Vaccines and the association with relapses in patients with neuromyelitis optica spectrum disorder

A retrospective study was conducted to determine whether vaccinations were associated with an increased risk of relapse in patients with Neuromyelitis Optica Spectrum Disorder (NMOSD). Patient records were reviewed from three NMOSD centers: the Johns Hopkins NMO Clinic in Baltimore, USA, NeuroCure research Center at Charité University Hospital in Berlin, Germany, and Neuroclinica in Medellín, Colombia. All patients with comprehensive health records related to their NMOSD and who had follow-up information for at least 90 days after their most recent vaccination were included in this analysis.

In order to determine whether there was an increased risk of relapse following a vaccination, the researchers compared relapses that occurred 30, 60, and 90 days after vaccination with relapses that occurred within randomly selected dates. For the purposes of this study, relapses were defined as “a new or worsening acute neurologic symptom lasting 24 hours, associated with a change in exam localizing to the [central nervous system] CNS and not explainable by fever, infection or metabolic condition.” The NMOSD patients were divided into two groups: those who were taking preventative immunotherapy medication such as rituximab, mycophenolate mofetil, azathioprine, methotrexate, or prednisone, and those who were not on a preventative immunotherapy, which included patients who were taking glatiramer acetate and interferon beta, as these medications have been found to worsen or not be effective in NMOSD.

Ninety patients who received a total of 211 vaccinations were included in this study. The median disease course was 6.6 years, and 340 relapses had occurred during this timeframe. Intramuscular influenza was the most common vaccine received (61% of the vaccines received).

The researchers found that vaccines were not significantly associated with relapses among patients on preventive immunotherapy such as rituximab, mycophenolate mofetil, azathioprine, methotrextate, or prednisone. However, the researchers found that vaccines were significantly associated with relapses in patients who were not on preventive immunotherapy. Also, among patients on preventive immunotherapy, routine vaccinations were associated with lower annualized relapse rates.

There were 7 patients who relapsed within 30 days of a vaccination, 6 patients who relapsed 31-60 days after a vaccination, and 3 patients who relapsed 61-90 days after a vaccination, for a total amount of 16 patients experiencing relapses within 90 days after a vaccination. Five of the inflammatory attacks were at the disease onset and eleven were relapses that occurred later in the course of the disease. The highest proportion of vaccination-associated relapses were after tetanus/diphtheria vaccines, as 15% of patients receiving this vaccination relapsed within 90 days.

118 of the 211 vaccinations in this study were administered to patients who were on immunosuppressive therapy. Most (13 of the 16) patients who experienced relapses were not on immunotherapy, and one patient was on glatiramer acetate, which is not an effective treatment for NMOSD. The remaining two patients were on immunosuppressive treatment for an average duration of 47 months.

As stated above, the researchers found that routine vaccination was associated with an 81% lower risk of relapse in patients who were using preventive immunotherapy than patients who were not vaccinated after their initial disease onset. A possible explanation for this finding is that relapses can be triggered by immune system activation, and vaccinations help prevent infections that cause immune system activation, which results in fewer relapses.

The researchers suggest that individuals with NMOSD take preventive immunotherapy treatment prior to receiving any future vaccinations.

The authors of the study note several limitations to this study. For example, they did not include patients who received live attenuated vaccines, such as Japanese encephalitis and yellow fever vaccines, which have been associated with relapses in NMOSD. Additionally, few patients had received the HPV vaccine, which has been associated with relapses in case studies of NMOSD patients. The authors also had limited information and could not include data on the adjuvants that were used for each of the vaccines. Also, there were few aquaporin-4 negative patients included in the study, so additional studies should confirm these findings with aquaporin-4 negative patients. Lastly, there are inherent biases in retrospective data analyses, which could have influenced the results of this study. The study also did not look at vaccine-preventable infections, such as the flu, and their potential association with relapses. The results of the study should be understood within the context of these limitations and biases.

To address the issues with this study, the researchers suggest that there should be a comprehensive, well-controlled prospective study that investigates relapses, vaccines, and infections.

Mealy MA, Cook LJ, Pache F et al. Vaccines and the association with relapses in patients with neuromyelitis optica spectrum disorder. Mult Scler Relat Disord. 2018 Jul;23:78-82. doi: 10.1016/j.msard.2018.05.003. Epub 2018 May 7.

