Marco Meglio

 pandemic was formally declared by the Centers for Disease Control in March 2020, countless questions swirled around what sort of short- and long-term effects the virus could have on an individual and their brain.

Vaccines aside, the symptoms of the COVID-19 have been well documented, even in the early stages of the pandemic. Infected patients can experience a range of symptoms—from mild to severe—that include fever or chills, cough, shortness of breath, fatigue, muscle or body aches, headache, loss of taste or smell, sort throat, congestion, nausea or vomiting, and diarrhea that can last from anywhere between 2-14 days.

As evidence began to pile up, it became clear that individuals who are immunocompromised may be more prone to a severe case of COVID-19, which could lead to hospitalization, intensive care, ventilator use, and death. Older adults have been proven to be at the highest risk for severe COVID-19. In fact, more than 81% of COVID-19 deaths occur in people over 65, and the number of deaths among people over that age is 97-times higher than the number of deaths in those between the ages of 18 and 29 years.

After closely following people who contracted the virus, the clinical community started to gain a better understand of potential post-acute sequelae (PASC). PASC of COVID-19 has had a wide prevalence range reported, mainly due the heterogenous definitions of the condition, differences in populations being assessed, and types of symptoms or signs included in rate estimates. Some patients have had ≥20 different symptoms, indicating that COVID-19 is a multisystem disease.

Men and women can both be affected by PASC. A recent meta-narrative review showed that men are at a greater risk for increased symptom severity and death; however, PASC is more common in women, and women are more likely to have persistent fatigue, anxiety, and depression and at a 6-month follow-up.

 Additionally, individuals with underlying pulmonary conditions, obesity, and older age are at increased risk for developing PASC.

For the management of PASC, clinicians have generally recommended controlling comorbid conditions, such as diabetes, hypertension, kidney disease, respiratory diseases, and ischemic heart disease, and treating specific complications when necessary. Anosmia and ageusia, otherwise known as the loss of sense of smell and taste, have been other PASC symptoms that had shown persistence even after recovery from COVID-19; although, it’s uncertain whether these symptoms are permanent or transient.

Over time, the FDA began to authorize certain medications for emergency use to treat COVID-19 and thus, the subsequent issues that follow. Nirmatrelvir (Paxlovid), an oral protease inhibitor that is active against MPRO, is packaged with ritonavir, a strong cytochrome P450 3A4 inhibitor that has been used to boost HIV protease inhibitors, was among those to receive authorization.

 A recently published large-scale trial included those treated with oral nirmatrelvir within 5 days after a positive test (n = 9217) and those who received no COVID-19 antiviral or antibody treatment during the acute phase of their infection (n = 47,123).

The findings were a success, as nirmatrelvir-treated patients showed a reduced risk of PASC (HR, 0.74; 95% CI, 0.69-0.81) including a reduced risk of 10 of 12 post-acute sequelae in the cardiovascular system, coagulation and hematologic disorders, fatigue, liver disease, acute kidney disease, muscle pain, neurocognitive impairment, and shortness of breath. Additionally, mirmatrlevir was associated with a decreased risk of post-acute death (HR, 0.52) and post-acute hospitalization (HR, 0.70). These associations remained true in unvaccinated, vaccinated, and boosted individuals, and in those with primary SARS-CoV-2 infection and reinfection.

Hyper Inflammation and Truths Behind Alzheimer Risk

At first, researchers believed that SARS-CoV-2 infection primarily affected the pulmonary system, but accumulating evidence suggested that it also affects the panvasculature in the extrapulmonary systems by directly or indirectly causing endothelial dysfunction and multi-organ injury. The consequential endotheliitis/endotheliopathy can incite multiple instances of endothelial dysfunction, including altered vascular tone, oxidative stress, inflammation/leukocyte adhesion, endothelial mesenchymal transition, mitochondria dysfunction, virus-induced senescence, cytokine storm, and coagulopathy.

