extremely high unmet treatment need. The agency also recently approved lasmiditan, the first drug in a new class of migraine therapies aimed at optimizing acute relief. The specialty has also seen a surge in new technologies for the treatment of migraine headache, including wearables such as Nerivio, a smartphone-controlled device worn on the arm that promotes migraine pain relief through a conditioned pain response.

However, many other groundbreaking drugs entered other therapeutic areas over the course of the year. In MS, for instance, the FDA approved 2 new drugs just days apart— siponimod, which was the first oral drug approved for the treatment of active secondary-progressive MS as well as relapsing forms of the disease, was quickly followed by the approval of oral cladribine, which is also indicated for the treatment of active secondary-progressive disease and well as relapsing MS. Ongoing pursuits in immunotherapy for MS have also made an impact in 2019, with very promising data emerging from recent clinical trials of ofatumumab, as well as other therapeutic targets, including the S1P receptor modulator ponesimod. I look forward to following the research into 2020 knowing that more treatment choices will benefit both the clinician and the patient.

Perhaps one of the most intriguing developments of the year arrived in October, when Biogen and Eisai announced that they would put their anti-amyloid drug aducanumab in front of the FDA despite shelving the investigational therapy earlier in the year after a disappointing futility analysis. The companies announced that additional analysis of an expanded dataset revealed that patients who received the higher-dose drug for longer showed statistically significant improvements on a clinical dementia rating scale. Although clinical skepticism is especially high when looking at treatments for Alzheimer disease and dementia, I know that I am one of many who hope that the data is strong enough to support regulatory review and approval.

So much awaits us in 2020. I hope that you will stay with 

® as your source for the latest updates in neurology, as well as key insights on topics that matter to you and your practice.

Clinical Insights

The director of the Jefferson Headache Center at Thomas Jefferson University detailed the most notable achievements from 2019, and what to expect in the coming year. 

A Neurology Pipeline for the Ages

To say that the road to finding a treatment for Alzheimer disease (AD) has been rough is quite the understatement. Countless hours and research dollars have been expended in a pursuit that has left some of the world’s most brilliant clinical minds scratching their heads.

In what seems to be failure after failure, some bright spots have emerged. In a surprising reversal, Biogen announced in October that they would pursue regulatory approval for aducanumab, an investigational, amyloid-targeting agent in development with Eisai that had been shelved earlier in 2019 after a disappointing futility analysis. However, additional analysis revealed that patients who received a higher dose of the drug for a longer time showed improvements in cognitive measures, reinvigorating the clinical research team.

Biogen and Eisai are 2 of the last-standing pharmaceutical companies that have continued to pursue amyloid-targeting agents despite multiple previous failures. Driven by the disease’s well established pathophysiology, Biogen and Eisai continue to stand firmly behind aducanumab as well as BAN2401, a humanized monoclonal antibody that selectively binds to soluble protofibrils that is in phase 2b/3 studies.

®, Harald J. Hampel, MD, PhD, MA, MSc, vice president and chief medical officer, Neurology Business Group at Eisai, discussed why the company has stayed the course on the amyloid theory despite many signals pointing in other directions.

Q: Given the results of many failed clinical trials, where do you stand on the amyloid theory?

In October, Eisai and Biogen announced that after consulting with the FDA, Biogen plans to pursue regulatory approval for aducanumab, an investigational treatment for early AD. This news, combined with previously presented BAN2401 data, strengthens the relevance of the amyloid biochemical pathway in the pathophysiology of AD and for targeted disease-modifying therapy.

It is well established that AD pathophysiology—including production, clearance, and brain accumulation of soluble and insoluble forms of amyloid-β and phosphorylated tau proteins&mdash; commences decades before any clinical symptomatic manifestation. A characteristic early temporal and spatial progression of AD pathophysiology during the asymptomatic preclinical stages involves distinct neuroanatomic structures, including the precuneus and the cingulate cortex. These brain areas belong to the so-called “default mode network,” which is a central functional brain network where neurotoxic amyloid-β evolves, accumulates, and aggregates. Novel techniques using molecular neuroimaging enable the in vivo assessment of the presence and progression of aggregated fibrillar amyloid-β across affected regions of the brain, such as the default mode network.

