2020 Research Updates
While 2020 was a challenging year, we continued to work on various research projects, and supported the work of several research publications. We know how important research is for improving the quality of life of our community and it remains a top commitment for us as an organization. We continue to do this work through The Pauline H. Siegel Eclipse Fund for research.
We share some of the research advances here with you.
Improving Diagnoses
SRNA maintains our commitment to advancing the scientific understanding of ADEM, AFM, MOGAD, NMOSD, ON, and TM to help improve diagnostic speed and accuracy. Some of this SRNA-supported research was conducted by former James T. Lubin Fellows, Drs. Olwen Murphy and Jonathan Galli, who published four research articles in 2020.
Neurosarcoidosis
Dr. Galli and colleagues published a paper on neurosarcoidosis, which is a chronic inflammatory disorder that occurs in the nervous system. Some individuals who are diagnosed with a rare neuroimmune disorder may also be diagnosed with neurosarcoidosis. They looked at clinical characteristics and treatments, and found that Infliximab was the most effective therapy, with 87% of patients remaining stable or improving on infliximab. Treatment response for methotrexate and azathioprine was mixed, and mycophenolate mofetil and rituximab were the least effective treatments in this cohort. Dr. Murphy and colleagues also published a paper about sarcoidosis, specifically about sarcoidosis-associated myelopathy. They found particular clinical features (chronically evolving myelopathy) and MRI features that can help differentiate this diagnosis from others.
Acute Flaccid Myelitis
Since 2012, there has been an alarming bi-annual pattern of increases in the number of acute flaccid myelitis (AFM) cases. Although the disorder that we now know of as AFM is not new, the bi-annual spikes, linked to an ordinarily innocuous enterovirus, have raised questions and alarm from a public health perspective. Following the increase in cases in 2018, a group of clinicians and researchers around the United States established The AFM Working Group (AFMWG). This multicentric and multidisciplinary group, led by Dr. Carlos A. Pardo from Johns Hopkins University, was formed and included health care providers, clinicians, and researchers from more than 25 institutions, and patient advocacy groups (such as the Siegel Rare Neuroimmune Association) to address the clinical needs of patients, families, and to support further research. The group began to outline consensus guidelines for improving diagnosis, developing management strategies of clinical concerns found in AFM, coordinating research efforts, and prioritizing research needs. This multi-disciplinary approach of clinicians, scientists, public health agencies, advocacy groups, and families was necessary and innovative. Building consensus from various yet shared experiences of this rare disorder, which at first had no clinical trials or treatment protocols available, has led to a collaborative and comprehensive effort.
This effort resulted in the first consensus publication of clinical guidance on AFM in the medical journal, The Lancet. Dr. Olwen Murphy led the publication of “Acute flaccid myelitis: cause, diagnosis, and management.” This paper summarized the critical and substantial work of the AFMWG. From definite to uncertain diagnosis, the authors provided a detailed and comprehensive clinical perspective necessary for medical professionals and families to recognize the symptoms, accurately diagnose, establish acute treatment protocols, as well as near and long-term rehabilitation and recovery strategies for those with AFM.
Earlier in the year, Drs. Murphy and Pardo published a clinical review of AFM, which included a discussion of the epidemiology, possible etiological factors, clinical features, differential diagnosis, treatment, and outcomes of AFM.
Understanding causation
In 2017, Dr. Michael Levy announced the discovery of a mutation in the VPS37A gene found in three people with transverse myelitis (TM): two sisters from a Polish origin and one unrelated Scotch-Irish woman. Given the rarity of this mutation in the world population and in the animal kingdom in general, he proposed to screen additional TM patients for mutations in this gene. They found five additional patients with VPS37A mutations. All of these mutations can potentially compromise protein function.
