Tori Rodriguez, MA

In recent decades, the development of therapies for patients with relapsing-remitting multiple sclerosis (RRMS) has significantly progressed, with FDA approval of numerous anti-inflammatory disease-modifying therapies (DMTs). However, advances in drug development for progressive forms of MS—affecting an estimated 10% to 15% of patients with MS&mdash;have lagged considerably in comparison.

“Disease modification for progressive MS continues to be challenging,” said Kathleen Costello, MS, a board-certified adult nurse practitioner and MS nurse specialist as well as the National Multiple Sclerosis Society’s associate vice president of healthcare access. “Most current therapies that are FDA approved for relapsing forms of MS include ‘active secondary progressive MS’ in the approval, but that implies that there is ongoing inflammation as seen on MRI or presenting as a relapse,” she told 

, whereas primary-progressive MS (PPMS) is characterized by steadily worsening neurologic function with no relapses.

This treatment gap is largely attributed to the continued lack of clarity regarding the mechanisms that drive disease activity in PPMS and secondary-progressive MS. Disease progression has been cited as the main contributing factor in MS-related disability accumulation, further underscoring the need for effective treatment strategies for the disease’s progressive forms.

“I think the biggest challenge in treating progressive MS is understanding its pathophysiology,” said Robert J. Fox, MD, staff neurologist at the Mellen Center for Multiple Sclerosis and vice-chair for research at the Neurological Institute of Cleveland Clinic in Ohio. “What is truly driving the insidious decline? Is it compartmentalized inflammation? A metabolic derangement? A mitochondrial dysfunction? At this point, we really don’t know.”

While it is understood that relapses in RRMS are driven by inflammation due to infiltration of peripheral leukocytes across the blood-brain barrier into the central nervous system (CNS), the relationship between inflammation and the blood-brain barrier in progressive MS is less clear.

 Historically, MS research has focused predominantly on the relapsing phase of MS, in which relapses and inflammation can be assessed on MRI.

 In progressive MS, the lack of specific biomarkers and outcomes measures have presented barriers to the development of new therapies.

The available evidence suggests that “progressive MS is characterized by ongoing inflammation that occurs within the CNS, with an intact blood-brain barrier,” according to Costello. “There appear to be more activated microglia as well as involvement of T and B lymphocytes in progressive MS, and there is evidence of mitochondrial and axonal damage from reactive oxygen species and nitrogen species, which can lead to neurodegeneration.”

The compartmentalized inflammation associated with progressive MS may limit or preclude the effectiveness of anti-inflammatory DMTs that have shown promise in RRMS.

“Currently, where there is ongoing inflammation, we know that stopping the infiltrating inflammation with anti-inflammatory therapies can be helpful—at least, modestly helpful,” Fox told 

. Aside from this benefit, the effects of such therapies on progressive MS pathologies remain unclear. “If there is no active infiltrative inflammation, the potential benefits of anti-inflammatory therapies are modest, with risks often outweighing them.”

In research described in 2019 in the European Journal of Neurology, investigators from the MSBase cohort study conducted an analyses of pooled data (n = 1284) to examine the effects of anti-inflammatory DMTs approved for RRMS and used off-label to treat progressive MS.

  The MSBase team found that these agents had no substantial effect on the short- to medium-term disability outcomes of progressive MS patients, as indicated by a lack of significant difference between treated and untreated patients in the hazard ratios of 3&#8208;month confirmed Expanded Disability Status Scale (EDSS) progression events (HR, 1.0; 95% CI, 0.6—1.7; 

 = .87), confirmed EDSS improvement (HR, 1.0; 95% CI, 0.6—1.6; 

 = .91), or reaching a confirmed EDSS step ≥7 (HR, 1.1; 95% CI, 0.7—1.6; 

Ocrelizumab, currently the only FDA-approved agent to treat PPMS, is the only therapy thus far that has demonstrated efficacy in reducing the accumulation of disability in this patient population. In the results of the phase 3 ORATORIO trial of 732 patients with PPMS, published in 2017 in the 

, the primary end point of confirmed disability progression at 12 weeks was observed in 32.9% of patients taking ocrelizumab compared with 39.3% of those in the placebo arm (HR, 0.76; 95% CI, 0.59-0.98; P = .03).

