Aquaporin 4 IgG Serostatus and Outcome in Recurrent Longitudinally Extensive Transverse Myelitis

Neuromyelitis Optica is an autoimmune disorder that affects both adults and children commonly causing severe recurrent bouts of optic neuritis and transverse myelitis. Patients often present with either optic neuritis or transverse myelitis only to have future relapses confirming the diagnosis of NMO. In 2004 an antibody was identified in a large number of NMO patients. This antibody recognized the AQP4 protein in astrocytes (a specialized cell in the central nervous system). Patients with this anti-AQP4 antibody have been shown to develop NMO when followed over time, but initially many patients tested negative for this antibody. In this scenario, scientists often question, do patients who test negative lack the antibody or is the test not sensitive enough to identify them?

Dr. Pittock’s group from Mayo Clinic recently published their original work focused on recurrent longitudinally extensive transverse myelitis (rLETM). The goal of the study was to study AQP4-IgG, a known clinical biomarker of NMO spectrum disorders, from patients with rLETM using a recombinant human AQP4 based assay who were initially classified as negative for this antibody based on an assay known as IIF. The authors did a search of the Mayo Clinic database based on diagnosis from Oct 2005 to Nov 2011 and identified 48 patients with rLETM, 75% of whom were positive for the NMO signature of AQP4 IgG using the IIF method with serial serum specimens. On retesting those that were negative using the recombinant human AQP4-based assays, the overall AQP4-IgG seropositivity increased from 75% to 89%.

The authors also set out to define the clinical characteristics and motor disability outcomes in those who were positive for AQP4 IgG. This study showed that 36% of rLETM patients who were seropositive will likely need a cane to walk within 5 years after onset, and the median time from onset to first optic neuritis attack was 54 months in those who went on to be diagnosed as NMO. The median number of acute attacks was 3 in those rLETM patients who were seropositive (ranged from 2-22 attacks). Immunosuppression reduced the relapse rate in both seropositive and seronegative rLETM patients.

The authors concluded that recombinant antigen based assays can better detect AQP4-IgG in rLETM patients and generally adults with rLETM are seropositive, and are likely to go on and be diagnosed as having NMO. For rLETM patients who are at higher risk to convert to NMO, testing for this antibody AQP4 using more sensitive assays is the recommendation of the authors if less sensitive tests show negative results.

Original research article: Jiao Y, Fryer JP, Lennon VA et al. Aquaporin 4 IgG serostatus and outcome in recurrent longitudinally extensive transverse myelitis. JAMA Neurol. 2014;71(1):48-54. doi:10.1001/ jamaneurol.2013.5055

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Bladder Management Research Study Opportunity

The research teams at the Universities of Michigan, Minnesota, and Utah have created a study to examine how patients feel about their bladder management options. They hope to discover not only what does and does not work, but how to provide better care for people with spinal cord injuries in the future. Participants must have a spinal cord injury or problem that was acquired during their life (for example, transverse myelitis) and not something that occurred at birth.

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Impact of Autologous Mesenchymal Stem Cell Infusion on Neuromyelitis Optica Spectrum Disorder: A Pilot, 2-Year Observational Study

Bone marrow-derived mesenchymal stem cells, or MSCs, are a type of stem cell that can differentiate, or turn into other types of cells. They are taken from a patient’s own bone marrow. They have been used in several autoimmune diseases, including multiple sclerosis. MSCs can repair tissue and also inhibit the immune system, offering a potential treatment for neuromyelitis optica spectrum disorder (NMOSD). MSCs are given through an infusion.

Researchers recruited participants between September 2013 and January 2015. Participants were individuals with a diagnosis of NMO (based on criteria from 2006; diagnostic criteria were recently updated and can be found here), or with either recurrent optic neuritis or longitudinally extensive transverse myelitis and who were anti-AQP4 antibody positive. They were assessed at baseline, which was the day before treatment with MSCs, and 1, 3, 6, 9, and 12 months after treatment. The researchers looked at functional and structural outcomes. Functional outcomes were a scale (EDSS) that measures disability, a visual acuity test, and a cognitive test called the Paced Auditory Serial Addition Test (PASAT). Structural outcomes were MRIs of the optic nerve, brain, and spinal cord, and optical coherence tomography (OCT), which looks at the retina. They looked for relapses, which were new or recurrent neurological symptoms that lasted at least 24 hours. These symptoms were not counted if they were because of fever or infection. To be counted as a relapse, there had to be at least 30 days of separation from a previous episode. They also looked at the safety of the MSC treatment.