“It can also ramp up amyloid deposition or decrease breakdown of amyloid, and potentially also tau tangle formulation,” said Jennifer Frontera, MD. “That’s the whole kind of viral or inflammatory hypothesis of Alzheimer [disease]. It’s led to people doing studies with valacyclovir for patients with HSE (herpes simplex encephalitis) and mild cognitive impairment. Just to see if treating the chronic infection or the reactivation of that infection will ameliorate some of the pathological changes.”

Frontera, a neuro-critical care specialist at NYU Langone, has experience on all levels of the pandemic, serving both on the front lines during some of the earliest days, to being a leader in the research field, where she’s conducted multiple trials exploring the effects of the virus on the brain and body. She believes the general concept of increased microglial activation from inflammatory states could be “in-play” when it comes to post-COVID cognitive disorders.

“The more we understand about what’s happening in COVID-19, or hypoxia, for example, may help us understand other Alzheimer-type pathologies and what interventions might be useful in people with sporadic Alzheimer [disease], for example,” Frontera added. “Hopefully there will be more evolution in terms of our understanding of cognitive processes in general, even as they relate to post-ICU patients.”

The link between COVID-19 and Alzheimer disease is still being understood, with some studies signaling a connection and others pumping the breaks. A retrospective study published in September 2022 suggested that individuals at least 65 years infected with the virus are at an increased risk for the neurodegenerative disorder. That trial, which included 6,245,282 older adults, also showed an elevated risk when stratified by age groups (65-74, 75-84, ≥85 years), race or ethnicity (Black, White, Hispanic, with the highest risk in those above 85 years old (HR, 1.89; 95% CI, 1.73-2.07), and in women (HR, 1.82; 95% CI, 1.69-1.97).

Some of the fears of long-term development of Alzheimer disease stem from “brain fog,” a term commonly used to describe the sluggish, fuzzy feelings patients experience weeks, and sometimes months after infection. Headed by the National Institutes of Health, a mouse study showed that even a mild case of COVID-19 could cause long-term changes to the immune system and neurons. Weeks after being infected, the microglia in the mice stayed reactive. Investigators concluded that this reactivation caused trouble with completing tasks, such as making new neurons in the hippocampus, a region of the brain that plays an important role in learning and memory.

Although the pathological mechanisms of COVID-19 still remain a question, research has debunked, or at least cleared up, some of the initial thoughts, the biggest being the virus’s role in central nervous system (CNS) invasion, according to Frontera. “We really don’t think that’s a major player here, or a pathological driver. Encephalitis, meningitis, that are related to direct SARS-CoV-2 is really not a thing,” she said.

A 2021 paper by Conor McQuaid et al reviewed SARS-CoV-2/COVID-19, ACE2 distribution and beneficial effects, the CNS vascular barriers, possible mechanisms by which the virus enters the brain, outlined prior health conditions, neurological COVID-19 manifestation, and the aging cerebrovascularture.

 After sifting through the literature, the authors concluded that there is no sound evidence of SARS-CoV-2 flux into brain to significantly contribute to the overall outcomes once the respiratory system is invaded by the virus.

The paper highlighted that although unknown, the normal route of infection and presence of SARS-CoV-2 in severely infected patients could be from the olfactory mucosa, an idea that has been brought up previously before. “It is possible that the neurological manifestations of COVID-19 are a consequence of mainly cardio-respiratory distress and multiorgan failure,” McQuaid et al wrote. “Understanding potential SARS-CoV-2 neuroinvasion pathways could help to better define the non-respiratory neurological manifestation of COVID-19.”

Throughout the pandemic, it has been widely understood that the severity of COVID-19 is one of, if not the, greatest predictors of long-term prognosis. In December 2020, the FDA issued the first emergency use authorization for a vaccine for the prevention of COVID-19 in individuals aged 16 years and older, with the goal to lower hospitalization rates, ventilation rates, and ultimately, death.

In fact, it worked. A 2022 retrospective study of nearly 200,000 hospitalizations showed that COVID-19-associated hospitalization rates ranged from 3.5 times to 17.7 times higher in unvaccinated persons than vaccinated persons regardless of booster dose status. Among sampled cases, vaccinated hospitalized patients with the virus were older than those who were vaccinated (mean age, 70 years vs 58 years; 

<.001) were more likely to have 3 or more underlying medical conditions (77.8% vs 51.6; 

As more vaccines were authorized over time, some were curious whether they could have a positive impact on the symptoms of long COVID in those already infected. “Vaccines are lowering the severity of COVID-19 if you do get it, and therefore you’re less likely to have long COVID, but I don’t think that if you already had long COVID and get vaccinated that it’s necessarily improving anything,” Frontera added.