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New Research on Epidural Electrical Stimulation in Spinal Cord Injury

Two research articles were recently published on the use of epidural electrical stimulation (EES) to help paralyzed individuals recover motor function. The first study was conducted by the Frazier Rehabilitation Institute and the Kentucky Spinal Cord Injury Research Center at the University of Louisville. It included four participants who had motor complete spinal cord injuries, meaning no motor function below the level of injury. Two of the participants had lost all sensation below their level of injury in the spinal cord, which is classified as AIS grade A, and the other two participants had retained partial sensory function below their level of injury, which is classified as AIS grade B. This grading system, The American Spinal Injury Association Impairment Scale (AIS), is used to describe and measure the severity and characteristics of a spinal cord injury. The second study was conducted by the Mayo Clinic Rehabilitation Medicine Research Center in Rochester, MN and included one participant who had a motor complete spinal cord injury and had lost all motor function below their level of injury.

In both studies, participants had received clinical rehabilitation after their spinal cord injury and were 2.5 to 3.3 years from when their injury was sustained. All participants received locomotor training at the start of each study, which lasted 8 to 22 weeks depending on the participant. The participants were then implanted with the EES system during a surgical procedure in which a 16-electrode array was implanted on the spinal cord and a spinal cord stimulator was implanted on the abdomen. After participants rested approximately three weeks, the EES system was tested to identify muscle groups in the legs using electromyographic (EMG) recording.

Next, participants in these studies received locomotor training with the aid of electrical stimulation. The participants practiced stepping on a treadmill, stepping over ground, and standing over ground. Participants used a body-weight support system (BWS), trainer assistance, and a walker when needed. They adjusted to not using these aids if progress was shown over the course of the training.

In the Frazier Rehabilitation Institute and the Kentucky Spinal Cord Injury Research Center study, the two AIS grade B participants were able to walk over ground while using assistive devices. The two AIS grade A participants were able to achieve some aspects of stepping on the treadmill with body-weight support, but they were unable to walk over ground. The participant in the Mayo Clinic Rehabilitation Medicine Research Center study was able to achieve stepping on a treadmill, independent standing, and stepping over ground while using a front-wheeled walker and occasional trainer assistance. All four participants were only able to perform these motor functions while the EES system was turned on and when they had the intention to move.

The results of these studies suggest that motor functions may be able to be restored in individuals with spinal cord injury with the use of electrical stimulation. The researchers at the Frazier Rehabilitation Institute and the Kentucky Spinal Cord Injury Research Center noted that the difference in outcomes between the two participants who were able to walk over ground and the two participants who were not able to walk over ground may be due to their sensory level below their injury or other factors. The researchers in both studies recommend a follow-up study be conducted with a larger number of participants.

Dr. Cristina Sadowsky, Clinical Director of the International Center for Spinal Cord Injury (ICSCI) at the Kennedy Krieger Institute, shared with us about how the results of these studies may be applicable to those with rare neuro-immune disorders.

The epidural stimulation case reports prove that some brain-spinal cord connections are dormant post injury and can be activated by ‘raising the excitability level’ of the neurons in the ‘gait center’ in the lumbar spine using the epidural spinal cord stimulator. The stimulator appears to work better in people with (sensory) incomplete injuries, which makes sense, as the number of tracts that connect the brain to the lumbar spine is probably higher than those with motor complete injuries. The stimulation does not work in everyone.

While the case series reports on results in individuals with traumatic spinal cord injury, the results of epidural stimulation could potentially be applied to paralysis related to non-traumatic conditions, like transverse myelitis (TM), neuromyelitis optica spectrum disorder (NMOSD), acute disseminated encephalomyelitis (ADEM), etc., as long as the injury spares the nerves leaving the cord and supplying the muscles in the legs. One way to determine that is to inquire about muscle spasms and reflexes – if they are present, the nerves to the legs are most likely intact.

What would the next steps be to advance this significant research discovery?

  1. Making someone’s gait more energy efficient, which would allow for smoother, longer distance ambulation. You would do that by working towards a more “normal” gait, including reducing assistance from other people to stabilize the pelvis, etc.
  2. Figuring out the best candidates for the procedure; establishing criteria that would preclude a person from getting the stimulator.
  3. Making the process of figuring out the best electrode parameters that give the optimal gait response easier by making this process short, reliable, and clinician friendly.
  4. Getting the smallest, safest, most reliable, customizable epidural stimulator.

There are also some concerns:

  1. Implanting a stimulator/foreign object leads to the possibility of technological failure.
  2. The implant might make it impossible to have an MRI study.
  3. The stimulator assisted gait is not independent and certainly not normal/efficient (yet).
  4. The hype it creates makes everyone think that they can walk if a stimulator is implanted.
  5. It’s still far away from actual use in clinical care. It takes a long time to program, programing is very personalized and requires a lot of knowledge. Dr. Susie Harkema and Dr. Reggie Edgerton, the senior scientists on each paper, have been working in the gait training field for many years!