In terms of secondary end points, confirmed disability progression at 24 weeks was noted in 29.6% of those taking ocrelizumab versus 35.7% with placebo (HR, 0.75; 95% CI, 0.58-0.98; 

 = .04); also, performance on the timed 25-foot walk declined by 38.9% with ocrelizumab versus by 55.1% with placebo (

 = .04). In addition, there was a 3.4% reduction in the total volume of brain hyperintense T2 lesions on MRI with ocrelizumab compared with a 7.4% increase with placebo (

 <.001), and brain volume decreased by 0.90% with ocrelizumab versus 1.09% with placebo (

Patients taking ocrelizumab experienced more frequent infusion-related reactions, upper respiratory tract infections, oral herpes infections, and neoplasms, compared with placebo. Rates of serious adverse events and serious infections did not differ significantly between groups.

“While these results are modest, they do indicate a place for ocrelizumab in the treatment of some individuals with PPMS,” Costello said.

Many researchers are trying “to better understand the true driving pathophysiology of progressive MS,” said Fox. “Once that is better understood, it should be easier to develop therapies for it.”

To effectively guide the development of new treatment strategies, Costello said that the immunopathological mechanisms involved in progressive MS, as well as mechanisms that inhibit remyelination, both need to be elucidated. “Treatments that can slow or stop progression and reduce damage to axons, and strategies that could promote remyelination, would certainly change the treatment paradigm in progressive MS” and improve disease stability, she said, allowing patients to participate in desired activities.

Potential therapies under investigation include agents to inhibit microglial activation and reduce oxidative stress.

 Additionally, researchers are currently aiming to identify the most appropriate biomarkers to use in screening progressive MS therapies. In this area, a wide range of potential measures may indicate disease progression, including plasma neurofilament light chain levels, unique volatile organic compounds in the breath, and other MRI, blood, and cerebrospinal fluid biomarkers.

“At this point, imaging biomarkers appear to hold the most promise in progressive MS,” said Fox. “Cortical atrophy and magnetization transfer ratio (MTR) imaging appear to have good reproducibility and dynamic change over time. The phase 2 SPRINT-MS trial found both of these to be particularly powerful in measuring the effect of ibudilast in progressive MS.”

The estimated rate of annual change in MTR over the 96-week study period was −0.0282 with placebo and −0.0051 with ibudilast (difference, 0.0231; 95% CI, 0.0003-0.0458). For cortical thickness, the estimated rate of annual change was −0.0105 with placebo and −0.0019 with ibudilast (difference, 0.0086; 95% CI, 0.0028-0.0144). “These markers may allow for smaller, shorter, and more efficient phase 2 trials in the future,” Fox said.

“Progressive forms of MS present increased challenges due to the accumulation of disability, which may include difficulties with mobility, cognition, balance, or other symptoms, leading to greater challenges with maintaining employment and other role responsibilities,” Costello explained. “These complex issues require a coordinated and comprehensive approach that may include rehabilitation, mental health, neuropsychology, vocational rehabilitation, and others to optimize function and ability to participate.”

Costello noted that not all practices have access to the resources listed above. To help, the National Multiple Sclerosis Society has a staff of highly trained MS Navigators available to partner with health care providers and patients to provide support, identify resources, and assist with job challenges and disability affecting individuals with progressive MS.

1. Lorscheider J, Kuhle J, Izquierdo G, et al; MSBase Study Group. Anti-inflammatory disease-modifying treatment and disability progression in primary progressive multiple sclerosis: a cohort study.&#8239;Eur J Neurol. 2019;26(2):363-370. doi:10.1111/ene.13834 

2. Hollen CW, Paz Soldán MM, Rinker JR 2nd, Spain RI. The future of progressive multiple sclerosis therapies.&#8239;Fed Pract. 2020;37(Suppl 1):S43-S49. 