The study included 15 patients, with an average age of 47 years. Most (87%) participants were anti-AQP4 antibody positive. All of them had failed a different treatment prior to the study, meaning they had had at least one attack after receiving treatment. These prior treatments were cyclophosphamide or azathioprine, with or without steroids.

The MSC treatment did not cause side effects for most participants. Only one patient developed a low-grade fever and knee pain after the treatment, but these symptoms went away after treatment was completed. Weekly blood tests after the treatment were normal and no participants developed tumors within one year of treatment.

Twelve patients had no relapse at 12 months after MSC treatment, and three had at least one relapse. The relapses were mild. Their disability scores did not get worse and their symptoms went away after a month. The average annualized relapse rate was significantly lower after MSC treatment. Also, there were significantly fewer lesions in the optic nerve and spinal cord after treatment. The average disability score was also lower, and there was improvement in visual acuity and cognition. They had increased retinal nerve fiber layer thickness, optic nerve diameter, and upper cervical cord area. Three months after treatment, levels of anti-AQP4 antibodies decreased, but these levels went back to baseline again at 6-12 months. During the second year of the study, 13 participants were relapse free. Like the first year, the average annualized relapse rate was lower than before treatment and the average disability score was also lower than before treatment.

This small study did not have any obvious, serious, adverse events and supports an investment in larger controlled studies to understand the potential benefit of MSC treatment for NMOSD.

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NMO spectrum disorders: clinical or molecular classification?

The International Panel for NMO Diagnosis (IPND) released an updated set of guidelines for diagnosing Neuromyelitis Optica (NMO) and Neuromyelitis Optica spectrum disorders (NMOSD) in 2015.  We published a summary of the updated guidelines earlier on The TMA Blog. Diagnostic criteria for AQP4-IgG-positive NMOSD, NMOSD without AQP4-IgG or with unknown AQP4-IgG status were established, along with a set of core clinical characteristics to aid in diagnosing those with potential NMOSD. Anti-AQP4 antibodies affect the nervous system in a very specific way that is different from other auto-immune disorders to cause damage.

Another article by Uzawa et al. described the use of these guidelines in four NMOSD patients who were negative for AQP4-IgG. They found that the new criteria would be useful for more accurately diagnosing NMOSD earlier in patients. In this article, Dr. Pittock discussed Uzawa et al.’s findings and talked about the potential issues with diagnosing someone with NMOSD. He stated that what we call NMOSD might actually be several different diseases that we don’t understand enough about to identify them as different diseases. For example, the four NMOSD patients in Uzawa’s article though classified as NMOSD, had different symptoms, their MRIs looked different from each other, and their lab findings varied. Also, the way the immune systems of anti-AQP4 antibody positive individuals attacks itself is different from how the immune systems of people who are AQP4-negative attacks itself. By using symptoms and MRI findings to diagnose people with NMOSD, physicians might be clumping together people with different disorders that have different causes, prognosis, and different responses to treatment.

Pittock states that as more biomarkers are discovered, it might make more sense to name diseases based on the biomarker associated with them. Other autoimmune neurological diseases have done this when biomarkers have been found. He suggests using “autoimmune AQP4 channelopathy” instead of NMOSD. He also thinks that by classifying diseases in this way, it will be helpful as medications that target the specific immune process for each disease are developed.

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Diagnosing Transverse Myelitis

Paula Barreras Cortes, MD
Postdoctoral Fellow
Johns Hopkins Transverse Myelitis Center, Baltimore, MD

Many patients struggle through the initial evaluation before receiving a transverse myelitis (TM) diagnosis. A primary focus of the TM Center at Johns Hopkins University School of Medicine (JHTMC) is to facilitate a precise diagnosis and treatment for TM. It is not infrequent that some patients are initially misdiagnosed and treated for conditions that they don’t have. Many patients are given diagnoses, such as Multiple Sclerosis, Guillain-Barré syndrome (GBS) or even psychogenic problems before reaching a final diagnosis of TM.