The case reports are more relevant for the fact that now there is a method to allow for meaningful remaining brain-spinal cord connections to be uncovered and used, and it points out to the absolute NEED to undergo extensive, well designed, meaningful activity based rehabilitative interventions.

Angeli CA, Boakye M, Morton RA et al. Recovery of Over-Ground Walking after Chronic Motor Complete Spinal Cord Injury. N Engl J Med. 2018;379(13):1244-1250.

Gill ML, Grahn PJ, Calvert JS et al. Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia. Nat Med. 2018 Sep 24.

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Three Articles About AFM Published in JAMA Pediatrics

On November 30th, The Journal of the American Medical Association (JAMA) Pediatrics published three articles about acute flaccid myelitis (AFM). One article, “A Parental Perspective on Strengthening Knowledge After Acute Flaccid Myelitis,” was written by three mothers of children with AFM, Dr. Riley Bove, Heather Werdal, and Erin Olivera.1 They discuss their experiences caring for their children, as well as supporting other parents faced with this diagnosis through a Facebook group for parents of children with AFM. They explained that when they brought their children to a physician for evaluation of weakness, the physicians often did not perform a neurological examination that would have revealed the limb weakness. Often, they dismissed this weakness as insignificant, which led to delays in diagnostic tests and treatment “…The delay in evaluation represented the first of a series of schisms between us and the health care system that eroded our trust that our children’s cases were taken seriously, reported to the CDC adequately, and followed up with care.” They also note their ongoing role as caregivers for their children and the need to deal with complications, such as scoliosis and pain. They urge medical providers to advocate for greater insurance allowances for rehabilitation, and a greater willingness to work with their children’s schools and therapists. The authors write, “We share this perspective with the hope that early awareness, intervention, and advocacy will prevent AFM from becoming more common and will help our affected children achieve a future where they are not defined by their AFM.”

Earlier this fall, several clinicians and health care providers established the AFM Working Group. The Group consists of medical professionals and researchers from approximately 25 institutions and is under the leadership of Dr. Carlos Pardo from the Johns Hopkins Transverse Myelitis Center. The TMA is a member of this working group, and is committed to advancing the knowledge, research and education regarding AFM.  Dr. Sarah Hopkins, Dr. Matthew J. Elrick, and Dr. Kevin Messacar, in partnership with the working group, wrote an article about the diagnosis, treatment, and future directions for AFM.2 They discuss key diagnostic features found through lumbar puncture and magnetic resonance imaging (MRI) of the spinal cord. They discuss the identification of infections associated with AFM, such as enterovirus D68 and enterovirus A71. They argue that when AFM is suspected, patients should be hospitalized with a concern for the progression of weakness or loss of the ability to breathe. They discuss potential treatment options and note that intravenous immunoglobulin (IVIG) has been widely used, but that there are mixed opinions about the use of steroids or plasma exchange. They argue that “this is an area in urgent need of further research” and note the importance of early and continued rehabilitation.

Following outbreaks of AFM in 2012 and 2014, the U.S. Centers for Disease Control and Prevention (CDC) and the Council of State and Territorial Epidemiologists created a standardized case definition for this illness which could be used for epidemiological surveillance.3 This definition has been used by clinicians to diagnose and treat children presenting with this illness and by scientists to define research cohorts. While the CDC’s definition has been used to identify cases for the purpose of surveillance, it may need to be refined so as not to encompass other rare neuro-immune disorders, such as transverse myelitis, Guillain-Barre syndrome, spinal cord stroke, acute disseminated encephalomyelitis, MOG antibody-associated disease, and other myelopathies.

Researchers, many of whom are part of the AFM working group, conducted a retrospective analysis which included the cases of 45 children younger than 18 who were diagnosed with AFM in the United States and Canada between 2012 and 2016. The records came from patients who self-referred or were referred by their physicians for a study of genetic susceptibility to AFM, and patients presenting with suspected AFM to the Johns Hopkins Transverse Myelitis Center between 2014 and 2017. The two goals of the study were to determine whether the CDC case definition of AFM includes patients with different diagnoses and to identify clinical characteristics that differentiate AFM from other diagnoses. Neurologists reviewed the medical records and MRIs (when available) of all patients and categorized them as either patients with “AFM with possible alternative diagnosis” (AFM-ad) or patients who met only the CDC case definition for AFM and no other alternative diagnosis, which they called “restrictively defined AFM”, or rAFM. The researchers then compared each clinical variable in the patients’ medical records to generate a description of rAFM; those characteristics that were present in all patients in the rAFM group. None of these characteristics were present in patients in the AFM-ad group. To further refine the rAFM case description, a blinded independent neurologist reviewed randomly selected cases, and the description was updated based on this review.