Moreover, functional magnetic resonance imaging studies indicate that hyperconnectivity exists within brain regions of the default mode network during the preclinical phase of AD. Such a hyperconnectivity may represent a very early compensatory mechanism of the brain that, after reaching a certain threshold, can break down, initiating a decompensation process characterized by the progressive loss of synaptic function across neurons within networks. The later event of this progressive detrimental path is represented by widespread failure of synaptic systems in neuronal networks that represent cognitive functions, the processes underlying AD cognitive and behavioral symptoms along its clinical continuum. Therefore, accumulating evidence does point at amyloid-β as an initiator, trigger, and subsequently driver of progressive loss of brain homeostasis, function, and structure, which ultimately leads to mild cognitive impairment and AD dementia. What the scientists are finding is that the contribution of the amyloidogenic cycle to Alzheimer pathophysiology is getting increasingly clear. So, rather than thinking of this biochemical pathway as a linear cascade, which I think is deceiving, we should see this more like a nonlinear, dynamic, chronically evolving cyclic proteinopathic pathway.

The idea would be that the compounds that are actually effectively targeting important soluble aggregated perpetrator molecules of this cyclic pathway would then reduce the bulk of the neurotoxic onslaught. Then, the brain’s immune system, through surrounding glia cells, both microglia and astrocytes, can digest and get rid of the rest and not be overwhelmed. This is partly hypothetical, but it’s getting increasingly substantiated, through evolving evidence, that brain glial cells play an important role. All of these critical elements of the pathophysiological pathway are getting increasingly clear from preclinical, ex vivo, animal research, and human clinical research, in early clinical, preclinical, asymptomatic cohorts that are systematically longitudinally observed. Also being studied are cohorts of autosomal dominant amyloid-β mutation carriers.

It also becomes clear that these cascades are modulated by the individual’s biological background, including human genetic variation.

The Arctic mutation, found in a Swedish family with a history of familial early-onset AD, has been essential to untangle the role of a particular critical form of the cyclic amyloid pathway, the amyloid-β protofibrils. The word is from the ancient Greek pro&#770;tos, “first,” plus fibrils or filaments, and protofibrils are a particularly toxic species of soluble aggregated amyloid-β. Like many autosomal dominant mutations in the amyloid precursor protein gene, patients bearing the Arctic mutation display high rates of synaptic and neuronal toxicity with an overall fast disease progression, including an early onset— usually their 50s or even 40s. This mutation leads to a substantially increased rate of formation of the soluble aggregated amyloid-β protofibrils. Subsequent studies conducted in the Arctic mutation family indicated that the amyloid-β protofibrils are particularly toxic species within the amyloid-β cycle.

An ever-increasing number of mutations—more than 200&mdash;have been found within the APP and PSEN 1 and 2 genes, often causing an overstimulation of the pathological amyloidogenic pathway. This results in high rates of production of amyloid-β byproducts, including the particularly toxic amyloid-β oligomers and protofibrils. These genetic mutations, however, account for only a small fraction of AD individuals. Most patients suffer from multigenetic, “sporadic,” late-onset forms of AD, which are likely characterized by imbalances between production and clearance of amyloid-β, rather than only overproduction. The accumulation of toxic amyloid-β species occurs gradually first in brain areas of the default mode network and then spreads strategically throughout important cortical areas of the brain related to cognitive functions, such as memory, learning, and attention.

Q: What is some of the most encouraging work being done in the biomarker space?

The Alzheimer biomarker science is currently gaining momentum and evolving in a dynamic and very positive way. For example, the BAN2401 phase 2 clinical trial gives confidence that in an early AD population, you see a consistent impact of treatment on core feasible biomarkers of Alzheimer pathophysiology. It is very useful to have these validated and standardized biomarkers that are very informative in regard to the underlying key molecular mechanisms of active pathophysiological pathways in AD. The research field is currently evolving from valuable cerebrospinal fluid biomarkers to blood-based biomarkers, and in the coming years, this will ultimately enhance the options of broad early detection and diagnostic use. We might even see use for patient screening algorithms and further implementation in clinical therapy trials.