Some of these issues are caused by a lack of understanding among some doctors in the community about TM and the diagnostic approaches required for patients who are experiencing symptoms suggestive of this disorder. This problem is further complicated when patients are dismissed and sent home from emergency departments or when patients need multiple visits or even multiple hospital admissions before obtaining a final diagnosis. Additional delays are created when patients are forced to find practitioners familiar with TM. All of these complications and delays ultimately postpone the correct treatments, almost all of which should be administered as quickly as possible.

One of the most important missions of the JHTMC is to identify better ways to improve the diagnosis of TM and to disseminate the strategies that would help doctors make a proper diagnosis from the very beginning. We have focused on studying the factors that may influence misdiagnosis and erroneous treatment. We are also interested in the identification of the factors that influence relapses and the outcomes of the disorder.

In one of our recent studies, we analyzed more than 500 clinical records from patients referred to the JHTMC for evaluation of TM. In our study, we found that nearly 40% of the patients were erroneously diagnosed as TM when they really had other problems, such as strokes, herniated disks, tumors and metabolic problems that affected the spinal cord. Not surprisingly, a high percentage of the patients that were properly diagnosed were also initially misdiagnosed as GBS or other neurological disorders. These findings immediately point out a lack of understanding of TM and a lack of understanding of the disorders that present with similar symptoms to TM but are not TM. As part of our study, we analyzed the presentation pattern of TM. By combining clinical information, the time-frame of clinical presentation, the findings of imaging of the spinal cord by magnetic resonance imaging and the results of the cerebrospinal fluid, we have been able to identify clinical profiles that facilitate an approach to achieve an accurate diagnosis of TM and differentiate TM from other disorders that may mimic TM. When looking at the factors that best predicted who really had TM versus other diagnoses, two things came up as the most important ones: the temporal profile of symptom presentation and the features of the first MRI of the spinal cord. The time from the onset to the peak of symptoms correlated with the diagnosis, as most strokes of the spinal cord occurred very fast (i.e., in a couple of hours), while the truly inflammatory problems took several hours to days to establish. The localization of the lesion in the MRI was also very helpful: the strokes of the spinal cord were more frequently located in the anterior part of the cord and were longer than the myelitis lesions.

We hope this information is useful to doctors in the community and for our patients to help with a proper diagnosis.  If we are able to avoid confusion between a diagnosis of TM and other problems of the spinal cord, we can avoid unnecessary and potentially harmful treatments, while offering the proper treatments as quickly as possible.

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A retrospective, multicenter US study on acute disseminated encephalomyelitis (ADEM)

A recent study published on acute disseminated encephalomyelitis (ADEM) is the largest study on ADEM that has been conducted. This study was a retrospective multicenter study where the authors looked at data from the past and from several sites. The authors searched five hospitals for billing codes used for ADEM to get the data.

The study included 228 patients who were initially diagnosed with ADEM; 122 were children and 106 were adults. The authors looked to see whether the diagnosis of ADEM was based on diagnostic criteria from the 2007 International Pediatric Multiple Sclerosis Study Group (IPMSSG). For 70% of the pediatric patients and 47% of the adult patients, the diagnosis was based on the IPMSSG criteria. Many patients included in this retrospective study (spanning years from 1985 to 2014) would not have been diagnosed with ADEM according to current criteria.

More than half (61%) of the patients had an infection less than four weeks prior to the onset of ADEM. Ten (4%) patients had received a vaccination less than four weeks prior to their onset, and seven of them also had an infection in that time frame. Seasonal differences in onset were not seen. The most common presenting symptoms reported were headache, issues with walking, weakness, and fever.

Patients were followed for a median of two years. At the end of follow-up, most patients (68%) did not have another attack, and 32% were given a diagnosis other than monophasic ADEM, which included MS (11%), and NMOSD (4%). The authors identified multiphasic ADEM as a diagnosis in 22 patients (10%). Most (85%) of the patients who had another attack, had it within 2 years of onset.

In this retrospective study, the authors reported that 82% of the patients received steroids, and some received IVIg and/or plasmapheresis (PLEX). The article did not describe the effectiveness of these treatments but found that those who needed PLEX or IVIg had a significantly lower chance of having a favorable outcome. A favorable outcome was defined as a modified Rankin Scale score that was equal or less to 2.

