Transverse Myelitis Association
Volume 5 Issue 1
December 2002
Page 6
Volume 5 Issue 1
December 2002
Page 6
| Research at the Johns Hopkins Transverse Myelopathy
Center Chitra Krishnan Centers of Excellence dedicated to the study of rare diseases provide a common platform for patients from all over the world in search of sophisticated treatment and understanding of their disease condition. Patients benefit from an interdisciplinary approach to providing state-of-the-art care that is constantly challenged and enhanced by ongoing research. Further, these centers aid the advancement of research to better understand the disease condition and to develop novel and effective therapies by bringing together interested physicians and patients. Study of rare diseases is very challenging because of the need for standard diagnostic criteria and acceptable protocols of care that need to be developed based on research and the experience of physicians and scientists and their understanding of the natural course of the disease. Acute transverse myelitis (ATM) is a very rare disease that affects people of all ages regardless of gender. To date, there have been two incidence studies published that establish an incidence rate of 1-4 new cases per million per year with peak incidences between the ages of 10-19 and 30-39 years 1;2. There is no single etiology for ATM. In many cases, the clinical syndrome with a sudden and acute onset may be the result of damage to neural tissue by an infectious agent or by the immune system or both. Studies to date that have characterized acute transverse myelitis have suggested that rapid progression of symptoms, the presence of back pain, signs of spinal shock, areflexia, flaccidity, abnormal somatosensory evoked potentials, abnormal imaging, and high deficit score at onset may serve as indicators of poor prognosis for ultimate recovery 3-8. Approximately a third of the patients have been reported to recover with little to no sequelae following the initial attack, one-third are left with a moderate degree of permanent disability, and one-third have virtually no recovery and are left severely functionally disabled 1;8;9. The Johns Hopkins Transverse Myelopathy Center was established in October 1999 as a multidisciplinary center dedicated to the diagnosis and treatment of acute transverse myelitis (ATM) and to better understanding of the pathophysiology and natural course of the disease. During the second International TM Symposium in July 2001, we formally established a network of regional centers of excellence in transverse myelitis. Institutions affiliated with the Consortium include Johns Hopkins University (Baltimore, MD), Mayo Clinic (Rochester, MN), Mayo Clinic (Scottsdale, AZ), Yale University (New Haven, CT), Washington University (St. Louis, MO), University of Miami (Miami Project to Cure Paralysis (Miami, FL), University of New Mexico (Albuquerque, NM), University of Kentucky (Lexington, KY), University Hospital of Antwerp (Belgium), Cleveland Clinic Foundation (Cleveland, OH), The Ohio State University (Columbus, OH), University of Washington (Seattle, WA), Tuft’s University (Boston, MA), The George Washington University (Washington, DC), Children’s Medical Center, University of Texas Southwestern Medical Center (Dallas, TX), University of Florida, North Florida/South Georgia Veterans Health System (Gainesville, FL), Barrow Neurological Institute (Phoenix, AZ), Indiana University School of Medicine (Indianapolis, IN). One of the first collaborative efforts of the consortium was the establishment of uniform diagnostic criteria and nosology of acute transverse myelitis (ATM) to ensure a common language of classification, to reduce diagnostic uncertainties and to lay the groundwork necessary for multi-center clinical trials. These criteria were developed using the existing review of the literature and the vast experience of the medical providers in the Consortium with patients who presented as ATM. Distinguishing the presentation of ATM as either idiopathic or disease-associated needs to be determined early in the acute phase as timely and accurate diagnosis and identification of the etiology is very critical to the management of the disease. We developed a diagnostic algorithm as a first uniform step to improved care by detailing a possible complete work-up to ensure timely and accurate diagnosis. The paper was recently published: Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology 2002; 59: 499-505. In order to gain an understanding of the disease, it is critical to determine what the various triggers of the inflammation are that induce neural injury in the spinal cord. It is also important to understand the cellular and humoral factors that play a role in the process. Finally, it is imperative that we discover ways to modulate the inflammatory response in order to improve patient outcome. Dr. Douglas Kerr, the Director of the Center and Harold Ayetey from the University of London, have recently published a paper on the “Immunopathogenesis of acute transverse myelitis.” The paper is a review of the potential immunopathogenic mechanisms in ATM summarizing all of the recent discoveries relying, when necessary, on data from related diseases such as ADEM, GBS and NMO. This review was recently published: Kerr, DA and Ayetey, H. Immunopathogenesis of acute transverse myelitis. Current Opinion in Neurology 2002; 15: 339-347. The JHTMC has established an ongoing extensive clinical database where we currently have more than 250 patients. All patients referred to the Center are given a questionnaire to complete during their initial visit. Data related to their illness, antecedent factors, clinical symptoms during the acute phase, radiologic characteristics and treatments received is gathered and entered into the database. They are then followed over time and their progress is charted and recorded. We currently are exploring the dataset to understand the demographics, natural course of the disease, characterize it further based on similarities, understand prognostic variables, and validate our diagnostic criteria. This database also serves as a clinical repository for future clinical studies and trials. In collaboration with Dr. Frank Pidcock and Dr. Melissa Trovato in the Department of Physical Medicine and Rehabilitation, we are currently analyzing our dataset to study any differences in pediatric and adult idiopathic ATM. Is pediatric ATM a clearly different entity? Can we predict the outcome of a child? To date, we have about 30 pediatric cases of idiopathic ATM referred to us