Rare Neuroimmunological Disorders: An Overview
David Irani, M.D.
Department of Neurology,
The Johns Hopkins University School of Medicine and
Department of Molecular Microbiology and Immunology,
The Johns Hopkins University Bloomberg School of Public Health

Introduction

Neuroimmunological disorders represent a spectrum of diseases that can affect both the central and the peripheral nervous systems.  Despite many unique features of the individual diseases, there are a number of advantages that come from studying them as a group, both in terms of developing a broad clinical perspective and in looking for common or overlapping disease mechanisms.  This overview will provide one framework for helping the lay population to think and learn about these diseases.

Hurdles that limit our understanding the neuroimmunological diseases

They remain largely unknown to the lay community and physicians alike.  As a group, the neuroimmunological diseases present many formidable challenges.  Individually these diseases are quite rare, and as a result, there is often little awareness or understanding of them among both the general public and many physicians.  Transverse myelitis (TM), for example, may affect only one person per million population per year.  Consequently, when a person is diagnosed with TM, or another rare disorder, such as Neuromyelitis Optica (NMO) or Acute Disseminated Encephalomyelitis (ADEM), patients and family members are hearing about  these diseases and concepts for the first time.  They often have limited access to information about these diseases, and their physicians are often unable to educate them due to their own lack of knowledge and experience with these rare disorders.  This uncertainty can create frustration and anxiety.

They are typically unheralded by any antecedent warning signs.  These disorders are a challenge to understand because they usually develop totally out of the blue.  There typically are no antecedent warning signs or any appreciation that certain patients may be particularly susceptible to developing these diseases. 

They are often rapid in their onset and progression.  These diseases often progress at frightening speed.  Some people develop severe illnesses almost instantaneously.  Consequently, patients and families have little time to make decisions, and clinicians and researchers have a narrow window of opportunity to intervene.

They are difficult to diagnose.  The neuroimmunological diseases are often a challenge to diagnose.  Physicians, patients, and families are all too familiar with the difficult experiences that can surround the time of clinical presentation.  The “In Their Own Words” articles in the Transverse Myelitis Association newsletters reflect numerous stories from people who have had difficult experiences in hospital emergency rooms.  The first line of medical intervention - the emergency physician, the pediatrician, the general practitioner, or the internist - will not likely have much experience or familiarity with these conditions. 

One perplexing issue surrounding the diagnosis of many neuroimmunological diseases relates to the criteria used by the medical community to define each of these diseases.  In some cases, these criteria do not even exist.  Accordingly, the diagnostic approach can be variable from hospital to hospital and even from doctor to doctor.  The practice of medicine is based on science; an evolving and developing base of knowledge that changes over time.  The definitions of a neuroimmunological condition should ideally be based on strict diagnostic criteria that are developed and published in the medical literature.  On the other hand, definitions are not static; as we learn more about these diseases, as research and diagnostic technology become more sophisticated, our definitions will change. 

Thus, is TM a disease itself or is it a syndrome that is a part of a wider spectrum of diseases?  Is multiple sclerosis (MS) really many different diseases?  Is Recurrent TM a form of TM or is it a type of NMO?  Is NMO a variant of MS, or is it a unique disease?  What is ADEM?  These are all significant questions being studied and debated among the physicians and scientists who focus on the neuroimmunological diseases.  The definitions used, and the diagnostic criteria applied, are not uniformly accepted or widely understood.  The fact that these disorders happen so suddenly, progress so rapidly, and are hard to diagnose creates a difficult set of circumstances for both physicians as well as the people who have these conditions.

We lack a uniform approach to treatment.  Once a diagnosis is established, treatment approaches that may be considered can be highly variable from case to case. We do not as of yet have uniform treatment protocols for many of these diseases, and this limits our progress.  Furthermore, a number of common treatments have not been scientifically studied in direct comparison to a control group, so we end up being guided in our approach based more on anecdotal experience than anything else.

These diseases are variable in their response to treatment and in their eventual outcomes.  Even when treatment is initiated promptly, there can be such a variable clinical response from patient to patient.  We know from TM, for example, that patients can be treated with the same dose of intravenous steroids and yet vary in their recovery of neurological function over time.  It is very frustrating from the clinician’s standpoint to not understand this lack of a uniform response to a given treatment. The end result for the patient is that there can be a very different spectrum of long-term outcomes; some people may experience a full recovery, some people may have only a partial recovery, and some people might not experience any recovery at all. 