3. Ruiz F, Vigne S, Pot C. Resolution of inflammation during multiple sclerosis.&#8239;Semin Immunopathol. 2019;41(6):711-726. doi:10.1007/s00281-019-00765-0 

4. Machado-Santos J, Saji E, Tröscher AR, et al. The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells.&#8239;Brain. 2018;141(7):2066-2082. doi:10.1093/brain/awy151 

5. Montalban X, Hauser SL, Kappos L, et al; ORATORIO Clinical Investigators. Ocrelizumab versus placebo in primary progressive multiple sclerosis.&#8239;N Engl J Med. 2017;376(3):209-220. doi:10.1056/NEJMoa1606468 

6. Multiple Sclerosis Society (United Kingdom). Biomarkers: the road to certainty. May 29, 2020. Accessed July 2, 2020. https://www.mssociety.org.uk/research/latest-research/latest-research-news-and-blogs/biomarkers-the-road-to-certainty 

7. Fox RJ, Coffey CS, Conwit R, et al; NN102/SPRINT-MS Trial Investigators. Phase 2 trial of ibudilast in progressive multiple sclerosis.&#8239;N Engl J Med. 2018;379(9):846-855. doi:10.1056/NEJMoa1803583 

Articles

New biomarkers of disease activity may help better vet investigational therapies aimed at slowing the insidious neurodegeneration seen in primary progressive multiple sclerosis.

Closing the Treatment Gap in Progressive MS

For more than 60 million headache sufferers worldwide, attempts to achieve pain relief have ironically led to increased headache frequency and progression.

 The neurology community has redefined medication overuse headache (MOH) many times since it first appeared in the International Classification of Headache Disorders (ICHD) in 2004. The most recent edition (ICHD-3) defines MOH as a headache disorder occurring on 15 or more days per month in a patient with a preexisting primary headache and developing as a consequence of regular overuse of acute or symptomatic headache medication for more than 3 months.

Prevalence rates for MOH tend to range from 1% to 2%, although certain countries have seen higher rates, and headache centers have reported significantly higher rates (30%-50%). Epidemiologic data suggest that the prevalence of MOH is highest among adults aged 30 to 50 years, with a preponderance of cases in female patients versus male patients (ratio, roughly 3-4:1). Furthermore, between 21% and 52% of pediatric patients with chronic headache meet the diagnostic criteria for MOH.

Although all acute headache medications can potentially lead to MOH, results of various studies have shown that the risk of MOH is higher with combined analgesics and opioids compared with triptans and ergotamine, with one investigation demonstrating a 2-fold—greater risk of developing chronic headache in patients using barbiturates or opiates compared with those using triptans or single analgesics.

 Research has also linked nonsteroidal anti-inflammatory drug (NSAID) use to a higher MOH risk in patients with more than 10 headache days per month.

Migraine and tension-type headache are the main risk factors for MOH, although some cases have been reported in patients with cluster headache.

 Regular use of tranquilizers (odds ratio, 5.2; 95% CI, 3.0-9.0), chronic musculoskeletal complaints, gastrointestinal complaints, higher scores on the Hospital Anxiety and Depression Scale, and a family history of MOH or substance abuse (more than 3-fold—increased risk) have been identified as additional risk factors.

“One of the most recent developments in the understanding of MOH has been scientific work published in the past several years showing that MOH may be associated with a genetic predisposition to brain function changes involving pain processing and addiction,” Jessica Ailani, MD, associate professor of clinical neurology at Medstar Georgetown University Hospital and director of the Medstar Georgetown Headache Center in Washington, DC, told 

Neuroimaging studies have linked MOH with structural and functional alterations in regions of the brain that have been implicated in pain processing and addiction (

 Although the pain processing effects appear to normalize after discontinuation of the overused drug, some of the abnormalities relevant to addiction may persist after discontinuation, indicating that they represent a “brain trait that predisposes certain individuals to medication overuse and MOH.”

This diagnosis “continues to be viewed with some skepticism by certain members of the headache research and clinical community,” Elizabeth K. Seng, PhD, research associate professor in the Saul R. Korey Department of Neurology at the Albert Einstein College of Medicine in Bronx, New York, said in an interview with 

®. One major point of debate is whether escalating medication overuse is a cause or consequence of the worsening headache trajectory, as individuals with more frequent attacks will logically tend to take acute medications more often than those with less frequent attacks.

Seng noted, however, that several acute medications that seem to be most closely associated with MOH (such as opioids) have demonstrated reduction of pain threshold in both migraine animal models and human and animal studies in other pain conditions. These findings underscore the importance of continued efforts to elucidate the nature of MOH.

“I sometimes feel we are overdiagnosing MOH and considering anyone who is frequently treating migraine to have MOH,” Ailani said. “It is actually very hard to prove that a patient’s migraine is getting worse because of acute medication overuse versus worsening for other reasons and that the patient is just treating symptoms. I find this to be the most challenging part of clinical practice.”