from all over the world and about 100 adult patients that meet our diagnostic criteria. To our knowledge, this is the largest database of idiopathic cases. Disease-associated ATM has a known etiology enabling a better characterization of the disease and consequent therapies. Idiopathic ATM, on the other hand, is a challenge to identify and manage. We hope to be able to capture the characteristics that distinguish idiopathic ATM patients that eventually completely recover from those who do not. To further assist this study, we have a clinical repository of blood and CSF of patients both in the acute and convalescent phase. Some of the ongoing studies include identification of serologic markers that define and characterize transverse myelitis both from a diagnostic and prognostic point of view. We work closely with the Department of Rheumatology (Dr. Laura Hummers and Dr. Fred Wigley) in an effort to understanding the mechanisms of ATM in patients with serologic or clinical evidence of connective tissue disease such as sarcoidosis, Behcet’s disease, Sjogren’s syndrome, SLE and mixed connective tissue disorder. In partnership with Dr. Neal Halsey and the Center for Immunization Safety Assessment, we are presently working on developing a case assessment/retrospective case-control study to determine whether there is any association between vaccination as a preceding event and idiopathic transverse myelitis. A subset of our patients with ATM (N=40) have been found to have recurrent transverse myelitis. We have defined recurrence as the presence of more than one episode meeting the criteria for ATM with intervening improvement and excluding the presence of MS. More than half of these recurrent cases are idiopathic in etiology. We are currently analyzing the serum of these patients for specific markers, such as antibodies to the SSA antigen (also known as Ro antigen) seen in patients with primary Sjogren’s syndrome, SLE, connective tissue diseases and in babies with neonatal lupus erythematosus that may be associated with recurrent events. Douglas Kerr, MD/PhD and David Irani, MD, Co-Director of the JHTMC, published a paper on the presence of 14-3-3, a neuronal protein, in the CSF as an indicator for poor prognosis in the Lancet 2000 Mar 11;355(9207):901. This is an ongoing study; we have analyzed the CSF of more than 50 patients with idiopathic ATM and are currently studying the association of the 14-3-3 with outcomes such as ambulation. We are also looking for various cytokines and other markers in order to correlate them with clinical outcome. Other studies include characterization of lymphocytes present in the CSF during the acute phase of ATM, and examination of the capacity of CSF from the acute phase of ATM patients to cause morphologic alterations and apoptosis of human cultures neurons. The JHTMC is considering the use of magnetic resonance spectroscopy to further define the spinal cord lesions in ATM patients. This would better enable us to characterize and follow recovery of patients with ATM. In order to further our research efforts, we are currently developing an internet-based ATM database on a secure server. We hope to include information from all of the patients who present with features of ATM at all of the Centers in the Consortium. This would further enable us to study clinical features and natural history of the disease, while assessing our diagnostic criteria and algorithm. By including more Centers, the data will tend to have less referral bias. Jointly with Dr. Adam Kaplin, MD/PhD in the Department of Psychiatry and Neuroscience, we are currently studying depression and cognitive function in ATM. ATM patients seen at the Center are given a questionnaire called the SCL-90 to assess the presence of depression and its severity. Depression is quite common among ATM patients. It often leads to decreased compliance with physical therapy regimens and adversely affects ultimate outcome. We also administer four neuro-cognitive tests to ATM patients. These tests look for subtle cortical and sub-cortical changes that might be reflective of neurocognitive deficits. Rehabilitation is a very integral part of the recovery and treatment of ATM patients. We work closely with the Physical Medicine and Rehabilitation team (Drs. Ling-Ling Cheng, Rosemarie Filart, R. Sam Mayer) constantly assessing and seeking effective rehabilitation measures and management. Patients are often left with permanent weakness following ATM and spasticity which limits the extent of recovery. Patients report stiffness, tightness, or painful spasms often in the buttocks and legs. Ongoing projects include spasticity evaluation and treatment with new drugs, such as tiagabine and use of a tone assessment device for formal functional gait assessment, intervention spasticity management with the Baclofen pump and use of 4-AP (fampridine) in the functional improvement of ATM patients. Bowel-bladder and sexual dysfunction are common problems in ATM patients. Current investigations are underway to characterize the extent of autonomic dysfunction and recovery, along with new therapies, such as sacral nerve stimulation that could allow patients to have reduced or eliminated need for intermittent catheterization. Using data from these preliminary studies, we hope to elicit recovery patterns in bladder and sexual dysfunction and provide the basis for clinical trials and other future interventions. Basic science studies are focused in two areas: neuro-regeneration and developing an understanding of neural injury in ATM through the creation of an animal model. Specifically, we have created a focal inflammatory mouse model which replicates many of the clinical and pathologic features seen in humans with ATM. We hope to utilize this to further understand how the immune system injures the nervous system. We are also exploring the clinical potential of embryonic stem cells, Schwann cells and olfactory ensheathing cells (OECs), which seem to show great promise in the near future. The JHTMC has a long-term and intensive commitment to both basic science and clinical research. We are focused on better understanding the disease process so that we can find effective treatments for the patient at the onset ATM. We are also dedicated to finding more effective treatments for patients who suffer from the chronic symptoms of ATM. Finally, we are committed to finding approaches to neuro-regeneration, in order to stimulate functional improvements for all short-term and long-term patients with ATM. References
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