The researchers found that 34 patients had a diagnosis consistent with rAFM while 11 patients had a diagnosis classified as AFM-ad. The most common alternative diagnoses for the AFM-ad patients were transverse myelitis and spinal cord ischemia (spinal cord stroke). The researchers identified four major characteristics shared by all rAFM patients. They also identified several key differences between rAFM and AFM-ad. These included differences in the pattern of limb involvement (rAFM cases were more likely to have an asymmetric onset and less likely to have both legs affected). rAFM cases were more likely to have decreased muscle tone, and less likely to have bladder and bowel issues, or sensory issues. AFM-ad cases were more likely to have an onset that reached its peak in less than an hour. rAFM cases were more likely to have an infection prior to the onset of symptoms. The researchers also found differing diagnostic and imaging characteristics between the groups. For example, rAFM cases were more likely to have gray matter predominant lesions in the spinal cord than AFM-ad cases.

The researchers suggest that their findings lend to a more well-defined case definition for AFM that should be used as a starting point for inclusion and exclusion criteria in research. Additionally, their findings may be used in the clinical setting to more quickly and accurately diagnose AFM, so that treatment can be administered immediately, and patients can be monitored for respiratory issues. Early diagnosis of AFM enables a better chance of identifying a pathogen in biological samples, and it may also provide prognostic information to guide long-term treatment and rehabilitation. While the researchers’ case definition of AFM may be useful in the clinical setting, it may be problematic for a small number of cases and should not automatically exclude all cases that don’t meet these criteria.

The authors of the study acknowledge that a major limitation of this study is the inability to independently validate the use of the proposed description of rAFM. Such validation would require a separate and prospectively defined cohort of children presenting with acute weakness including other pathologies, such as ischemic myelopathies. They also state that the criteria described is provisional and expect that an iterative process of refinements can better serve the research needs of the AFM community.

[1] Bove R, Werdal H, Olivera E. A Parental Perspective on Strengthening Knowledge After Acute Flaccid Myelitis. JAMA Pediatr. 2018 Nov 30.

[2] Hopkins SE, Elrick MJ, Messacar K. Acute Flaccid Myelitis-Keys to Diagnosis, Questions About Treatment, and Future Directions. JAMA Pediatr. 2018 Nov 30.

[3] Elrick MJ, Gordon-Lipkin E, Crawford TO et al. Clinical Subpopulations in a Sample of North American Children Diagnosed With Acute Flaccid Myelitis, 2012-2016. JAMA Pediatr. 2018 Nov 30.

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Upcoming Phase I remyelination trial using Q-Cells in Transverse Myelitis

The University of Texas Southwestern Medical Center recently posted a press release on an exciting upcoming Phase I remyelination trial using Q-Cells in Transverse Myelitis. The TMA 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. We hope you are excited too!

Q Therapeutics developed a glial-restricted precursor cell, called a Q-Cell, that develops into oligodendrocytes. Oligodendrocytes produce myelin, the insulation around nerves, and other factors that are necessary for healthy Central Nervous System (CNS) function. This Phase I trial will include nine non-ambulatory adult transverse myelitis patients. The Q-Cells will be surgically implanted into the spinal cord at the level of a lesion. Participants will be followed for both safety assessments and multiple measurements to determine if the cells are inducing any level of repair. If you’d like to learn more about the study, please visit the FAQ page.

This Phase I study is expected to cost approximately $2.5 million. The CONQUER program at The University of Texas Southwestern secured a $1.5 million gift towards funding of the Phase I trial. The TMA, through  The  Pauline  H.  Siegel  Eclipse  Fund, and Q Therapeutics have committed the remaining funds to cover participant travel expenses, the production and testing of the cells for the trial, and the cost of a contract research organization (CRO) that will manage the clinical trial.

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New Research Presented at American Academy of Neurology Meeting

A few weeks ago, we published a blog on TMA-supported research that was presented at the 70th American Academy of Neurology Annual Meeting. Below is other research on rare neuro-immune disorders that was presented at the meeting.