The authors also looked at what factors predicted relapses. Females were more likely to have relapses. Patients without encephalopathy at onset were more likely than those with encephalopathy to have relapses (and would not have met strict ADEM criteria under current approaches). Pediatric patients who had relapses were more likely to be diagnosed with multiphasic ADEM than adults. This might be because physicians may not want to diagnose children with MS because it is a disease that requires treatments throughout life. Children were more likely to have a favorable outcome than adults.

This study indicates that follow-up after the onset of ADEM should happen for at least two years to monitor for recurrence. This is because most relapses occurred within two years. 10% of patients in this study who were monophasic for two years had a relapse after this time (some had a relapse 5-10 years after onset). This study is limited by the fact that patients were not followed consistently, patients who had a multiphasic disease were followed for a longer period of time than those with a monophasic disease. Also, because there is no biomarker for ADEM, this makes a proper diagnosis especially hard to get. The authors argue that the IPMSSG diagnostic criteria may be more useful for diagnosis in children than in adults. The authors also state that, “most patients with a relapsing disease after an initial ADEM diagnosis are probably representations of MS.”

Notably missing from this study was an analysis of outcomes other than relapse or modified Rankin Scale. Patients, especially pediatric patients, will require longer follow up to understand the potential cognitive impacts of ADEM. Also, this study did not include anti-Myelin Oligodendrocyte Glycoprotein (MOG) antibody testing, which may explain the percent of patients who relapsed. In general, ADEM (when strict criteria are applied) remains a one-time event. Prospective studies, or studies that follow patients starting at diagnosis and into the future, are needed.

Original Research: Koelman DL, Chahin S, Mar SS et al. Acute disseminated encephalomyelitis in 228 patients: A retrospective, multicenter US study. Neurology. 2016 May 31;86(22):2085-93.

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Diffusion tensor imaging in pediatric transverse myelitis: A case study

Barakat et al. published a case study in 2012 about using diffusion tensor imaging in a pediatric transverse myelitis patient. Magnetic resonance imaging (MRI) is commonly used to diagnose transverse myelitis. Diffusion tensor imaging (DTI) is another imaging technique that can be used to assess the spinal cord. It looks at the diffusion of water molecules in the spinal cord and can identify white matter, differentiate between white and grey matter, and identify damaged areas of the spinal cord.

The authors used DTI to look at the spinal cord of a seven-year-old with transverse myelitis, and compared his results with those of healthy controls and with others with traumatic spinal cord injuries. The child’s initial MRI showed an area of myelitis, but after several years and some recovery, the child’s MRI looked normal. DTI of his spinal cord did pick up abnormalities that were different from both the control group and the SCI group though, which the authors note indicates how sensitive DTI is. Furthermore, the patient’s DTI results were significantly different from the results of those with traumatic SCI, once again showing the sensitivity of the imagine technique. They argue that DTI paired with standard MRI could be used to make quicker and more accurate TM diagnoses.

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Neuroviruses Emerging in the Americas Study (NEAS)

By Laura Munoz-Arcos, MD
Postdoctoral Fellow
Johns Hopkins Transverse Myelitis Center, Baltimore, MD

Since January 2016, researchers from the Johns Hopkins Transverse Myelitis Center have focused their attention towards the emergence of neurological complications associated with the Zika virus in Latin America and the Caribbean. The Zika virus was discovered in the 1950s in Africa where it was documented to cause a mild-febrile illness with no neurological complications described. Little to no information regarding the virus was available until 2007 when the Zika virus caused the first epidemic of infection in the Yap Islands. In 2013, the Zika virus led to a similar outbreak of illness in French Polynesia and the medical community was advised about the risk of developing neurological disorders secondary to this viral infection. In fact, in 2015 when the Zika virus reached the Americas, neurological complications such as Guillain-Barré syndrome (GBS) and microcephaly were observed. The temporal relationship of the Zika infection outbreak and the emergence of such neurological problems suggested a possible link between them.