“Theoretically, it could still, but I think the interest in that area kind of fell off as people weren’t seeing an association between post COVID vaccination and long-term outcomes. I don’t know if it’s a myth, but we probably underestimate the impact of pandemic-related stressors on outcomes and how people are doing. Are there comorbidities like mood disorders, anxiety, depression, and so forth, that exacerbate symptoms or are even sometimes, the progenitor of symptoms. For example, untreated depression can present as brain fog. That doesn’t mean everyone with brain fog has depression, and that’s the reason there are comorbidities that should be looked at and addressed.”

While severe COVID-19 cases continued to cause concern, researchers started to uncover that even those with a mild case or no symptoms can develop long COVID. In a 2022 study that featured 486,149 non-hospitalized adults with confirmed SARS-CoV-2 infection and 1,944,580 propensity score-matched adults with no evidence of infection, a total of 62 symptoms were significantly associated with SARS-CoV-2 infection after 12 weeks.

The trial, led by Anuradhaa Subramanian, MSc, a research fellow at the University of Birmingham, also showed that the risk of developing long COVID increased along a gradient of decreasing age. The largest adjusted HRs for symptoms of long COVID included anosmia (6.49; 95% CI, 5.02-8.39), hair loss (3.99; 95% CI, 3.63-4.39), sneezing (2.77; 95% CI, 1.40-5.50), ejaculation difficulty (2.63; 95% CI, 1.61-4.28) and reduced libido (2.36; 95% CI, 1.61-3.47). In a post-hoc subgroup analysis of patients infected during the first and second stages of the pandemic in the United Kingdom, the association between SARS-CoV-2 infection and the reported symptoms was more pronounced among those infected during the second wave of the pandemic.

There are several aspects of COVID-19 that are still not fully understood and will continue to be researched in the coming years. “There’s been a lot of press related to the neurological aspect, and at the end of the day, the shortness of breath and pulmonary recovery is probably the main issue people are facing,” Frontera added. “The neurological components are probably a factor for some percentage of people. How much of them are directly related to COVID? It’s hard to know.”

People with Certain Medical Conditions. Centers for Disease Control and Prevention. 

https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html

. Updated December 6, 2022. Accessed December 14, 2022.

Munipalli B, Seim L, Dawson NL, Knight D, Abu Dabrh AB. Post-acute sequelae of COVID-19 (PASC): a meta-narrative review of pathophysiology, prevalence, and management. SN Comprehensive Clinical Medicine. 2022;4:90. doi:10.1007/s42399-022-01167-4

Huang C, Huang L, Wang Y, et al. 6 month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet. 2021;397:220-32. doi:10.1016/S0140-6736(20)32656-8.

Agyeman AA, Chin KL. Smell and taste dysfunction in patients with COVID-19: a systematic review and meta-analysis. Mayo Clin Proc. 2020;95(8):1621-31. doi:10.1016/j.mayocp.2020.05.030

Coronavirus (COVID-19) update: FDA authorizes first oral antiviral for treatment of COVID-19. News release. FDA. December 22, 2021. Accessed December 14, 2022. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19#:~:text=Today%2C%20the%20U.S.%20Food%20and,of%20age%20and%20older%20weighin

Xie Y, Choi T, Al-Aly Z. Nirmatrelvir and the risk of post-acute sequelae of COVID-19. Published online November 5, 2022. medRxiv. doi:10.1101/2022.11.03.22281783.