A team from Johns Hopkins University, Johns Hopkins TM Center, and the Kennedy Krieger Institute presented research that aimed to investigate the differential diagnosis of pediatric myelopathy at the Johns Hopkins TM Center. They looked at the records of 55 children (under age 21) who had been seen at the Center between 2015 and 2017. They reviewed the temporal profile of symptoms, clinical presentation, and cerebrospinal fluid (CSF) analysis results of these children. They then compared the clinical features of non-inflammatory and inflammatory myelopathies. 71% of the cases they reviewed were inflammatory. Most of the patients presented with infectious (para-infectious and post-infectious) myelopathies (n=23, 42%), followed by vascular (n=15, 27%), autoimmune demyelinating (n=13, 24%) (including idiopathic transverse myelitis (n=3), neuromyelitis optica (NMO) spectrum (n=3), multiple sclerosis (n=7)) and of uncertain etiology (n=4, 7%). Those with non-inflammatory myelopathies were significantly more likely than those with inflammatory myelopathies to have a hyperacute onset (that is, less than six hours from onset to their peak neurological symptoms), sphincter dysfunction, lower extremity weakness, and symmetric involvement (meaning both sides of the body). Those with inflammatory myelopathies were significantly more likely than those with non-inflammatory myelopathies to have a preceding infection, cranial nerve involvement, and an increased white blood cell count in their cerebrospinal fluid.

Additional research was presented on Chiari malformations and TM. Chiari malformation is a condition in which brain tissue extends into the spinal canal. The researchers looked at patients (under age 21) who were referred to the Johns Hopkins TM Center between 2010 and 2017, and who had a diagnosis of TM and Chiari malformation. Of the 86 patients seen at the TM Center, seven patients (8%) with TM and Chiari malformation were identified. Six of seven (88%) were male. They all presented with hyperacute onset flaccid quadraparesis associated with longitudinally extensive cervical myelopathy. The prevalence of Chiari malformation in this study was eight times that of the prevalence of Chiari malformation in the general pediatric population reported in prior studies. The researchers believe these cases are not inflammatory but are vascular instead.

Maureen Mealy and Dr. Michael Levy from Johns Hopkins University School of Medicine, and Dr. Philippines Cabahug from the Kennedy Krieger Institute presented research on sexual quality of life in women with NMOSD. They conducted an analysis of women with NMOSD from the Johns Hopkins NMO Clinic Facebook Group, and online patient community. These women completed the Sexual Quality of Life-Female Questionnaire (SQOL-F), an 18-item assessment of the impact of sexual dysfunction on quality of life in women. They compared their data to healthy controls and to data from women with traumatic spinal cord injury (SCI). They found that sexual quality of life was significantly worse in women with NMOSD than women with SCI or the healthy controls.

We hope to see additional research presented at upcoming conferences and look forward to sharing the findings with you. For more information on this and other research, please visit https://myelitis.org/shaping-the-future/research/.

References

Munoz LS, Gordon-Lipkin E, Barreras P, Gómez S, Piedra W, Castañeda-Valderrama MJ, Yeshokumar A, Mealy M, Murphy O, Levy M, Becker D, Newsome S, Pardo CA. The spectrum of myelopathies in children: Beyond idiopathic transverse myelitis. Poster presented at: 2018 American Academy of Neurology Annual Meeting; April 2018; Los Angeles, CA.

Gordon-Lipkin E, Munoz L, Barreras P, Castañeda M, Gailloud P, Pardo CA. Chiari malformations associated with transverse myelitis: Are these myelopathies truly inflammatory? Poster presented at: 2018 American Academy of Neurology Annual Meeting; April 2018; Los Angeles, CA.

Mealy MA, Cabahug P, Levy M. Impaired sexual quality of life in women with neuromyelitis optica spectrum disorder. Poster presented at: 2018 American Academy of Neurology Annual Meeting; April 2018; Los Angeles, CA.

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The TMA at the American Academy of Neurology Annual Meeting

One very important part of the TMA’s mission is to advance the scientific understanding of and therapy development for ADEM, MOG Antibody-Associated Disease, NMOSD, ON, and TM (including AFM). We do this by supporting the training of clinician-scientists and by supporting basic and clinical research about these disorders. Part of doing research involves disseminating or sharing research findings to the medical community, and this is often done through peer-reviewed publications, or by presentations at conferences. We are proud to announce that TMA supported research was presented at the 70th American Academy of Neurology Annual Meeting, which was held from April 21-27th in Los Angeles, California.