GBS is described as a post-infectious disorder which affects the nerves that are responsible for movement, sensory functions and even vital functions, such as the beating of the heart and breathing. Frequently, GBS is confused with TM and vice versa. Clinically, patients with GBS present with a rapidly progressive ascending paralysis that commonly starts in the lower extremities and in a matter of days or weeks ascends and can potentially involve the respiratory muscles. Even though GBS has the strongest evidence of a link with Zika virus infections, other neurological disorders, such as myelitis and encephalitis have also been described in adults affected by the infection.

As part of our studies, researchers from the Johns Hopkins TM Center, and investigators and health care providers in South America established a collaborative network known as Neuroviruses Emerging in the Americas Study (www.neasstudy.org). NEAS is a multi-center study looking to combine the efforts of researchers, health care providers and patients in the Americas to establish a comprehensive registry of the clinical, radiological and laboratory profile of patients with new onset of neurological disorders associated with Zika virus infections, including GBS, myelitis, encephalitis and acute disseminated encephalomyelitis (ADEM). The purpose of our study is to determine whether there is a causal relationship between Zika virus infections and neurological complications in adults, as well as the underlying mechanisms which can help in the development of treatments, and prevention strategies, such as vaccines.

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Pregnancy Outcomes in Neuromyelitis Optica Spectrum Disorder

A recently published study looked at pregnancy outcomes in individuals with aquaporin-4-positive (AQP4) neuromyelitis optica spectrum disorder (NMOSD). Studying pregnancy in NMOSD is important because NMOSD is more common in women and often occurs during childbearing years.

60 women with a history of at least one pregnancy who had AQP4-positive NMOSD from three countries (UK, Portugal, and Japan) were enrolled in the study. The researchers looked at pregnancy outcomes, including miscarriage and preeclampsia. Miscarriage was defined as a spontaneous loss of pregnancy during the first 24 weeks of pregnancy. Preeclampsia occurs when there is high blood pressure in pregnancy and protein in urine.

NMOSD disease onset occurred at an average age of 46.4 years. Onset was with optic neuritis in 42% of the women, transverse myelitis in 38% of the women, and brain lesions in 18% of the women.

The study included data from 85 pregnancies from 40 women in the miscarriage part of the study. 71 pregnancies occurred before NMOSD onset and 14 pregnancies occurred after NMOSD onset. Eleven pregnancies in total (12.9%) in 6 women ended in miscarriage, which is not different from the miscarriage rate in the general population.

In this study, the miscarriage rate was found to be higher after the onset of NMOSD (42.9%) than before NMOSD onset (7.04%). There was also an increased odds of miscarriage in pregnancies after or in the three years before the onset of NMOSD, even when controlling for older maternal age and miscarriage in the most recent pregnancy. The miscarriage rate also differed by race: the miscarriage rate after NMOSD onset was 60% in Caucasian women and 0% in Afro-Caribbean women. The NMOSD relapse rate in the preconception and intrapregnancy period was higher in pregnancies that ended in miscarriage compared with pregnancies that did not end in miscarriage after NMOSD onset. These women were also more likely to be receiving treatment for NMOSD, but the miscarriages were not from the medication. These women had more attacks which made them more likely to be receiving treatment.

The study included data from 113 pregnancies from 57 women in the preeclampsia part of the study. 13 cases (11.5%) of preeclampsia occurred. NMOSD onset was not a risk factor for preeclampsia, although the rate of preeclampsia was higher in the study participants than in the overall population. In particular, the study reported that the odds of preeclampsia were greater in women who had multiple other autoimmune conditions or who had had a miscarriage in their most recent pregnancy.

Annualized relapse rates (ARR) were also calculated. Pregnancies that didn’t end in miscarriage were associated with a significantly increased average ARR in the first 3 months after birth compared with the average ARR up to 9 months before conception.

The authors state that it is possible that AQP4 can contribute to miscarriage risk because of the results of this study and other studies done on animals, but they state that further studies are needed in this population. It also appears as though some women were prone to miscarriage in this study. Of note, in this study, the number of women TREATED before and during pregnancy were too small to determine if the rates of miscarriage could be lowered by using treatment. As a result, the data set in this study is too small to base decisions on, but should be taken into account when consulting with a neurologist about pregnancy planning.

Nour MM, Nakashima I, Coutinho E et al. Pregnancy outcomes in aquaporin-4-positive neuromyelitis optica spectrum disorder. Neurology. 2015;86(1):79-87.