Xu S, Ilyas I, Weng J. Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies. Acta Pharmacologica Sinica. Published online October 17, 2022. doi:10.1038/s41401-022-00998-0

Wang L, Davis PB, Volkow ND, Berger NA, Kaelber DC, Rong X. Association of COVID-19 and new-onset Alzheimer disease. Journal of Alzheimer’s Disease. 2022;89(2):411-414. doi:10.3233/JAD-220717

A possible mechanism behind brain fog. News release. National Institutes of Health. Updated August 30, 2022. Accessed December 14, 2022. https://covid19.nih.gov/news-and-stories/a-possible-mechanism-behind-brain-fog

McQuiad C, Brady M, Deane R. SARS-CoV-2: is there neuroinvasion? Fluids and Barriers of the CNS. 2021;18:32. doi:10.1186/s12987-021-00267-y

FDA takes key action in fight against COVID-19 by issuing emergency use authorization for first COVID-19 vaccine. December 11, 2020. Accessed December 14, 2022. https://www.fda.gov/news-events/press-announcements/fda-takes-key-action-fight-against-covid-19-issuing-emergency-use-authorization-first-covid-19

Havers FP, Pham H, Taylor CA, et al. COVID-19-associated hospitalizations among vaccinated and unvaccinated adults 18 years or older in 13 US states, January 2021 to April 2022. JAMA Intern Med. 2022;182(10):1071-1081. Doi:10.1001/jamainternmed.2022.4299.

Subramanian A, Nirantharakumar K, Hughes S, et al. Symptoms and risk factors for long COVID in non-hospitalized adults. Nature Medicine. 2022;28:1706-1714. doi:10.1038/s41591-022-01909-w.

Articles

Almost 4 years since the beginning of the pandemic, continuous research efforts have begun to paint a better picture of the impact the virus has on the brain and the central nervous system.

COVID-19 and the Brain: Understanding the Neurological Effects of the Virus as the Pandemic Evolves

For years, the conversations surrounding care for patients with 

 (MS) mainly centered around drug development and the optimization of disease-modifying therapies (DMTs). There are now more than a dozen DMTs approved for MS, administered in various forms such as tablets, injections, or infusions. Although, as clinicians have learned, the management of these patients extends past treating solely the relapses.

Integrative wellness is a practice based around the belief that treating patients involves much more than only disease and symptom management and has become an approach adopted by more clinicians in recent years. This all-purpose type of method encompasses aspects of diet and nutrition, exercise, sleep, and ongoing preventive care, among others.

 Although there are no set guidelines on how to conduct this care, there are several overlapping themes and ideas.

The conceptual idea of integrative wellness often also carries a stigma, with many assuming these practices are not backed by scientific evidence. Contrary to this belief, ongoing research and the COVID-19 pandemic have confirmed the need for alternative approaches, particularly for patients with MS, who may benefit from interventions tailored to their individual needs.

Kathy Zackowski, PhD, OTR, senior director of patient management, care, and rehabilitation research, National Multiple Sclerosis Society (NMSS), has been at the forefront of researching and advocating for this new style of care. Her organization funds work that ranges from better understanding the use of acupuncture and yoga, to the resilience of psychosocial approaches, to the relationship of dieting and changes in the gut microbiome.

“The whole idea with wellness is that this is something that everyone can do right now,” Zackowski told 

®. “You don’t need a lot of equipment, but you need to understand the important elements of a wellness strategy for you. For someone in pain, we might recommend some of these psychosocial strategies looking at resilience and pain management, but for someone who’s weak, they may need just exercise. Exercise is its own intervention. It's not simple to go out and say, ‘go exercise.’ We need to understand what elements of that intervention are important for that person.”

The variety and usage of these integrative wellness approaches differs from clinic to clinic, which has added to its natural phenomenon. At Cleveland Clinic,

 physicians recommend maintaining a low-salt Mediterranean diet, getting at least 150 minutes of moderate movement per week, maintaining vitamin D levels between 40-70 ng/mL, not smoking or using tobacco products, and undergoing routine mental health screening.

Although there is a migration towards a better understanding of the need for collaboration and comprehensive care, some specialties are not consistently included in the model. Registered dietitians, for example, have historically been excluded from the multidisciplinary care team, with information on nutrition coming instead from integrative or alternative practitioners.