Given the heterogeneity in cases depending on the overused medication and other factors, no standard treatment approach exists for MOH. The expert consensus is that “patients should be educated about overuse of medications and how and when to treat migraine attacks with a variety of treatments—medications but also behavioral techniques, and neuromodulation&mdash;preventive medication should be started, and the overused medication should be gradually withdrawn, with alternatives provided to treat migraine attacks,” according to Ailani.

Patient education is an essential component of MOH management that appears to be underused. Results of several studies have revealed that most patients with MOH are unaware of the risk of headache chronification related to excessive use of acute headache medications. In one study, only 14.5% of patients surveyed in pharmacies reported that they had ever been advised to limit their intake of acute headache medications, although research supports the effectiveness of educational strategies preventing MOH.

In a multicenter German study of 182 patients with migraine with frequent use of triptans or analgesics, investigators found both a home-based cognitive behavior therapy program and an educational brochure to be effective in preventing MOH in all participants. In addition, both groups demonstrated significant reductions in the number of headache days, migraine days, and medication intake over the study period, and these improvements were sustained at the long-term follow-up (P <.001 for both groups).

"Often when patients have MOH, they have other comorbid conditions like anxiety and insomnia that need to be addressed. Looking at the patient as a whole and involving a multidisciplinary approach is especially important for these patients," Ailani stated. 

Along with education’s role in prevention, other research supports the effectiveness of patient education in the treatment of MOH. The randomized controlled BIMOH trial (NCT01314768), published in 2015, investigated the use of brief intervention for MOH, in which general practitioners conducted a simple screening and then educated patients on reducing their use of acute headache medication. Headache days and medication days decreased by 7.3 and 7.9 (95% CI, 3.2-11.3 and 3.2-12.5) days per month, respectively, in the intervention group, and resolution of chronic headache was observed in 50% of these patients versus 6% of the usual-care group.

In other cases, clinicians may need to facilitate abrupt withdrawal (typically for triptans, ergots, NSAIDs, and simple and combination analgesics) or progressive reduction of the overused medication. Inpatient withdrawal may be indicated for patients taking opioids, barbiturates, and benzodiazepines or those with other complicating factors.

Whether initiating prophylactic treatment at the beginning of withdrawal is more effective than later in the process is yet to be determined. Although some experts believe that immediate prophylaxis is not needed for successful detoxification, it may be warranted in certain patients.

A meta-analysis of random controlled trials (RCTs) determined that insufficient evidence exists to determine the superiority of any particular prophylactic drug compared with the others. Data from a post hoc analysis indicate that topiramate and onabotulinumtoxinA are effective without early discontinuation of the overused drug.

“Historically, headache experts believed that unless an overused medication was stopped, preventive medication would not work,” said Ailani. “There have been newer studies, including studies with CGRP [calcitonin gene-related peptide] monoclonal antibodies, showing that some preventive treatments can work even if a medication continues to be overused.” For example, a significant number of patients with medication overuse were enrolled in RCTs investigating erenumab, fremanezumab, and galcanezumab for migraine prevention, and these patients did not undergo detoxification prior to treatment initiation.

A post hoc analysis of data from the phase 3 HALO trial (NCT02638103) found reductions in monthly migraine days and medication overuse in chronic migraineurs receiving fremanezumab. A significantly greater percentage of patients in the monthly (61%) and quarterly (55%) fremanezumab groups reported no medication overuse during the treatment period compared with placebo (46%).

“Ultimately, the identification of proper prophylaxis should be driven by clinical history, comorbidity, contraindications and [adverse] effects of the possible drugs,” wrote Vandenbussche et al in a 2018 review published in the Journal of Headache and Pain.

 Although their ease of use and safety profile are generally more favorable compared with other agents, CGRP drugs “cannot represent the first-line treatment for migraine prevention” because of their high cost and thus “should be reserved for patients who cannot be managed with the oral treatments or with onabotulinumtoxinA,” the authors wrote.

Emerging findings indicate that the small molecule CGRP receptor antagonists (gepants) may not cause MOH.