VPS37A, which stands for Vacuolar Protein Sorting-associated protein 37A, makes a protein that is important for shuttling proteins around the cell. This gene is involved in what’s called vesicle recycling – when you have a cell and it has something on its membrane, when it takes that thing in to interrogate it, it transports it to some intracellular machinery, and then it transports it back out to the membrane. Dr. Levy is not exactly sure how transportation of this vesicle is involved in the development of transverse myelitis, but when the body is exposed to viruses, if there is a disruption in that process, then perhaps the immune system sees that disruption, and then reacts to it. These findings suggest that these mutations in this part of the VPS37A gene predispose someone to TM. This mutation seems to only be associated with the monophasic TM. Even though these people have the mutation their whole lives, they only have one attack. So, even with that mutation, it seems to be a pretty rare event.
One of those women with the transverse myelitis genetic lesion happened to pass away from an unrelated gastrointestinal infection. Her family was gracious enough to send Dr. Levy’s lab her tissue so that they could study it further to really understand how this gene is involved in the development of TM. They now have her spinal cord including the lesion itself, so they’re going to take a really deep look at this lesion to understand how this gene is involved in this process. If we can understand how monophasic transverse myelitis happens, we might be able to prevent it or treat it better.
Restoring function
Beyond the personal health impacts, economic impacts, and changes to our medical system, the COVID-19 pandemic has dramatically impacted basic science and clinical research efforts across the world. The Study to Investigate the Safety of the Transplantation of Human Glial Restricted Progenitor Cells Into Subjects With Transverse Myelitis at UTSW Medical Center in Dallas was impacted in 2020. Since the mandates to enact social distancing were put into effect, basic science labs and clinical trials were paused. Thus, we were unable to proceed with our first surgery as planned.
We have received FDA clearance to proceed with this phase one trial in paralyzed TM patients. The trial currently plans to enroll nine patients for the surgical implantation of Q Cells. This is a safety study with many regulatory requirements, including a requirement focused on training the surgical team to perform the procedure with novel technology. As we worked during the year to get complete licensing and credentialing requirements for the team, the COVID-19 pandemic began, halting plans for first enrollment and surgery.
Nevertheless, we are preparing to do the first surgery in 2021, are still screening for additional participants, and will keep the community informed about the trial’s progress.
SRNA James T. Lubin Fellows
In addition to some of the research described above, we remain committed to funding Fellowships to train clinician-scientists in rare neuroimmune disorders. In 2020, SRNA continued to support two Fellows and their research projects. Our Fellowship program is a key piece of our mission to advance research on rare neuroimmune disorders.
Dr. Kyle Blackburn, University of Texas Southwestern
During his fellowship, Dr. Blackburn launched a study that collects patient-reported outcome measures on adult and pediatric patients with transverse myelitis. The study aims to assess current outcomes in transverse myelitis and to inform the development of outcome measures for future clinical trials.
Dr. Jonathan Galli, University of Utah
As part of his fellowship training, Dr. Galli conducted research to look for biomarkers in individuals with NMOSD. He investigated whether individuals have aquaporin-4 (AQP4) autoantibodies prior to their symptom onset of NMOSD, and also look for other inflammatory biomarkers. The goal of the study is to help us understand how biomarkers occur over the course of the disorder, which will hopefully help identify predictors of disease development, and ultimately therapeutic targets.
SRNA-Led Research
Study on Vaccinations
SRNA completed the analysis of a study about experiences with vaccinations after a rare neuroimmune disorder diagnosis. The goal of the study was to understand and learn from our member community about their experiences with receiving vaccinations before and after a rare neuroimmune disorder diagnosis, with a focus on their experiences after diagnosis. The study involved participation in a survey administered using Surveymonkey and through postal mail. Respondents who reported that they experienced a repeat inflammatory attack within 30 days of receiving a vaccine were further requested to participate in an interviewer-administered questionnaire over the phone. Of those 600 who were randomly selected, 223 completed the survey. Thank you to all who participated in the study!