Dr. Olwen Murphy, a current James T. Lubin Fellow, and a team at The Johns Hopkins Hospital presented research on pediatric myelopathies. They conducted a retrospective review of 43 patients who were less than 21 years old who were referred to the Johns Hopkins TM Center with a diagnosis of TM between 2010-2017. They reviewed the temporal profile of symptoms, clinical presentation, cerebrospinal fluid analysis and spinal cord magnetic resonance imaging of the patients. They found that clinical, laboratory and imaging findings were consistent with inflammatory myelopathy in 29 patients (infectious [n=10], idiopathic [n=5], neuromyelitis optica [n=1], neuromyelitis optica spectrum disorder [n=1], clinically isolated syndrome [n=1], other [n=11]) and non-inflammatory myelopathy in 11 patients (SC ischemia [n=9], metabolic [n=2]). In 3 patients, the cause was unclear.

Maureen Mealy, also from the Johns Hopkins TM and NMO Centers, presented similar research that looked at 1000 patients who were referred to the Johns Hopkins TM Center between 2010 and 2017. They reviewed patients’ clinical/temporal profile, their neuroimaging, and laboratory findings to establish a final diagnosis. They found that 62% were confirmed to have an inflammatory cause for their myelopathy, of which 35% was idiopathic. They found 41% of patients had myelopathy attributable to an underlying disease such as multiple sclerosis or neuromyelitis optica spectrum disorder.

Dr. Murphy, Dr. Pardo, and Dr. Gailloud also presented research on a group of 100 patients with symptomatic low-flow spinal arteriovenous fistulas (SAVF). Low-flow SAVFs are the most common spinal vascular malformation and they can cause severe disability, including paraparesis, pain, bladder and sexual dysfunction. Most low-flow SAVFs can be treated, but they are frequently misdiagnosed, which can delay treatment. They identified clinical features that may help physicians identify this diagnosis, such as older age, male gender, history of intermittent cramping pain in the legs because of low blood flow during exercise, and risk factors for venous thrombosis.

Dr. Stacey L. Clardy at The University of Utah, one of the James T. Lubin Fellowship training sites, also presented research at AAN. Her team’s research aimed to determine the rate and characteristics of patients not meeting diagnostic criteria for neuromyelitis optica spectrum disorders who tested positive for autoantibodies to aquaporin 4 (AQP4). They found 48 patients in the University of Utah medical system who tested positive for AQP4, but only 20 of them met the clinical criteria for NMOSD. They argue that individuals should be tested for AQP4 multiple times to ensure patients do not receive false negative results.

Dr. Jonathan Galli, who will start his James T. Lubin Fellowship this summer, worked with Dr. Clardy on another research study that aims to characterize patients with NMOSD in the Department of Defense (DoD) population. They identified 131 patients within the DoD system who had the code for NMOSD documented in their medical record, 39 of whom were service members. Only 17 of this cohort of 39 met the criteria for NMOSD. Their clinical characteristics matched other reports of individuals with NMOSD, except for the distribution between men and women, but this may be because of the characteristics of the DoD population as a whole.

For more information on other research and clinical publications supported through the generosity of the TMA community, please visit https://tma.ong/2IsdzqW.

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Studying the Pathology of Transverse Myelitis Through Biopsies

Idiopathic transverse myelitis (TM) is rare, and spinal cord tissue demonstrating the pathology of idiopathic transverse myelitis is even rarer. In fact, there are no confirmed cases of human idiopathic transverse myelitis that have been published in the medical literature!

Why would someone want to look at the spinal cord tissue of someone with TM? The reason is that we don’t know what is happening in the spinal cord at the time of an attack. Researchers can stain spinal cord tissue to see many different types of immune cells that may be involved. They can also get a sense of the target of the immune response that is occurring in TM. For example, is the immune system attacking astrocytes, myelin, neurons and/or other structures?

Getting a biopsy of the spinal cord is not routinely done to make a diagnosis of idiopathic TM. However, some patients with unique cases may have undergone a biopsy to rule out a tumor or other process. If you had a biopsy done in the past, and were ultimately diagnosed with idiopathic TM, Dr. Michael Levy and his team at Johns Hopkins Medicine would like your permission to access the biopsy material and study it.

If you are among the rare TM patients who have had a biopsy, you can learn how to participate here.

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Serum IL-27 and IL-35 levels and disease severity in neuromyelitis optica spectrum disorders

Researchers in 2016 conducted a study to investigate the role that interleukins play in the development of neuromyelitis optica spectrum disorder (NMOSD). Interleukins are a type of protein created by white blood cells that respond when there is a suspected disease in the body. Interleukins have been shown to play an important role in autoimmune diseases. In order to investigate the role of a family of interleukins (IL-12) in the pathology of NMOSD, researchers measured their levels in the blood (serum) and cerebrospinal fluid (CSF) of individuals with NMOSD and assessed their relationship with clinical symptoms presented by these individuals.