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Announcing the 2016-2018 James T. Lubin Clinician-Scientist Fellowship Awards

Powell, OH (April 14, 2016) – The Transverse Myelitis Association is pleased to announce that our Board of Directors have approved two TMA James T. Lubin Fellowship Award recipients this year, Dr. Elena Grebenciucova and Dr. Cynthia Wang. Dr. Elena Grebenciucova will receive clinical and research training under the mentorship of Dr. Brenda Banwell at the Perelman School of Medicine of The University of Pennsylvania and Dr. Cynthia Wang will be mentored by Dr. Benjamin Greenberg at The University of Texas Southwestern and Children’s Health.

The James T. Lubin Clinician Scientist Fellowship Award supports up to two years of clinical care and research training in an environment where clinicians learn to use the most current scientific tools to treat and advance knowledge about rare neuro-immune disorders, that include TM, AFM, ADEM, NMOSD, and ON. After completing the program, Fellows are prepared for a combined clinical and research career in academic medicine, directing robust research programs important to rare neuro-immune disorders.

Dr. Grebenciucova received her medical degree from East Carolina University in Greenville, North Carolina. She then completed a neurology residency at the University of Chicago in Chicago, Illinois. Dr. Grebenciucova has been interested in autoimmune disorders of the central nervous system, including rare neuro-immune disorders, since medical school. She hopes “…to be able to study how clinical features at the time of presentation and over the course of the disease, as well as their biochemical and radiological correlates can be used to prognosticate patients’ motor outcomes and predict future relapses.” “We are very grateful for the support provided by the TMA. Training top clinician-researchers is an essential step towards accelerating research and to improvements in care for individuals with TM. Our program at UPenn specifically addresses the impact of TM in children and adults, in order to understand the needs of all patients, even the youngest infants,” shared Dr. Brenda Banwell, Professor and Chief of Neurology at Children’s Hospital of Philadelphia.

Dr. Wang received her medical degree from University of Texas Southwestern Medical Center in Dallas, Texas and completed a pediatrics and pediatric neurology residency at Mott Children’s Hospital, University of Michigan Health System in Ann Arbor, Michigan. Dr. Wang’s goal “…is to work in an academic setting to provide excellent clinical care to children with demyelinating disorders and engage in clinical and translational research that will lead to therapeutic advancements in this field.” Dr. Benjamin Greenberg, Associate Professor and Director of the TM and NMO and Pediatric Demyelinating Disease Program at UTSW shared, “We are excited to have Dr. Wang join our team at UT Southwestern and Children’s Health here in Dallas. The support from the TMA is incredible and makes it possible for us to train future specialists and expand both our clinical care and research programs. Dr. Wang’s involvement in the clinic and focus on ADEM research will benefit many and we are grateful to all of those in the TMA community who made it possible.” Her research study is a prospective, longitudinal study on acute disseminated encephalomyelitis (ADEM) to identify the clinical characteristics, treatment methods, and follow-up interventions that are associated with better and worse patient-centered outcomes.

The TMA is thrilled to have Dr. Wang and Dr. Grebenciucova as the James T. Lubin Fellows; they are both exceptional physicians and will ultimately make a tremendous difference for our community.  They will be trained as clinicians and researchers over the next two years by leaders in the rare neuro-immune discipline.  Under the mentorships of Dr. Benjamin Greenberg and Dr. Brenda Banwell, respectively, we know that they will receive the best training.  There is nothing that I am more proud of than the James T. Lubin Fellowship – and in my mind, this is one of the most important programs that we support.  Through this fellowship, we make available the best possible clinical care to the people in our community, we facilitate the opportunity for critical research, and we develop teachers who can motivate this passion in their students to pursue this important discipline.  It is so fitting that this fellowship is named to honor Jim Lubin.  He is a remarkable human being.  He has been a full quad and vent dependent going on 27 years.  In spite of his challenges, he has made the most profound contributions to the people who have these rare disorders and their families.

Sandy Siegel, President and Founder of The TMA

For more information about the James T. Lubin Fellowship, please visit: https://myelitis.org/shaping-the-future/our-programs/james-t-lubin-fellowship

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