The phase 2 data analysis of the BAN2401 trial showed a significant reduction of the cerebrospinal fluid (CSF) concentrations of a number of core pathophysiological biomarkers. These included 1) neurogranin, a surrogate marker of synaptic dysfunction; 2) neurofilament light chain (NfL) protein, a biomarker of axonal damage; and 3) phosphorylated tau protein, a biomarker of tau-related pathophysiology, which is another driver of synaptic toxicity and neurodegeneration that acts in detrimental coexistence with amyloid-β, apparently driving disease progression. Of note, these study results were reported from a comparison investigation between 23 BAN2401- treated patients versus 16 placebo-treated controls. Therefore, these promising data need to be corroborated in a larger sample, which is currently being pursued in the large-scale phase 3 Clarity AD trial.

These biomarkers reflect AD pathophysiological hallmarks, and their development is ongoing and increasingly supporting clinical trials. In collaboration with Japan-based Sysmex (the US regional affiliate of Kobe), Eisai is currently developing a blood-based biomarker assay that is very robust and has the potential to provide, in coming years, a plasma assessment of amyloid-β peptides 1-40 and 1-42. Blood-based biomarkers could represent a future first-line screening tool, enabling a globally feasible and accessible large-scale multistep diagnostic process, starting in primary care, to accurately identify amyloid-positive people in the earlier, clinically silent stages of the disease. Such a tool may perhaps be able to reduce the use of expensive and invasive positron emission tomography (PET) scans and lumbar punctures, which also are not globally accessible. Sysmex-based plasma amyloid-β 1-40 and 1-42 concentrations correspond with CSF measurements. A robust body of studies already indicated that plasma amyloid-β 1-40 and 1-42 concentrations have concordance with results obtained using amyloid PET scans. A recent study indicates that plasma amyloid-β 1-40 and 1-42 concentrations might be even more sensitive and be positive earlier than CSF assessment and PET scanning, at the earliest preclinical stages of disease. Therefore, it seems particularly promising that blood-based assays may become available and support a timely and comprehensive identification of at-risk individuals with initial cerebral amyloid upregulation. To follow, other biomarkers currently measurable in CSF, such as NfL, YKL-40, tau proteins, neurogranin, and others, may soon be validated in blood.

Global biomarker development is progressing rapidly. Globally accessible, reliable, and qualified tools might become available even for primary care in the near future to screen and identify asymptomatic individuals in a timely fashion. By evaluating distinct active pathophysiological pathways in the brain, including the amyloid pathway, [the earliest stages of AD] could be effectively targeted with an evolving spectrum of potential pathway-based disease-modifying therapies, such as the investigational candidates aducanumab and BAN2401.

Clinical Viewpoint

The vice president and chief medical officer of the Neurology Business Group at Eisai discussed the company's decision to continue efforts on amyloid therapy despite prior setbacks. 

Eisai Stays the Course on Amyloid Despite Setbacks

When caring for people with movement disorders, neurologists have long relied on treatment options that target the symptoms of the disease. In Parkinson disease (PD), for example, current therapies address motor symptoms and nonmotor symptoms such as psychosis or cognitive decline.

While such therapeutic options have steadily improved in terms of availability and efficacy, a void remains in the treatment of movement disorders that only disease-modifying therapies can fill.

“So far, we only have symptomatic therapies available: These are dopamine replacement thera- pies, which can be quite effective, especially in the early stage of Parkinson disease. However, after a while, these therapies tend to lose their effectiveness and health problems get worse for patients,” said Lars To&#776;nges, MD, head of the Movement Disorders Unit in the Department of Neurology, Ruhr University, Bochum, Germany. Indeed, symptomatic treatments do not target the root cause of a disease and may even lead to undesirable adverse effects for patients.

Addressing the longstanding need for a novel curative treatment for movement disorders, immunotherapy has emerged as a promising area of development.

To&#776;nges, who is involved in multiple studies exploring possible strategies to cure movement disorders, said interest in immunotherapy to treat PD is very high “because it is an entirely novel approach to treat PD. So far, we have no therapy to tackle the pathogenic origins of the disease. However, immunotherapies will not only improve symptoms; they may also stop or at least slow down the disease itself.”

Recent studies in neurology and immunology show that the immune response may be significantly involved in countering the progression of movement disorders. In particular, researchers are increasingly exploring the role that the pathology of α-synuclein may play in treating movement disorders.

While much of this research is still in the development phase, Howard Gendelman, MD, the Margaret R. Larson Professor of Internal Medicine and Infectious Diseases and chairman of the Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center in Omaha, said he believes that “immunotherapy for movement disorders has a bright future.” Indeed, clinical development of immunotherapies for move- ment disorders is progressing rapidly, with many studies shifting from animal trials to human clinical trials.

