Queen’s University researchers make major myelin repair discovery

Queen’s University Belfast scientists have discovered that specific cells from the immune system are key players in repairing myelin in the central nervous system – a fundamental breakthrough that could revolutionize the treatment of debilitating neurological disorders such as multiple sclerosis (MS) and many demyelinating conditions such as transverse myelitis, neuromyelitis optica spectrum disorder and acute disseminated encephalomyelitis. In all these conditions, the myelin is damaged, and there are immune cells present at many sites of damage in the central nervous system. Myelin is important because without it, nerves are not able to conduct or send signals where they need to go.

The research study, led by Dr Yvonne Dombrowski and Dr Denise Fitzgerald at the Wellcome Wolfson Institute for Experimental Medicine at Queen’s University Belfast, is being hailed as a landmark study in unravelling the mysteries of how the brain repairs damage.

The research breakthrough, which was published in Nature Neuroscience, shows that a growth regulatory protein made by certain cells within the immune system, called regulatory T cells (Treg), triggers the brain’s stem cells to mature into oligodendrocytes, which are cells that repair myelin. What the Fitzgerald group and collaborators have discovered in different settings of myelin damage (including spinal cord and brain tissue), is that this specific immune cell, Treg, is critical for driving efficient repair of myelin. The Tregs accomplish this by producing a protein, CCN3, that triggers immature oligodendrocytes to mature, start producing myelin, and re-wrap nerves.

They studied this using a focal demyelinating mouse model induced by injecting lysolecithin into spinal cord white matter. They confirmed their findings with a second demyelinating model at a different central nervous system site using another drug called cuprizone. Further, in brain slice cultures, they were able to show that Tregs promoted brain tissue myelination and remyelination in the absence of inflammation. The discovery means that researchers can now use this new knowledge to develop medicines which will boost these particular cells and develop an entirely new class of treatments for the future.

Senior author of the study, Dr Denise Fitzgerald from Queen’s, was diagnosed with transverse myelitis when she was 21 and had to learn to walk again. Commenting on the findings, Dr Fitzgerald said: “This pioneering research, led by our team at Queen’s, is an exciting collaboration of top scientists from different disciplines at Cambridge, San Francisco, Edinburgh and Nice. It is by bringing together these experts from immunology, neuroscience and stem cell biology that we have been able to make this landmark discovery. This is an important step forward in understanding how the brain and spinal cord are naturally repaired and opens up new therapeutic potential for myelin regeneration in patients. We continue to work together to advance knowledge and push the boundaries of scientific knowledge for the benefits of patients and society, in a bid to change lives for the better, across the globe.”

Original Research: Dombrowski Y, O’Hagan T, Dittmer M et al. Regulatory T cells promote myelin regeneration in the central nervous system. Nat Neurosci. 2017 Mar 13.

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Collaborative Meeting on Acute Flaccid Myelitis

On January 23, 2017 the TMA cosponsored a collaborative meeting on acute flaccid myelitis (AFM) that was hosted by the CONQUER Program of UT Southwestern and Children’s Health Dallas. Twenty-four health care providers, researchers, Centers for Disease Control (CDC) representatives, and the TMA participated in this meeting. The purpose of the meeting was to bring stakeholders together to compare data and experiences about AFM, learn about the initiatives led by different stakeholders, review the current case definition and identify research needs and potential collaborations.

Here are the top ten takeaways from the AFM meeting:

  1. Dr. Benjamin Greenberg of UT Southwestern started the meeting by giving a background about AFM, including the history of the disorder. He emphasized that AFM has likely been around for many years, but that we are only now aware of it and are describing it as AFM.
  2. There remains some ambiguity on the case definition of AFM that gets reported to the CDC, but researchers and medical professionals are working hard to come to a consensus about this. Dr. Sarah Hopkins from the Children’s Hospital of Philadelphia shared her experience as a case reviewer for the CDC and at CHOP, and that imaging interpretation continues to be difficult with regard to involvement of gray matter and the timing of the MRI.
  3. Dr. Manisha Patel from the CDC discussed the number of AFM cases that have been reported to the CDC. There were fewer cases reported in 2015 than 2014.
  4. Dr. Thomas Briese from Columbia University Medical Center discussed the role of enterovirus D68, a virus that is capable of causing an infection in the central nervous system. Enterovirus D68 may be a factor in recent clusters of AFM.
  5. Dr. Carol Glaser from Kaiser Permanente and Dr. Avi Nath from the National Institutes of Health shared their views on whether or not enterovirus D68 could be a cause of AFM, and came to the conclusion that there was significant data linking EVD68 to AFM, but more research would be useful.
  6. Dr. Ken Tyler and his team from the University of Colorado have developed an animal model of AFM that will hopefully help researchers better understand the mechanisms behind AFM.
  7. Dr. Teri Schreiner from the University of Colorado reported findings from a study on outcomes after pediatric AFM. She found that all the children they followed improved functionally but continue to have limb weakness.
  8. Dr. Greenberg reviewed the CAPTURE study which is an ongoing study in pediatric transverse myelitis, including AFM, which will hopefully help us better understand this disorder.
  9. While the CDC does not currently recommend IV steroids or plasma exchange (PLEX) in the treatment of AFM, physicians treating patients with AFM have seen improvement in their patients with these treatments.
  10. Determining the proper diagnostic tests and the correct timing for these tests is critical to improving the care and treatment of people with AFM.

Overall, the meeting was an excellent opportunity to learn about what is currently being done to better understand AFM, to improve the case definition, and improve diagnosis and treatment options. It was a great step in building collaborative approaches to addressing this growing public health concern. We look forward to sharing more updates with the community as we learn more.

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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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