Mona Bostick, RDN, LDN, a nutritionist living with MS with a dedicated passion for optimizing nutrition, commented on this exclusion, adding that while nutrition is often miscast as an “integrative” approach, diet and how patients eat is not an alternative treatment for MS, but it is rather a pivotal aspect of overall health. Bostick is the founder of her private practice, Food Matters 365, now called MSBites, a source for evidence-based nutrition and wellness advice to help patients with MS.

“I believe the shift toward the integrative exists precisely because dietitians have not been included in the care team. With MS being such a disease [that] steals control over the things you thought you had control over, when alternative practitioners are promising to heal, beat, reverse, or give you that control back, the vulnerability that MS presents is going to make someone take a risk on that,” she told 

®. “It’s important to know that nutrition and what you eat plays an important role in your overall health, but it doesn’t offset demyelination—nuance and context around what food can do is missing a lot of times in these integrative and alternative messages of this practitioners. I find that to be disconcerting because there is a vulnerability to the MS population, for sure.”

Zackowski echoed similar thoughts to Bostick, adding that even the general public should be exposed to nutritional dietitians. “With MS, it’s complicated. We don’t have the cure yet, and one of the ways the [National MS] Society talks about this is the pathway to cures. The idea that there’s not just one cure, there are multiple cures, and people define cure in a different way. One way of defining cure is taking away symptoms. If diet can provide some improvements in the symptoms people [with MS] have that’s one form of an MS cure,” she explained.

Sharing Best Practices for a Sense of Community

Amidst the ongoing COVID-19 pandemic, the shift to telemedicine challenged clinicians to provide care remotely, whether that be for symptom management or for integrative approaches. Interestingly, some clinicians say the use of telemedicine had a positive effect in increasing collaboration and information sharing within the MS field, as the unknowns associated with COVID-19 generated a need for experts to share timely data relating to the virus and overall best practices with one another.

Mitzi Joi Williams, MD, CEO, Joi Wellness Group Multiple Sclerosis Center, spoke on this increased sense of community within the MS field since the onset of the pandemic and over the course of 2021. Williams noted that her colleagues were not afraid to share findings and information from registries, whereas in the past, the scientific community had cultivated a sense of protectiveness in terms of clinical data that had yet to be published.

“The information sharing that has emerged from the COVID-19 pandemic has really been amazing, and to see the collaboration from people from different academic centers, from the academic centers in the community, to across the pond, across the world, across the globe, has really been astounding,” Williams told 

Social media has been crucial in establishing this sharing of information and collaborative attitude, allowing experts in the MS field to share information quickly and freely via online platforms like Twitter, Williams said. Monthly webinars and conferences also aided in the dissemination of updated data, with experts then able to implement practices in real time.

“I hope this collaborative approach amongst MS specialists, general neurologists, and my colleagues around the globe stays,” Williams said. “There has been this amazing unity amongst everyone to try to find the scientific answers we need to be able to adequately care for our patients. We've seen a lot of synergy with people creating registries fairly quickly—a lot of things that we thought couldn't get done are absolutely getting done, [and] a lot of things we thought couldn't be done remotely are absolutely being done remotely.”

Zackowski spoke on ongoing work of the NMSS to improve this collaboration and sharing of information as it pertains to wellness, which includes the development of the Wellness Research Group and 3 different subgroups: physical wellness, nutritional wellness, and psychosocial wellness.

 Information published online is tailored specifically to patients or clinicians, making it easier to access veritable, valuable sources, Zackowski said, noting that patients “do not need to be scientists” in order to understand findings from ongoing studies. This is not, however, a foolproof method for getting the word out about wellness, particularly due to the need for practices and information to be adjusted for individual patients.

“The idea of integrating just those 3 areas is challenging—and that's not really addressing everything—there's so many symptoms that people have with MS that I think can be addressed by different wellness approaches,” Zackowski said. “I think it's really hard to get the message out to people about what to do because there's no regulatory body on how to make sure the standards are the same everywhere, and that's something we as a society are trying to grapple with a little bit more.”

Although there is good reason to be excited about these integrative approaches, clinicians themselves also agree that there is a need for extended research that aims at understanding and optimizing these methods. As of now, clinicians use their better judgement, paired with what’s been observed in the literature and through the help of their multidisciplinary teams. There is no current law-abiding guideline that the community has developed or strictly follows.