 “Gepants block the effect of CGRP, and we know from evidence relating to the CGRP monoclonal antibodies that blocking CGRP reduces migraine frequency,” said Ailani. She further noted that a long-term safety study (NCT03266588) evaluating rimegepant over 52 weeks allowed patients to use the medication up to 15 days per month, and migraine frequency did not increase.

 “Having an acute migraine treatment that does not cause medication overuse is extremely helpful for many patients,” she added.

The management of comorbidities is an important component of care for individuals with MOH. “Often when patients have MOH, they have other comorbid conditions like anxiety and insomnia that need to be addressed,” Ailani said. “Looking at the patient as a whole and involving a multidisciplinary approach is especially important for these patients.”

In general, comorbid psychiatric disorders have been linked to poor treatment adherence and outcomes, increased illness burden, and reduced quality of life in patients with headache, highlighting the need to screen patients for anxiety and depression and facilitate appropriate treatment. Although numerous studies have observed high rates of depression and anxiety in patients with MOH—for example, 40.0% and 57.7% in the COMOESTAS trial (NCT02435056)&mdash;practitioners should interpret these results with caution.

“This common stigma, that [patients] who use acute headache medication frequently must have psychiatric issues, is likely an observation based on confounding,” Seng said.

Regarding other recent psychological research in this area, recent work by Peck, Roland, and Smitherman “showed that the overuse of medication was associated with increased escape and avoidance responses to pain. This result tracks with what we know about use of opioid medication in chronic pain conditions,” Seng said.

 She believes that a better understanding of how these responses influence the decision to use acute medication may “improve our ability to coach patients in appropriate use of acute medication during headache attacks.”

Along with acute headache treatments that do not cause MOH, a clearer understanding of why only some patients develop MOH is also needed, according to Ailani. “In the end, I attempt to treat migraine with empathy and education,” she said. “Having some [abortive] options for patients with frequent migraine that needs treatment while we find a good preventive strategy for them has been extremely helpful in my practice.”

1. Chong CD. Brain structural and functional imaging findings in medication-overuse headache. Front Neurol. 2020;10:1336. doi:10.3389/fneur.2019.01336 

2. Vandenbussche N, Laterza D, Lisicki M, et al. Medication-overuse headache: a widely recognized entity amidst ongoing debate. J Headache Pain. 2018;19(1):50. doi:10.1186/s10194-018-0875-x 

3. Thorlund K, Sun-Edelstein C, Druyts E, et al. Risk of medication overuse headache across classes of treatments for acute migraine. J Headache Pain. 2016;17(1):107. doi:10.1186/s10194-016-0696-8 

4. Kristoffersen ES, Lundqvist C. Medication-overuse headache: a review. J Pain Res. 2014;7:367&#8208;378. doi:10.2147/JPR.S46071 

5. Schwedt TJ, Chong CD. Medication overuse headache: pathophysiological insights from structural and functional brain MRI research. Headache. 2017;57(7):1173-1178. doi:10.1111/head.13037 

6. Fritsche G, Frettlöh J, Hüppe M, et al; Study Group. Prevention of medication overuse in patients with migraine. Pain. 2010;151(2):404-413. doi:10.1016/j.pain.2010.07.032 

7. Kristoffersen ES, Straand J, Vetvik KG, Benth JŠ, Russell MB, Lundqvist C. Brief intervention for medication-overuse headache in primary care. the BIMOH study: a double-blind pragmatic cluster randomised parallel controlled trial. J Neurol Neurosurg Psychiatry. 2015;86(5):505&#8208;512. doi:10.1136/jnnp-2014-308548 

8. Tiseo C, Ornello R, Pistoia F, Sacco S. How to integrate monoclonal antibodies targeting the calcitonin gene-related peptide or its receptor in daily clinical practice. J Headache Pain. 2019;20(1):49. doi:10.1186/s10194-019-1000-5 

9. Moreno-Ajona D, Pérez-Rodríguez A, Goadsby PJ. Gepants, calcitonin-gene-related peptide receptor antagonists: what could be their role in migraine treatment? Curr Opin Neurol. 2020;33(3):309-315. doi:10.1097/WCO.0000000000000806 

10. Lipton RB, Berman G, Kudrow D, et al. Long-term, open-label safety study of rimegepant 75 mg for the treatment of migraine (Study 201): interim analysis of safety and exploratory efficacy. Poster presented at: American Headache Society 2019 Annual Scientific Meeting; July 11-14, 2019; Philadelphia, PA. Poster P235LB. 