Recent studies exploring immunotherapy for movement disorders revolve around 2 main strategies: the use of antibodies to target the α-synuclein pathology and harnessing the neuroprotective properties of regulatory cells.

The role of antibodies in α-synuclein pathology

Α-synuclein performs various functions, including communication among neurons.

 In PD, α-synuclein can become a pathological agent that leads to toxic effects on neurons and drives neuroinflammation.

“Due to α-synuclein and its aggregation in the brain and the central nervous system (CNS), there are many resulting disturbances in cell function. Protein ubiquitination systems are affected, the synaptic vesicle release is disturbed, and new inflammatory

a-Synuclein Immunotherapy processes are fostered,” To&#776;nges said. Subsequently, a common goal in developing immunotherapy for PD is to reduce the α-synuclein burden in the CNS.

 “Our primary goal is to find a cure for Parkinson disease. This means targeting the α-synuclein pathology, which is undoubtedly the primary pathology,” he said.

The use of immunologic, antibody-based technologies is a novel approach to reduce the burden α-synuclein has on the CNS.

 “Antibodies can directly counteract α-synuclein pathology in the brain,” To&#776;nges said. “Those antibodies that have the goal of binding pathogenic α-synuclein aggregates are seen as an effective means to eliminate α-synuclein pathology to a certain extent, and thereby reduce its pathogenic alterations.” The results of research underway by To&#776;nges and his colleagues have shown reductions in pathogenic alterations when α-synuclein antibodies are given as immunotherapy. However, To&#776;nges did note that studies in this area are still only in phase 2: “Currently, the antibody approach represents a new and very important therapeutic approach, but we cannot say yet if it will be effective. Two big clinical trials are still ongoing: the PASADENA study and the SPARK study.”

The PASADENA study is a randomized, double-blind, phase 2 clinical trial of prasinezumab (RO7046015/ PRX002), an investigational monoclonal antibody directed against α-synuclein aggregates.

 The antibody is intravenously introduced into patients diagnosed with mild or moderate idiopathic PD. Roche and the biotechnology company Prothena began the study in April 2017 and have completed the recruitment stage. The study is set for primary completion before the end of 2019, with full completion expected in 2021 (

The SPARK study aims to evaluate the safety, pharmacokinetics, and pharmacodynamics of the humanized monoclonal antibody BIIB054 in patients with early-stage PD.

 Preclinical data have shown that BIIB054 contributes to a reduction in the spread of α-synuclein and limits its impact on neuron damage.

 Biogen began the study in January 2018; its initial completion is set for May 2020, with full completion scheduled for June 2021. 

“Both the PASADENA and SPARK studies apply α-synuclein anti-bodies intravenously," Tonges said. "Primarily, the aim of these 2 big trials is to see whether these Parkinson disease treatments are safe and well tolerated in patients. The changes in motor and nonmotor symptoms are secondary endpoints. If these phase 2 endpoints are fulfilled, only then will we have larger phase 3 trials and only then can we evaluate whether these antibody therapies are effective in the Parkinson disease patient population."

The role of regulatory cell activites in neuroprotection 

According to Gendelman, "What is known to date is that the healthy immune system can temper brain inflammation as it occurs in stroke and in autoimmune and neurodegenerative diseases such as Alzheimer disease, amyotrophic lateral sclerosis, and Parkinson disease.” To leverage the ability of a healthy immune system to mitigate inflammation, researchers are exploring the use of T cells and B cells, as well as mononuclear phagocytes, as a novel strategy to potentially treat movement disorders. T cells and B cells play a role in maintaining peripheral immune tolerance and help to regulate immune response in the body.

 Mononuclear phagocytes such as microglia, macrophages, and dendritic cells also help regulate tissue damage and repair neuroinflammation.

“Recent work by several laboratories in vitro, ex vivo and in vivo have shown how regulatory cells can be harnessed as cell-based therapies for neurological disorders,” Gendelman said. ”Regulatory T cells, B cells, and mononuclear phagocytes are cells mediating brain homeostasis. Regulatory immune cell therapies can attenuate inflammation-associated brain injury and thus affect brain repair.”