“When you talk about exercise, diet, or even cognitive rehabilitation, no one knows exactly the right dose, Zackowski stressed. “How much do you need as a person with MS to address your particular issue? We do this automatically with medications because the FDA dictates that you have to put a particular dose and explain what that dose is. In the wellness area, we need to address those things, we need to understand the dose, the intensity, the setting that this is done in, and how that approach will be effective in people who have more than one symptom.”

Despite advances in research in recent years, the space is stilling being held back. Without backing from pharmaceutical companies or industry leaders, it has been difficult to conduct large scale trials that further help validate these methods. These groups have yet to formally recognize integrative wellness as something that has significant therapeutic benefit, especially since the data thus far has been hard to quantify.

That, ultimately, leaves supporters of integrative wellness practices like Bostick and Zackowski to fend for themselves in terms of powering research, or forces them to turn to organizations such as the NMSS in hopes of acquiring funding and materials.

“I’m thinking of getting pharmaceutical companies interested in this combined approach that uses a medication and a wellness strategy,” Zackowski said. “This might be another way to encourage greater funding for this, but it will take time and money to get this understood better. We are right on the forefront though—we’re at a place where this can be studied now, and I’m encouraged by that.”

In addition to the need for increased research, there remain complexities in the integration of dietitians into standard of care, according to Bostick. “Out in the community, there are dietitians everywhere. At this point, the obstacle is that continuing education hours are expensive and difficult to obtain. There’s not been a reason for a dietician to justify becoming educated and informed on this topic, because they’ve not yet been welcomed into the comprehensive care team,” she said.

Bostick added that once the talents of these specialists are more appreciated, they may go back to their communities and advocate for these roles as well as provide information for newcomers to feel more comfortable. While a dietitian may have a broad knowledge of nutrition, they may not be as equipped at that moment to treat the MS-specific component. “Broadly speaking, multiple sclerosis is not discussed in our education and training. That’s the obstacle,” she said.

Much like how the efficacy of drugs continues to be optimized in post hoc analyses, it will only be a matter of time before similar studies to further validate these wellness approaches. Overall, the commitment to these nontraditional, forward-thinking ideas represents the general trend within the medical system in recent years to treat the patient from a complete holistic perspective that addresses all downstream aspects of the disease, and not just the root cause.

This contribution to HCPLive’s 2021 This Year in Medicine series comes from sister publication 

REFERENCES
1. Latimer-Cheung AE, Pilutti LA, Hicks AL, et al. Effects of exercise training on fitness, mobility, fatigue, and health-related quality of life among adults with multiple sclerosis: a systematic review to inform guideline development. 

. 2013;94:1800-1828. doi:10.1016/j.apmr.2013.04.020
2. Fitzgerald KC, Tyry T, Salter A, et al. Diet quality is associated with disability and symptom severity in multiple sclerosis. 

. 2018;90:e1-e11.doi:10.1212/WNL.0000000000004768.
3. Farinotti M, Vacchi L, Simi S, Di Pietrantonj C, Brait L, Fillipini G. Dietary interventions and multiple sclerosis. 

. 2012;12:CD004192. doi:10.1002/14651858.CD004192.pub3
4. Skovgaard L, Bjerre L, Haahr N, et al. An investigation of multidisciplinary complex health care interventions--steps towards an integrative treatment model in the rehabilitation of people with multiple sclerosis. 

. 2012;12:50. doi:10.1186/1472-6882-12-50
5. Alphonsus KB, Su Y, D’Arcy C. The effect of exercise, yoga and physiotherapy on the quality of life of people with multiple sclerosis: Systematic review and meta-analysis. 

. 2019;43:188-195. doi:10.1016/j.ctim.2019.02.010
6. Rensel MR. Wellness Practices That Can Improve Multiple Sclerosis Outcomes. August 14, 2017. Accessed December 10, 2021. https://consultqd.clevelandclinic.org/wellness-practices-that-can-improve-multiple-sclerosis-outcomes/
7. Petajan JH, Gappmaier E, White AT, Spencer MJ, Mino L, Hicks RW. Impact of aerobic training on fitness and quality of life in multiple sclerosis. 