In order to complete the study, researchers recruited 45 patients with NMOSD from the Neurology Department of Tianjin Medical University General Hospital from January 2012 to July 2015. These patients had all been diagnosed with NMOSD using identical criteria and had also been receiving similar steroid treatment to manage their diagnosis. Researchers also created a control group of healthy individuals matched for sex and age to compare to the group of patients diagnosed with NMOSD.

The researchers found that serum IL-27 and serum IL-35 levels were lower in individuals with NMOSD than the control group. They also found that serum IL-27 and serum IL-35 levels were similar among individuals who were anti-aquaporin 4 (AQP4) positive and those that were negative. When they separated AQP4 positive people from AQP4 negative people, they found that serum IL-35 levels were significantly lower in AQP4 positive individuals than the control group. While not statistically significant, IL-35 serum levels were lower in AQP4 negative individuals compared to the control group as well. Both IL-27 and IL-35 were below detectable levels in the CSF of people with NMOSD and controls.

After data were collected for serum levels, the researchers performed various statistical analyses in order to know whether the correlation between serum levels of IL-27 and IL-35 and disease severity or corresponding MRI indications were statistically significant.

The study participants showed a negative correlation between levels of IL-27 and disease severity and spinal cord lesion length. This means that as the levels of IL-27 decreased, the disease severity and spinal cord lesion length increased. In addition, researchers saw that levels of IL-35 had a negative correlation between disease severity and annual relapse rate.

The researchers thus concluded that the levels of these two interleukins are decreased in patients with NMOSD, which ultimately means these may be involved in the pathology of NMOSD. The researchers speculate these interleukins may be important in mechanisms that reduce inflammatory responses based on the way they play a role in NMOSD. Dr. Benjamin Greenberg from the University of Texas Medical Center noted that one possible issue with this study is that the individuals in the study were treated with steroids, so it may be possible that the levels of these cytokines may be lower because of the steroids and not because of the NMOSD disease process. Additional studies could control for immunosuppressive treatment.


Original research:  Zhang DQ et al. Decreased serum IL-27 and IL-35 levels are associated with disease severity in neuromyelitis optica spectrum disorders. J Neuroimmunol. 2016 Apr 15;293:100-4.

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New Study on Scrambler Therapy for the Treatment of Neuropathic Pain in NMOSD

Chronic neuropathic pain can be a debilitating symptom of damage to the spinal cord that occurs in transverse myelitis, neuromyelitis optica spectrum disorder, and acute disseminated encephalomyelitis. Treatment for neuropathic pain includes medications such as antidepressants, antiepileptic drugs, opioids, and patches/creams, physical therapy, psychological therapy, and stimulation techniques. Despite using many of these treatment options, some individuals still experience chronic neuropathic pain, so additional research is needed to develop new treatments.

Scrambler Therapy was developed by Giuseppe Marineo, a biophysicist.1 This therapy is thought to re-organize the pain system. It does this through transcutaneous electrical stimulation that activates C fibers. C nerve fibers carry sensory information and are thought to play a role in neuropathic pain. Scrambler Therapy’s electrical stimulation replaces the pain signals with “non-pain” signals, and it is thought that this retrains the brain to think areas that are painful are not painful anymore.1 This therapy has been studied as a treatment for chronic neuropathic pain in chemotherapy-induced peripheral neuropathy, post-herpetic neuralgia and post-surgical neuropathic pain. In these studies, patients report sustained relief after undergoing daily treatment sessions for 10 consecutive weekdays.

To study this therapy in individuals with neuromyelitis optica spectrum disorder (NMOSD), Dr. Michael Levy and his team at the NMO Clinic at Johns Hopkins are conducting a randomized single blinded, sham-controlled trial of patients with NMOSD who have central neuropathic pain. They will use Scrambler Therapy and patient reported outcomes to determine if Scrambler Therapy is a feasible and effective add-on treatment of chronic neuropathic pain.

This trial will recruit twenty-two adult patients diagnosed with NMOSD who have chronic neuropathic pain despite empiric treatment with an anti-epileptic, antidepressant, opioid and/or an NSAID medication. Patients will be randomized 1:1 to undergo Scrambler Therapy or blinded sham daily for 10 days. The sham group will serve as the “control” group and will not receive the therapy, although they will not know that they are not receiving the therapy. The control group and the experimental group’s outcomes will be compared to assess the efficacy of the treatment. This study is randomized, meaning the researchers will randomly select who is in the control group and who is in the group receiving Scrambler Therapy. This is done to increase the chances that the effects seen in the study are the result of the treatment and not other factors.