Gendelman and colleagues are working on the use of “smart” drugs that are packaged into immunocytes as a “Trojan horse” cell-based mechanism to bypass the blood—brain barrier and enter diseased brain areas. “We are working on long-acting forms of granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim) that may be packaged into nano formulations,” Gendelman said. “GM-CSF can modulate microglial-associated neurotoxicity and is effective in traumatic brain injury, stroke, amyotrophic lateral sclerosis, Alzheimer disease, and Parkinson disease. However, these solutions remain in development.”

Research on the neuroprotective responses of GM-CSF has moved on from a spectrum of animal models toward human trials. For instance, a phase 1 study conducted by Gendelman and colleagues on the safety and immunomodulatory effects

of sargramostim in PD has since been translated into human trials.

 These trials were based on animal investigations span- ning more than 10 years, which demonstrated the neuroprotection features of regulatory T cells in the dopaminergic pathway, revealing a potential for immune transformation in PD.

“Through our prior published works, we have demonstrated that sargramostim treatment modulates the microglial activation and the consequent secretion of proinflammatory factors that ultimately damage neurons,” Gendelman said.

He further explained that such neurons are in the pars compacta, which is part of the brain’s substantia nigra located in the midbrain and formed by dopaminergic neurons that may be damaged in PD. “We have shown that the modulation by GM-CSF treatment can occur through induction of regulatory T cells that can migrate from the periphery across the blood—brain barrier and, as such, lead to neuroprotective activities during Parkinson disease,” he said.

In their early clinical trials, Gendelman and colleagues have shown that the effects of modulation by sargramostim treatment is linked to improved motor functions in patients with PD. Furthermore, patients administered sargramostim showed modest improvements according to the Unified Parkinson’s Disease Rating Scale. Patients also showed improved motor activities and regulatory T cell numbers and function, demonstrating the potential for using GM-CSF to modulate immune response and thus provide thera- peutic gain for patients with PD.

In another ongoing study, yet to be published, Gendelman demonstrates how restoration of the balance in regulatory cells can improve disease conditions. Specifically, he is looking at how a transforma- tion from effector cells to regulatory cells can lead to neuroprotection in a broad range of neurodegenerative conditions.

Beyond Parkinson Disease: Immunotherapy for Other Movement Disorders

Studies on the potential therapeutic gain of harnessing antibodies and regulatory cells in the immune system are mostly geared toward developing treatments for PD. “In my opinion, there has been a very strong development in immunotherapy and Parkinson disease because we now know the disease not only on a pathological level but also on a neuromolecular level. We now know that multiple immune processes are associated with neurodegeneration,” To&#776;nges said. He pointed out that, fortunately, “There are new technologies, where we can find immunotherapeutic targets in Parkinson disease that we can also use as therapeutics for other diseases.”

Specifically, the research so far on antibodies against α-synuclein might also apply in other etiologies and forms of parkinsonism as well as in other movement disorders with α-synuclein co-pathology.

Multiple system atrophy (MSA) is a severe neurodegenerative condition characterized by symptoms similar to those in PD. One study found that antibody levels that are significantly low in PD were almost absent in MSA. This indicates that patients with MSA have impairments in the processes that block the toxic effect of α-synuclein aggregation and that modulate the progression of inflammatory symptoms.

The pathogenesis of MSA remains unknown because of a lack of understanding of the causative mechanisms underlying the condition.

 However, MSA is another disease with a strong α-synuclein pathology, involving the aggregation of the protein. “Antibodies are a potential treatment in MSA and should be studied soon,” To&#776;nges said.

Huntington disease (HD) is an inherited neurodegenerative disorder that involves uncontrolled tremors, cognitive impairment, and psychiatric issues for which no disease-modifying treat- ments exist.

 However, understanding of the pathogenesis of HD has been increasing, allowing the identification of potential therapeutic targets and research into disease-modification approaches. While not all clinical trials regarding HD disease modification have produced favorable results, immunotherapies are still believed to hold promise in modulating neuroinflammation.

 For instance, the SIGNAL trial, a randomized, double-blind phase 2 study, is investigating the effect of mAb 67-2 (a monoclonal antibody) on semaphorin 4AD, a protein that modulates neuroinflammation pathways in the nervous system.

The modulation of α-synuclein also has application in efforts to develop a treatment for HD. “We know that α-synuclein pathology spreads out in the brain and that, of course, antibodies offer a very clear first approach to directly target this pathology,” To&#776;nges said. “Other therapies could also be directed toward lowering α-synuclein levels, such as antisense oligonucleotides. These have been successfully implemented in HD to downregulate the protein huntingtin.” Indeed, pharmaceutical companies are harnessing antisense oligo- nucleotides, which can interfere or silence the gene that promotes HD, to develop treatment for the condition.