. 1996;39(4):432-41. doi:10.1002/ana.410390405
8. Mokry LE, Ross S, Ahmad OS, et al. Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study. 

. 2015;12(8):e1001866. doi:10.1371/journal.pmed.1001866
9.Wellness and Lifestyle Research. NMSS website. Updated 2021. Accessed December 10, 2021. https://www.nationalmssociety.org/Research/Research-News-Progress/Wellness-and-Lifestyle
10. Society-Supported Wellness Research Group Publishes Strategies for Improving Diet Studies in People with MS. NMSS Website. April 27, 2020. Accessed December 10, 2021. https://www.nationalmssociety.org/About-the-Society/News/Society-Supported-Wellness-Research-Group-Publishe
11. Fitzgerald KC, Sand IK, Senders A, et al. Conducting dietary intervention trials in people with multiple sclerosis: Lessons learned and a path forward. 

. 2020;37:101478. doi:10.1016/j.msard.2019.101478

Clinicians have begun to incorporate more holistic ways to approach the treatment of multiple sclerosis symptoms by focusing on better overall health, exercising, and dieting.

The Expansion Toward Integrative Wellness Approaches in MS Care

This article was originally published in NeurologyLive.

The US Food and Drug Administration (FDA) has approved JZP-258 (Xywav) for the treatment of idiopathic 

, making it the first treatment cleared for this indication. The approval was granted to Jazz Pharmaceuticals. 

The combination agent of calcium, magnesium, potassium, and sodium oxybates will be available to patients in the fourth quarter of 2021 following Risk Evaluation and Mitigation Strategies (REMS) implementation.

The company announced the acceptance of its supplemental new drug application (sNDA) for JZP-258 in February, which included data from a positive phase 3 study (NCT03533114) that showed the investigational agent was effective and safe for adults with idiopathic hypersomnia. 

The oral solution received fast track designation from the FDA in September 2020 for this indication, and in December was granted a rolling submission, allowing for the submission of portions of the application as completed.

Idiopathic hypersomnia is a debilitating neurologic sleep disorder characterized by chronic excessive daytime sleepiness (EDS). A majority of physicians in the space have turned to off-label use of wake-promoting therapies typically used in patients with narcolepsy to help address the sleepiness issues.

"We are excited that with today's approval Xywav will become the first and only medicine indicated to treat idiopathic hypersomnia, a unique medical condition that can have significant effects on the lives of those diagnosed with the condition," Bruce Cozadd, chairman and chief executive officer, Jazz Pharmaceuticals, said in a 

 "This milestone exemplifies our patient-focused R&D strategy and internal development capabilities, and underscores oxybate as a key growth opportunity for Jazz. With this launch we will have achieved our goal of five product launches in two years."

The double-blind, multicenter, randomized phase 3 trial featured patients who had EDS associated with idiopathic hypersomnia, and all of those treated with the agent experienced clinically meaningful improvements in Epworth Sleepiness Scale (ESS) scores–the primary end point–during the open-label titration period.

A randomized withdrawal portion of the study included 115 patients who were assessed on primary and key secondary end points including Patient Global Impression of Change (PGIC) and Idiopathic Hypersomnia Severity Scale (IHSS). 

Those who received JZP-258 reported clinically meaningful maintenance of efficacy as measured by all 3 evaluations. Furthermore, highly statistically significant worsening was observed for those who received placebo compared with JZP-258 for ESS (

Xywav has a Boxed Warning as a central nervous system (CNS) depressant and for its potential for abuse and misuse. The most common adverse reactions, occurring in at least 5% of adults in the phase 3 study, were nausea, headache, dizziness, anxiety, insomnia, decreased appetite, hyperhidrosis, vomiting, diarrhea, dry mouth, parasomnia, somnolence, fatigue, and tremor.