188 participants in this study (from 45 states) were diagnosed with TM (66.8%), NMOSD (13.9%), ADEM (3.6%), MOGAD (2.7%), AFM (2.2%), and recurrent TM (1.3%). We asked questions about vaccination history including 30 days prior to the onset of symptoms. 35 participants (15.7%) reported a vaccination within 30 days before their onset, 13 of whom received a subsequent vaccination, and none of them reported another attack within 30 days of a vaccination.
More than half (65.0%) of participants reported that they got one or more vaccinations after their disease onset. 6 respondents, or 4% of those who had received vaccinations after their onset, reported a subsequent inflammatory attack within 30 days of a vaccination, although some were unsure if new inflammation was found on imaging during this subsequent attack.
We also wanted to understand from our community their concerns about not receiving vaccinations. About half of those who did not receive any vaccinations after their onset noted that their healthcare provider advised them not to receive a vaccination because of their rare neuroimmune disorder, more than a third (37.3%) said they did not want to receive vaccinations because they were concerned there are problems with their immune system, and about a third (28%) reported that they did not want to receive vaccinations because they believed a vaccination caused their disorder.
We hope to submit these findings to an academic journal in 2021 and will inform our community about any publications that are accepted.
SRNA Registry
SRNA also continues to collect data for our patient Registry. The purpose of this registry is to help advance research about rare neuroimmune disorders, collaborate with researchers from around the world, and identify participants for clinical trials. In 2020, 58 people participated in the registry. Now with over 500 participants, SRNA will conduct an analysis of the data to better understand the diagnostic experiences of those with rare neuroimmune disorders. Below are some preliminary results.
As of March 2021, there were 531 participants in the registry. 73% of respondents were diagnosed with transverse myelitis, 9% with neuromyelitis optica spectrum disorder, 5% with acute disseminated encephalomyelitis, acute flaccid myelitis, and MOG antibody disease, and 3% with another disease or have yet to receive a diagnosis.
37% were diagnosed less than one week after symptom onset, but for 31% of respondents it took longer than six weeks to be diagnosed.
These results show that the majority of patients did not receive a quick diagnosis (less than a week) after their onset of symptoms, which can delay the administration of acute treatments. Time is critical in the early stages of a rare neuroimmune inflammatory attack, so quicker diagnoses are needed to start acute treatments and prevent damage to the central nervous system. Further, less than one-third of participants in the registry received a second acute treatment during their initial inflammatory attack. While more research is needed to determine the effectiveness of a second form of acute treatments, steroids, plasmapheresis (PLEX), IVIG, and cyclophosphamide have all been used during the onset of these disorders.
83% of participants received treatment after their first acute attack. However, of those who received a first acute treatment, only 30% of participants received a second treatment that was different than the first. 80% of participants received rehabilitative therapy.
80% of participants currently have weakness or paralysis, 81% of participants currently have numbness or loss of sensation, and 63% of participants have spasticity or uncontrolled muscle spasms. 53% experience neck or back pain, 77% of participants experience neuropathic pain, and 70% of participants have bladder and/or bowel symptoms. This shows that the majority of participants experienced lasting symptoms following their diagnosis of a rare neuroimmune disorder, including weakness, paralysis, numbness, pain, spasticity, bladder dysfunction, and bowel dysfunction. While there are currently a variety of methods for treating these symptoms, more research is needed to improve the quality of life for these individuals and find stronger solutions for symptom management.
COVID-19 Study
In response to the COVID-19 pandemic, SRNA was interested in how the pandemic was impacting our community, which led us to launch our COVID-19 study. The goal of the study is to understand and learn from the SRNA member community about their experiences with COVID-19, experiences accessing care during the pandemic, and other potential social challenges (e.g., job loss, issues accessing medication or other supplies). Some of those with rare neuroimmune disorders are considered high risk for severe COVID-19 disease, are on medications that suppress the immune system, or have complex, ongoing medical needs. Understanding these issues for our community during this pandemic allows us to create relevant programming and inform the medical community about the effects of this pandemic on those with rare neuroimmune disorders. The study involves participation in an interviewer-guided survey administered over the phone using Surveymonkey.