Paraneoplastic movement disorders (PMDs) are neurological conditions characterized by either hyperkinetic or hypokinetic movements. A recent review showed that identifying the right antibody could be essential for applying immunotherapy to the treatment of PMDs.

Specifically, PMDs are immune-mediated, as demonstrated by the presence and rapid onset of antineuronal antibodies in biological samples of patients during diagnosis. Two classes of antineural antibodies exist: those against intracellular neuronal antigens and those against surface antigens (NSAs). The former are considered markers of the so-called “classical PMDs,” but they do not have a direct pathogenic role in movement disorders. Measuring the antibodies against these antigens, therefore, does not provide a full picture of the potential of immunotherapy for treating PMDs.

NSAs were found to respond more frequently to immunotherapy than intracellular neuronal anti- gens, demonstrating that the antibodies reacting against NSAs have a direct pathogenic role in PMDs.18 “When the antibody has a direct pathogenic role, it is easier to target it with immunotherapy compared with intracellular neuronal antigens,” said Carlo Colosimo, MD, chairman of the Department of Neurology at Santa Maria University Hospital in Terni, Italy.

In terms of the future of immunotherapy for PMDs, Colosimo has high hopes: “We see great potential, particularly in increasing the knowledge and diagnosis of PMDs. The earlier these patients are diagnosed, the better their outcome will be in terms of survival, considering that PMDs may manifest up to 6 years before full onset. More patients will also be enrolled in future clinical trials and new disease-modifying treatment options will be available.”

Recent studies on the potential therapeutic uses of antibodies and regulatory cells augment clinicians’ current clinical understanding of movement disorders and their common disease pathways. “We now have a very good molecular understanding, with new insights into the pathology of movement disorders,” To&#776;nges said.

Neurologists should pay attention to developments in immunotherapies for movement disorders, as they could lead to improved clinical benefit for patients. Moreover, neurologists may be able to apply existing immunotherapies for movement disorder treatment, thus helping to optimize the use of currently available immunotherapies. “In movement disorders, we use exactly the same therapies that are used in other fields, and the main progress in immunotherapies has already been done for autoimmune diseases as well as for oncological disorders,” Colosimo said.

Clinical benefit has yet to be clearly demonstrated, but To&#776;nges is optimistic: “We see that these antibodies really meet their goal of precise molecular targeting.” In addition to precision targeting, advancements in immunotherapy for movement disorders could ultimately lead to the development of treatments that target the cause of the disease in the near future.

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2. Zella SMA, Metzdorf J, Ciftci E, et al. Emerging immunotherapies for Parkinson Disease. Neurol Ther. 2019;8(1):29-44. doi: 10.1007/s40120-018-0122-z.

3. Aquino CC, Fox SH. Clinical spectrum of levodopa-induced complications. Mov Disord. 2015;30(1):80- 89. doi: 10.1002/mds.26125.

4. A study to evaluate the efficacy of prasinezumab (RO7046015/PRX002) in participants with early Parkinson’s disease (PASADENA). clinicaltrials.gov/ct2/show/NCT03100149. Updated April 26, 2019. Accessed October 3, 2019.

5. Evaluating the safety, pharmacokinetics, and pharmacodynamics of BIIB054 in participants with Parkinson’s disease (SPARK). clinicaltrials.gov/ct2/show/NCT03318523. Updated September 6, 2019. Accessed October 3, 2019

6. Bendor JT, Logan TP, Edwards RH. The function of α-synuclein. Neuron. 2013;79(6):1044-1066. doi: 10.1016/j.neuron.2013.09.004.

7. Sulzer D, Edwards RH. The physiological role of α-synuclein and its relationship to Parkinson’s disease. J Neurochem. 2019;150(5):475-486. doi: 10.1111/jnc.14810.

8. Zella MAS, Metzdorf J, Ostendorf F, et al. Novel immunotherapeutic approaches to target alpha-synuclein and related neuroinflammation in Parkinson’s disease. Cells. 2019;8(2):E105. doi: 10.3390/cells8020105.