11. Peck KR, Roland MM, Smitherman TA. Factors associated with medication-overuse headache in patients seeking treatment for primary headache. Headache. 2018;58(5):648-660. doi:10.1111/head.13294 

A whole-patient approach to management, coupled with new, more targeted treatments, may help reduce the incidence of medication overuse headache.

Treating Medication Overuse Headache: Opportunities for Improvement

Rapid eye movement (REM) sleep behavior disorder (RBD), in which people act out their dreams, affects an estimated 0.5% of the general population, with the highest prevalence found among elderly individuals and males.

 A sizeable body of research supports a multifaceted link between RBD and certain neurogenerative diseases.

“There is a convincing, consistent, and extremely strong association between RBD and the alpha-synucleinopathies, including Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA),” Erik K. St. Louis, MD, MS, co-director of the Center for Sleep Medicine and associate professor of neurology at Mayo Clinic College of Medicine, told NeurologyLive®. The presence of idiopathic RBD (iRBD) in older adults is likely a prodromal marker of eventual conversion to an alpha-synucleinopathy rather than a truly idiopathic condition.

“The rate of conversion is dependent on the duration of the diagnosis of RBD, with longer duration incurring higher risk,” noted Andrew Varga, MD, PhD, assistant professor in the Division of Pulmonary, Critical Care, and Sleep Medicine at the Icahn School of Medicine at Mount Sinai.Longitudinal studies have reported an 80% to 90% risk of conversion to an alpha-synucleinopathy within 14 to 16 years after RBD symptoms emerge. The prevalence of RBD in patients with MSA, DLB, and PD is 80% to 95%, 50% to 80%, and 30% to 50%, respectively.

“Time from the diagnosis of RBD to the diagnosis of neurodegenerative disease is 6 years on average, but for some individuals it can be 10 years or longer,” according to Emmanuel During, MD, director of the Stanford Parasomnia Clinic and clinical assistant professor in the Department of Psychiatry, Division of Sleep Medicine, and in the Department of Neurology at Stanford University.

 In patients with PD, studies have observed faster motor progression, reduced treatment response, and greater postural instability in those who converted from RBD.

RBD can also occur secondary to other neurologic or sleep disorders and certain other conditions, and as an adverse effect of some medications, including antidepressants.

 Some evidence indicates that these cases may foretell the development of neuro-degeneration, albeit to a lesser extent than iRBD. 

In a 2013 study, for example, patients with RBD who were taking antidepressants showed abnormalities in 12 neurodegenerative markers compared with matched controls: olfaction (

 = .004), Unified Parkinson Disease Rating Scale II and III (

 <.007), Timed Up and Go (P = .003), alternate-tap test (

 <.001), and prevalence of mild cognitive impairment (13% vs 60%; 

Overall, these patients had a lower 5-year risk of developing neuro-degenerative disease versus patients with RBD not taking antidepres-sants (22% vs 59%; risk ratio 0.22; 95% CI, 0.06-0.74). While the connection with possible neurodegenerative risk in this group needs to be further studied, RBD “due to other known conditions such as multiple sclerosis or narcolepsy is not associated with risk of developing a synucleinopathy,” During said in an interview with NeurologyLive®.

RBD affects up to 60% of patients with narcolepsy,

 although “RBD is not predictive of narcolepsy or vice versa,” said Meena Khan, MD, assistant professor in the Division of Pulmonary, Critical Care, and Sleep Medicine at the Ohio State University Wexner Medical Center. In addition, “iRBD tends to occur around age 55 years or older and mostly in males, while narcolepsy tends to manifest in the second and third decades of life.” It is possible that, in some cases, RBD may result from medications used to treat narcolepsy that can lead to loss of REM atonia.

“In the setting of narcolepsy, RBD may manifest as a breakdown in the normal boundaries across states, with intrusion of REM sleep without atonia (RSWA) and clinical dream enactment behaviors into REM sleep,” explained St. Louis. “There has been evidence in children and adults with narcolepsy that the presence of RSWA during polysomnography may help to discriminate narcolepsy type 1, in which RSWA is more likely to be present, from type 2, in which RSWA is less prominent or absent.”

