2019 Research Updates
2019 was another exciting year for research on rare neuroimmune disorders. 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 do this through The Pauline H. Siegel Eclipse Fund for research. This fund drives critical research priorities including improving diagnosis, understanding causation, investigating novel therapies, and restoring function.
We share some of the research advances here with you.
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 presented at the American Academy of Neurology Annual Meeting, which was held from May 4th-10th in Philadelphia, PA.
Dr. Olwen Murphy, a former James T. Lubin Fellow, and a team at The Johns Hopkins Hospital presented research on sarcoidosis-related myelitis. The research was a retrospective study of patients diagnosed with sarcoidosis-related myelitis at the Johns Hopkins Transverse Myelitis Center. The goal of the study was to identify characteristic clinical, imaging and CSF features of sarcoidosis-related myelitis. They found that distinct imaging patterns occur in sarcoidosis-related myelitis and recognition of these features may aid in coming to a correct diagnosis. Most of the patients in the study had a long symptom evolution (81%), meaning it took more than three weeks from symptom onset to when symptoms were at their worst. Most had sensory symptoms (87%) and motor symptoms (53%). Enhancement patterns suggest that the blood-spinal-cord barrier may play a role in the development of sarcoidosis-related myelitis lesions. Dr. Murphy and colleagues also presented a case report on a 68-year-old man who presented with a 2-year history of severe muscle spasms in the lower back and pelvic region. The patient was ultimately referred to their clinic for evaluation of “treatment-resistant” stiff person syndrome after baclofen and benzodiazepines had no clinical effect. He was correctly diagnosed with an anterior disco-osteo-arterial conflict and underwent surgery to correct the problem. Six months post-surgery he reported marked improvement in his symptoms and increased exercise tolerance. The findings from these studies provide additional information about these diagnoses, which are important for ensuring people receive an accurate diagnosis.
Dr. Jonathan Galli, another James T. Lubin Fellow, worked with Dr. Clardy on another research study about stiff person syndrome. The goal was to describe epidemiological characteristics, antibody status, and treatment outcomes of stiff person syndrome patients within University of Utah Health. Stiff person syndrome (SPS) is an autoimmune disease that classically causes severe muscle rigidity and spasms. They identified 31 patients with stiff person syndrome. Patients were predominantly female (78%). Some of their cohort had co-existing autoimmune diseases (63%) and malignancy (13%). Diazepam and baclofen was effective in a majority of patients. IVIg was the most commonly utilized immunotherapy (used in 69% of patients) with benefit demonstrated in 41% of patients who received this treatment. Dr. Galli and colleagues also presented a case series with the goal to describe atypical epilepsy presentations in patients with common variable immunodeficiency (CVID) within the University of Utah Healthcare system. Patients with CVID are at increased risk of infection, malignancy, and autoimmune disease. They presented a case series of 5 patients with CVID and co-existing epilepsy. All patients had atypical seizure symptoms including behavioral arrest, alterations in consciousness, and/or amnestic episodes. Most of the patients had improvement with antiepileptic therapy.
Dr. Cynthia Wang, another former James T. Lubin Fellow, and colleagues presented a case report of a 6-year-old boy with new-onset seizures and altered mental status associated with multifocal right hemispheric lesions resulting from primary CNS vasculitis. Primary CNS vasculitis is a rare vascular inflammatory brain disease. The child was treated with cyclophosphamide with gradual improvement in cerebral edema, and he also underwent cranioplasty four weeks after hemicraniectomy. He improved significantly over one month in inpatient rehabilitation and he regained the ability to ambulate independently. The researchers note that this case demonstrates an unusual presentation of this condition in a child.
In 2017, Dr. Michael Levy announced the discovery of a mutation in the VPS37A gene found in 3 people with acute idiopathic transverse myelitis (ITM): 2 sisters from a Polish origin and 1 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 ITM patients for mutations in this gene. VPS37A, which stands for Vacuolar Protein Sorting-associated protein 37A, makes a protein that is important for shuttling proteins around the cell. The mechanism for how this gene is involved in the development of ITM is active area of research in Dr. Levy’s lab. While his lab worked to understand the scientific basis of the mutation in exon 6 of this gene and its role in the immune surveillance of the spinal cord, they expanded their efforts to look at the rest of the VPS37A gene.
They screened the 89 original cases from samples already banked in the lab, and also recruited an additional 45 samples remotely from sources such as Facebook and the Siegel Rare Neuroimmune Association. The VPS37A gene contains 12 exons – regions of genetic sequence that encode the protein. Exon 6 was the location of the known mutation. They then looked at the rest of the 11 exons for additional mutations.
They found 5 additional patients with VPS37A mutations, 3 of them in exon 7 and 2 of them in exon 5. All of these mutations, including the original mutation in exon 6, can potentially compromise protein function. Additional studies of the VPS37A gene in mice will shed light on the role of this protein in TM. Similar to the mutation in exon 6, the mutation discovered in exon 5 is exceedingly rare in the world. More notably, the mutation in exon 7 among 3 ITM patients was not previously reported in any human being. It is also notable that exon 5, 6 and 7 are very closely opposed to each other within the VPS37A gene. These findings suggest that these mutations in this part of the VPS37A gene predispose to ITM.
Once damage had been done to the brain, spinal cord, or optic nerve, it is important to try to find therapies that can reverse all or part of this damage and help restore function. SRNA is incredibly excited to be working with UT Southwestern Medical Center and Q Therapeutics to study the safety and efficacy of implanting cells that produce myelin into the spinal cord. It is the first study of its kind in transverse myelitis. For more information on the study click here.
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. The UT Southwestern team worked during the year to get complete licensing and credentialing requirements for the team, with hopes to start the first surgery in 2020. Then, the COVID-19 pandemic began, halting plans for first enrollment and surgery. Research is expected to reopen at UT Southwestern in 2020.
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 2019, SRNA supported three Fellows and their research projects.
Dr. Olwen Murphy, Johns Hopkins University
Dr. Murphy’s research was on predicting outcomes after a diagnosis of transverse myelitis using current imaging techniques and spinal fluid analysis. The goal of the research project was to identify patterns or biomarkers that can be used in day-to-day clinical practice to identify benefits from therapies and help make better decisions about care.
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. Blackburn 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 also launched 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. We were interested in researching the following questions:
- What percentage of individuals with rare neuroimmune disorders have received vaccinations after their diagnosis
- What has been their physician’s advice regarding vaccinations?
- Of those who received vaccinations, what vaccinations did they receive, and did they experience any complications, including a new inflammatory attack 30 days or less after a vaccination?
We randomly selected 600 people from our membership database and sent them the survey. Ten of these individuals were deceased, five had no valid contact information, two ended up getting a different diagnosis, three were not in the US, nine had a symptom onset less than a year before, and all of these individuals were excluded. 220 participants fully completed the survey. Data analysis is ongoing, with results expected in 2020.
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 2019, 256 people participated in the registry.