The primary outcomes of the study will be acceptability and feasibility. The secondary outcome will be efficacy. This will be measured as a change in pain scores of more than two points recorded daily by the patient using an 11-point visual analog scale. Quality of life (QoL), neurologic function, anxiety, depression, sleep disturbance, and pain will also be evaluated at baseline, at the end of therapy, and at 4 and 8 weeks following completion of treatment. It is hypothesized that Scrambler Therapy will be an acceptable, feasible, and efficacious intervention that significantly reduces pain in patients with NMOSD.

For more information on the study and how to participate, click here: http://tma.ong/2IateHZ. You can also contact the research team by phone (410-502-8672) or email (nmo_research@jhmi.edu).

Are you interested in getting updates on new research opportunities? Please fill out this form to be notified of new research studies: http://tma.ong/research-form

References:

  • Majithia N, Smith TJ, Coyne PJ et al. Scrambler Therapy for the management of chronic pain. Support Care Cancer. 2016 Jun;24(6):2807-14.
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Clinical biomarkers differentiate myelitis from vascular and other causes of myelopathy

Barerras et al. recently published a study in which they analyzed the clinical presentation, spinal cord MRI findings, and cerebrospinal fluid (CSF) features of patients who were initially diagnosed with transverse myelitis (TM). Their goal was to see how these characteristics may help differentiate inflammatory myelopathy (TM) from other causes of myelopathy.

Myelopathy is a general term used to describe a disease of the spinal cord. Myelopathy can be caused by inflammation, as is the case with transverse myelitis, but myelopathy can be caused by cancer (neoplastic), vascular issues (related to blood vessels), compression (spondylotic), or metabolic issues (for example, B12 deficiency). In a podcast about the study, Dr. Carlos Pardo expresses the importance of making the distinction between myelopathy versus TM to avoid an incorrect diagnosis of TM and, most importantly, immunosuppressive treatments that are not truly indicated.

In order to investigate effective approaches to making a definite TM diagnosis, 457 patients with a newly established diagnosis of TM who were referred to the myelopathy center between 2010 and 2015 were included in the study. 58% were female (n=265), with a median age of 46 years.

First, they looked at how specific characteristics were associated with different myelopathies. These myelopathies were

  1. inflammatory myelopathy (IM)
  2. vascular myelopathy (VM)
  3. spondylotic myelopathy (SM)
  4. other causes of myelopathy (OM)

The characteristics they looked at were demographic/medical histories, clinical presentations, neurologic examinations, MRI findings, and CSF findings.

After looking at the clinical, MRI, and CSF characteristics of the participants, 55% of 457 patients (n=247) were classified as true inflammatory myelopathy, 20% (n=92) were reclassified as vascular myelopathy, 8% (n=35) as spondylotic myelopathy, and 18% (n=83) as other myelopathy.

Their analysis showed that a shorter time between symptom onset and when an individual’s symptoms were at their worst was associated with different types of myelopathies. IM’s temporal profile most often was subacute (between 49 hours and 21 days between onset and symptoms being at their worst), while VM’s temporal profile was most often hyperacute (less than 6 hours).

The researchers emphasize the importance of biomarkers and minute aspects of a patient’s medical history, family medical history, and the temporal progression of symptom onset for accurate diagnosis of inflammatory myelopathy. As stated by Dr. Pardo in the podcast, the literal “clinical dissection” of a patient’s clinical presentation, combined with past medical history and diagnostic MRI imaging is paramount for successful diagnosis of true myelitis of inflammatory origin.

The study analyzed the inflammatory group as one category, which as the authors state “…may not reflect important differences among specific etiologies within the inflammatory group such as MS vs NMOSD or NMOSD vs sarcoidosis myelopathy as has been shown previously.” Also, because the study took place at a referral center for myelopathies, and because the center often receives patients who may be difficult to diagnose, it is possible that these cases may be overrepresented in the study, and that these findings may not be entirely reflective of the larger population of individuals with inflammatory myelopathy.

You can learn more about the study from Dr. Carlos Pardo’s presentation at the 2017 Rare Neuro-Immune Disorders Symposium: http://tma.ong/2sXs5Qq

Article: Barreras P, Fitzgerald KC, Mealy MA et al. Clinical biomarkers differentiate myelitis from vascular and other causes of myelopathy. Neurology. 2018 Jan 2;90(1):e12-e21. doi: 10.1212/WNL.0000000000004765. Epub 2017 Dec 1.

Full text: http://tma.ong/2CmUvXU

Podcast featuring an interview with Dr. Pardo about this publication: http://tma.ong/2owdqWK

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