During advised that other nondegenerative disorders—such as RBD associated with posttraumatic stress disorder (PTSD), which is increasingly reported in veterans&mdash;should also be considered.

In study results recently published in Sleep, researchers at the VA Portland Health Care System and Oregon Health & Science University found overall prevalence rates of 9% for RBD, 7% for RSWA, and 31% for other parasomnias in a sample of 394 veterans (94% male; mean age, 54.4 years).

 The prevalence of RBD was even higher in participants with PTSD (15%) and those with both PTSD and traumatic brain injury (21%). It is unclear whether RBD associated with these disor-ders increases the risk of synucleinopathy, as observed in iRBD.

“Importantly, among the non-synucleinopathies, patients tend to develop RBD concurrently or after the onset of the disorder, whereas in alpha-synucleinopathies, RBD typically presents as a prodromal condition years or decades before the symptomatic onset of the core diagnostic features of PD, DLB, and MSA,” wrote Suescun et al.

“The fact that RBD regularly occurs in alpha-synucleinopathies and rarely in other neurodegenerative diseases is supported by the concept of early involvement of the brainstem neuronal networks that control REM sleep, with a temporal sequence that begins in the medulla and eventually ascends to more rostral structures, compromising the sublaterodorsal nucleus and leading to RSWA and RBD.”

“When a patient complains about abnormal behavior in sleep, it is important to distinguish whether it sounds consistent with RBD versus non-REM parasomnia, which involves behaviors that the patient is not aware of, [such as] if they are awakened, they are disoriented and cannot describe a vivid dream they were acting out,” Khan said. “If the history sounds consistent with RBD, a sleep study should be done to look for loss of REM atonia. Also, the sleep study will diagnose if the patient has obstructive sleep apnea (OSA), as untreated OSA can increase the frequency of RBD by fragmenting sleep, and there are case reports of RBD resolving by treating OSA.”

In cases in which RBD behaviors are frequent or dangerous, treatment initially involves educating patients about good sleep hygiene, treating the underlying etiology such as OSA, followed by medication—typically clonazepam or melatonin&mdash;if the behaviors persist. “All patients with RBD should be counseled on the association with development of Parkinson and Parkinson-like diseases,” advised Khan.

Along with the opportunity to identify a synucleinopathy as the likely cause of disease in patients with parkinsonism or neurocognitive disorder if RBD and/or RSWA are present, St. Louis said that other benefits of “considering polysomnography in these patients can include the opportunity to diagnose and treat other sleep comorbidities such as sleep-disordered breathing, periodic leg movements of sleep with significant associated arousal and sleep comfragmentation, or discovery of sleep-related stridor (implying underlying multiple system atrophy),” thus improving their sleep quality, cognition, and quality of life (

Predictors of Conversion From iRBD to Synucleinopathy

“Once RBD is diagnosed, there are certain symptoms, such as loss of sense of smell and constipation, that predict more likely conversion to a synucleinopathy,” said Varga. In a large prospective multicenter study published in Brain, Postuma et al examined risk factors and rates of conversion to primary dementia or parkinsonism among 1280 patients with iRBD from 24 centers of the International RBD Study Group.

The overall conversion rate was 6.3% annually, with a median time to conversion of 8.0 years. The risk of conversion was 73.5% after 12 years.

They identified the following predictors of conversion: abnormal quantitative motor testing (HR, 3.16), objective motor examination (HR, 3.03), olfactory deficit (HR, 2.62), mild cognitive impairment (HR, 1.91-2.37), erectile dysfunction (HR, 2.13), motor symptoms (HR, 2.11), an abnormal dopamine transporter scan (HR, 1.98), color vision abnormalities (HR, 1.69), constipation (HR, 1.67), REM atonia loss (HR, 1.54), and age (HR, 1.54). These prodromal markers can be used to stratify patients for future trials investigating potential neuroprotection in patients with iRBD.

St. Louis and colleagues recently demonstrated that quantitative RSWA is a biomarker for synucleinopathies such as PD even in the absence of clinically overt dream enactment of RBD.9 Among 77 patients with parkinsonism, elevated submentalis muscle activity distinguished synucleinopathy from tauopathy with high sensitivity (70%-77%) and specificity (95%-100%). In another study, they found that increased RSWA during polysomnography was predictive of more rapid phenoconversion to parkinsonism in patients with iRBDs.