9. Bashir H. Emerging therapies in Huntington’s disease. Expert Rev Neurother. 2019;19(10):983-995. doi:10.1080/14737175.2019.1631161.

10. 10. Weihofen A, Liu Y, Arndt JW, et al. Development of an aggregate-selective, human-derived α-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson’s disease models. Neurobiol Dis. 2019;124:276-288. doi: 10.1016/j.nbd.2018.10.016.

11. Romano M, Fanelli G, Albany CJ, Giganti G, Lombardi G. Past, present, and future of regulatory T cell therapy in transplantation and autoimmunity. Front Immunol. 2019;10:43. doi: 10.3389/fimmu.2019.00043.

12. Locatelli G, Theodorou D, Kendirli A, et al. Mononuclear phagocytes locally specify and adapt their phenotype in a multiple sclerosis model. Nat Neurosci. 2018;21(9):1196-1208. doi: 10.1038/s41593-018-0212-3.

13. Gendelman HE, Zhang Y, Santamaria P, et al. Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson’s disease trial. NPJ Parkinsons Dis. 2017;3:10. doi:10.10.1038/s41531-017-0013-5.

14. Folke J, Rydbirk R, Løkkegaard A, et al. Distinct autoimmune anti-α-synuclein antibody patterns in multiple system atrophy and Parkinson’s disease. Front Immunol. 2019;10:2253. doi: 10.3389/fimmu.2019.02253.

15. Monzio Compagnoni G, Di Fonzo A. Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives. Acta Neuropathol Commun. 2019;7(1):113. doi: 10.1186/s40478-019-0730-6.

16. Malcolm E. Antisense oligonucleotides. Huntington’s Disease News website. huntingtonsdiseasenews.com/antisense-oligonucleotides/. Accessed October 3, 2019.

17. SIGNAL: a new investigational approach to early treatment of Huntington’s disease. Huntington Study Group website. huntingtonstudygroup.org/current-clinical-trials/signal-trial/. Accessed October 3, 2019.

18. Chirra M, Marsili L, Gallerini S, Keeling EG, Marconi R, Colosimo C. Paraneoplastic movement disorders: phenomenology, diagnosis, and treatment. Eur J Intern Med. 2019;67:14-23. doi: 10.1016/j. ejim.2019.05.023. 

A greater understanding of the role of the immune system in movement disorders may illuminate a path to treatments that target the central causes of disease.

Exploring the Potential of Immunotherapy for Movement Disorders

The luxury of a good night’s sleep waxes and wanes throughout life, but for over 40% of elderly adults, a restful and fulfilling sleep is far from reality.

 Complicated by comorbidities and polypharmacy, diagnosing and treating sleep problems in this population is particularly difficult.

In an effort to better educate the health care community about these concerns, Karl Doghramji, MD, medical director of the Jefferson Sleep Disorders Center at Jefferson University Hospitals in Philadelphia, Pennsylvania, sat down with 

® for an in-depth interview on the optimal management of sleep disorders, particularly insomnia, in elderly adults.

How do sleep patterns change in the elderly and what are the consequences of those changes?

We know that the prevalence of insomnia increases as we age, and there are a number of reasons for that. One of the major and most important reasons is that sleep seems to naturally fragment as we age. We sleep less during the course of the night, and older individuals become sleepier during the course of the day and nap more. In addition, they seem to have a shortened amount of slow- wave sleep or some of the deeper stages of sleep, and an increased amount of shallow sleep or stage I sleep.

The question has always been, are these changes a result of the natural process of aging, or are these caused by medical and psychiatric and other conditions, which also increase in prevalence as we age? The data seem to suggest that not all these changes are due to comorbid conditions, and that there seems to be a natural degradation in sleep as we age.

Karl Doghramji, MD, medical director of the Jefferson Sleep Disorders Center, reviews optimal management strategies for elderly patients with insomnia disorder.

December 2019

Judgment Call: Exploring Treatment Tactics in Clinically Isolated Syndrome

Managing Vestibular Migraine: Optimizing Diagnosis and Treatment

A Neurology Pipeline for the Ages

Eisai Stays the Course on Amyloid Despite Setbacks

Exploring the Potential of Immunotherapy for Movement Disorders

Addressing Insomnia in the Elderly

Studies Investigate 2 Doses of Fenfluramine in Dravet Syndrome

Targeting the NF-kB Pathway in Duchenne Muscular Dystrophy

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