JZP-258 originally received approval for the treatment of cataplexy or EDS in patients 7 years of age or older with narcolepsy in July 2020. The basis of that approval was built on data from a phase 3 double-blind, placebo-controlled, randomized-withdrawal, multicenter study, for which the drug demonstrated statistically significant differences (

 <.0001) in the weekly number of cataplexy attacks and ESS scores compared with placebo.

"Idiopathic hypersomnia can have a significant impact on the social, educational and occupational functioning of people living with the condition. Today's FDA approval is a major milestone for the entire idiopathic hypersomnia community as Xywav becomes the first medicine approved to manage this chronic sleep disorder," Dianne Powell, board chair and chief executive officer, Hypersomnia Foundation, said in a statement.

"Our mission and values have consistently centered around supporting patients and scientific discovery and this announcement truly provides a sense of hope for those living with idiopathic hypersomnia."

The combination agent breaks ground as the first treatment approved for this indication.

JZP-258 Receives FDA Approval for Idiopathic Hypersomnia

High-dose blarcamesine resulted in a significant improvements in symptom scores for patients with 

The full results from the proof-of-concept phase 2 study of blarcamesine suggests the drug’s impact on increasing sigma-1 receptor (SIGMAR1) mRNA expression corresponded significantly with responses on primary and secondary end points in this patient population.

Anavex Life Sciences noted it plans on submitting these data to the US Food and Drug Administration (FDA) to seek regulatory guidance.

Treatment with blarcamesine, formerly known as ANAVEX 2-73, resulted in significant (

= .035) mRNA expression increase of SIGMAR1, which correlated with clinical efficacy as measured by the Cognitive Drug Research (CDR) system Continuity of Attention (CoA; 

= .029) and CDR system Power of Attention (PoA; 

The correlation also remained true on secondary end points such as Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III (

"This is now the second independent placebo-controlled clinical ANAVEX 2-73 phase 2 study to confirm the predictive biomarker of response established with SIGMAR1 mRNA expression,” Christopher U. Missling, PhD, president and chief executive officer, Anavex, said in a statement. "We believe that the easily accessible predictive biomarker combined with the observed efficacy is a consistent explanation of the efficacy in this second largest CNS indication with unmet medical need. This data further strengthens the foundation of ANAVEX 2-73 as a cross-platform [central nervous system] drug.”

The phase 2 study included 132 patients with PDD randomized 1:1:1 to blarcamesine 30 mg, 50 mg, or placebo for up to 14 weeks. Study participants were allowed to be on a stable regimen of anti-PD medications, including levodopa, dopamine agonists, MAO-B inhibitors, or entacapone.

Those included in the high-dose group demonstrated statistically significant improvements compared to placebo for MDS-UPDRS total score (

By the end of the study period, the MDS-UPDRS total score improved by ­10.98 points in the 50-mg dose group and worsened by 3.53 points in the placebo group, corresponding to a relative improvement of 18.9%. This far exceeds an empirically established cutoff of a 7.1-reduction for detecting meaningful clinical change.

The clinically meaningful improvements observed in patients with PDD suggest that the agent has the capability of slowing and reversing symptoms that progress in PD, an urgent unmet need for this patient population. Notably, blarcamesine did not impair sleep and had a positive effect on rapid eye movement (REM) sleep behavior disorder.

Previously reported data presented at the Clinical Trials on Alzheimer’s Disease (CTAD) 2020 Annual Meeting showed a dose-dependent (

= .003), statistically significant improvement of CDR system Episodic Memory of 42.22 points between 50-mg blarcamesine and placebo. CDR system Episodic Memory has been shown to be highly correlated (70%) with the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog).

Patients in the high-dose group also experienced an ADAS-Cog mean change from baseline of –1.9, an 8% mean improvement from baseline to 14 weeks. Investigators documented a 4-point improvement difference of calculated corresponding ADAS-Cog score between the blarcamesine treatment group and the placebo group from baseline to the end of the study period. Anavex is also evaluating blarcamesine in a phase 2b/3 study that features 

The company recently announced that they have exceeded their target enrollment goal of 450 patients, and topline results from the ongoing study are expected to be announced by mid-2022.

Patients included in the high-dose group demonstrated statistically significant improvements compared to placebo for MDS-UPDRS total score.