As an early predictor of underlying synucleinopathy, “the most promising diagnostic marker is cutaneous deposition of alpha-synuclein, which can be detected with high sensitivity in about two-thirds of patients with iRBD, and with total specificity, meaning that synuclein deposition in the skin is not found in other neurolog-ical diseases or with ‘normal’ aging,” During said.

 “Furthermore, if a skin biopsy does not detect synuclein in an individual with RBD, it may be positive if repeated 1 to 2 years later, and then becomes diagnostic.” The skin biopsy could have 100% predictive value, based on the current evidence; however, this test is not yet widely accessible, as it is available at only 4 medical centers worldwide, including Stanford University and Harvard University—Beth Israel Deaconess Medical Center.

“Other tests to support a diagnosis of RBD due to an underlying alpha-synucleinopathy include tests of heart rate and blood pressure, to detect early specific patterns of autonomic dysfunction, as well as smell tests, since loss of smell is another early sign of neurode-generation,” During added. A 2015 study reported that results of the Sniffin’ Sticks test (both the entire test and the identification subtest) predicted conversion from iRBD to Lewy body disease with 82.4% accuracy (95% CI, 66.1%-92.0%) over a period of 5 years in a sample of 34 patients. Compared with the top 2 tertiles of olfactory function, the relative risk for a Lewy body disease was 7.3 in the lowest tertile (95% CI, 1.8-29.6).

 Additionally, smartphone apps are available that can detect subtle motor impairments indicative of parkinsonism that cannot be detected on standard examination by a physician. “These various biomarkers may be used individually or in combination to estimate the likelihood that someone has RBD due to synucleinopathy versus RBD due to another cause such as PTSD,” noted During.

“There are many remaining research needs, starting with an expan-sion of treatment options for RBD, as well as tools to validate the efficacy of those treatments, since often subjects are not good about recalling dream enactment event frequency or vigor,” Varga told NeurologyLive®. “There are also ample research opportunities to evaluate interventions that could potentially slow or eliminate the progression of idiopathic RBD to a synucleinopathy.”

During and colleagues are currently pursuing this avenue in research, with support by the National Institutes of Health. He noted that many patients with RBD are aware of the conversion risk since the topic and supporting evidence are widely discussed online. “The next question is, ‘What can be done to prevent this progression, and [when] is it too late?’ We believe that these patients would most benefit from neuroprotective drugs, as they typically have several years until their neurological disease becomes manifest,” said During. However, current drug research focuses solely on patients at later disease stages—that is , those with a formal diagnosis of PD or DLB.

During and colleagues at Stanford and several other large academic centers in the United States and Canada are collaborating in preparation for the first neuroprotective trial in patients diagnosed with RBD. “This effort is called the North American Prodromal SynucleinopathyConsortium, and this study, the first of its kind, should soon lead to the enrollment of patients in clinical trials of drugs that could slow down or reverse disease progression,” During explained.

St. Louis pointed to the need for further prospective studies to “confirm the utility of polysomnography as a diagnostic tool for parkinsonism and cognition impairment in adults without dream enactment behavior symptoms.” He also noted that some patients in the general population show RSWA on polysomnography without having yet developed RBD. This represents a “research frontier during the course of future prospective cohort studies to determine whether such patients are at risk of conversion to clinical RBD or alternative overt synucleinopathy/Lewy body disease phenotype.”

Another promising focus of research involves the use of wearable technology or devices to measure RBD activity in the home environment. Even simple measures of movement—via actigraphy or accelerometers, for example&mdash;have shown approximately 80% accuracy in distinguishing between RBD and other movements during sleep, according to During. “Other technologies to stage sleep and [to track] abnormal muscle activity need to be explored outside the laboratory setting, using [tools like] video or motion sensors, electroencephalography, eye movement signals, and muscle sensors,” he said. “These technologies, used individ-ually or in combination in patients’ homes and over several nights or weeks, could allow for early diagnosis and large-scale population screening. [But] until such technologies are validated, the in-lab poly-somnography will remain the gold standard procedure.”

As a marker of impending neurodegeneration, urgency surrounds efforts to slow or stop the progression of REM sleep behavior disorder.

REM Sleep Behavior Disorder: Predicting Conversion to Synucleinopathy

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. 

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

Tori Rodriguez, MA

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