Rare neuroimmunological diseases: Common themes

While there are considerable challenges surrounding the study and treatment of the rare neuroimmunological diseases, we are also learning more about them.  One of the reasons behind this progress is that we are thinking about these diseases as a group of disorders and we are specifically studying both the similarities and the differences between them.  Some common themes among these conditions are highlighted below.

Many of these disorders likely develop as a result of some specific triggering event.  These conditions, as a group, are generally considered to have some specific immunological trigger.  While we do not necessarily understand what these triggers are in many cases, searching for them will be critical to the rapid identification and even the prevention of some of these diseases in the future.

These disorders are driven by aberrant and/or excessive immune responses.  These diseases are likely driven by some over-activity or aberrancy in the immune system.  In essence, the immune system is causing direct damage to the nervous system.  While there are undoubtedly differences in terms of the type of immune response that leads to a given disease and in how the various components of the immune system become involved, we are beginning to unravel these scientific mysteries.

These disorders occur within tissues that ordinarily have limited exposure to the immune system.  Tissues of the nervous system have quite a limited exposure to the immune system under ordinary circumstances.  Thus, they are not used to interacting with the cells of the immune system, and they have a deficient capacity to protect themselves from the immune system compared to other tissues. 

These disorders occur in tissues with limited regenerative capacity.  The nervous system has a much more limited capacity to repair or regenerate itself compared to other organs.  While these reparative functions are not totally lacking, they are often not sufficient to keep up with some ongoing immune-mediated injury.  Thus, the likelihood of recovering neurological function in these settings is less than it would be in immune disorders that affect the skin, liver, or other tissues. 

How can we position ourselves to better attack the neuroimmunological diseases?

While these diseases pose significant clinical and scientific challenges, we are working diligently to better understand and treat them.  The challenges themselves are often a source of inspiration; we regularly ask ourselves how we can be better positioned to advance the field and to help our patients with these diseases.

We must develop uniform disease definitions and diagnostic criteria.  The first thing we must do, and indeed that we have made substantial progress on for some of these diseases, is to develop uniform definitions and diagnostic criteria for the individual neuroimmunological diseases.  One of the first efforts undertaken by the Johns Hopkins Transverse Myelitis Center was to establish some uniform criteria to diagnose TM patients.  In this way, we help individual patients and we set a high standard for future research protocols. 

We need to establish specialized clinical centers.  We think that because these diseases are so rare and poorly understood, one of the best ways to attack them is to develop specialized clinical and research centers to provide optimal care to these patients. 

We should aggressively recruit patients to these specialized facilities.  Once established, we want to recruit patients to these centers for evaluation.  As these diseases are so rare, the only way we are going to learn more about them is to see a critical mass of these patients.  Specialized centers for these diseases will aid in accurate diagnosis and in developing optimal treatment protocols.

We should collect data on every patient.  We want to learn something new from every patient.  While I don’t want to imply that patients are research guinea pigs in coming to one of these centers, I really think that my colleagues and I look at the interactions with an individual patient as a learning experience.  If you don’t learn something new from each patient you see, you are missing opportunities. 

We should create sample and tissue repositories.  There are a number of ways to generate new scientific information about these diseases.  While studies may involve collecting data from x-rays or MRI’s, some of the most significant progress can be made through the collection and study of clinical samples – blood, cerebrospinal fluid, and sometimes even tissue specimens themselves.  It is these studies that will ultimately reveal the real nuts and bolts of the molecules that drive these diseases.  We need to establish repositories of these clinical samples for clinicians and scientists to be able to ask research questions about these diseases.  

We should use forums such as the Rare Neuroimmunological Diseases Symposia to develop rational treatment protocols and clinical trials.  Finally, we want to use the symposia where we bring professionals together – researchers and healthcare providers - to talk about these diseases and to develop rational protocols for treating patients.  We can optimally test new therapies in the context of clinical trials.  This is one very important function that these symposia serve.  These are the kinds of approaches that will help to move our understanding forward and will provide for better and more effective treatments and therapies.

Conclusions

Although diverse, many rare neuroimmunological diseases share common underlying mechanisms.  The neuroimmunological diseases are a spectrum of diverse diseases.  Some affect the brain, some affect the spinal cord, some affect the peripheral nerves and muscles, and some cut across more than one of these regions.  Still, we believe they share some common pathogenetic mechanisms, and that is why bringing the physicians and scientists together who study these diseases is extremely helpful.  If we can understand and get ideas from the study of one disease, then we might be able to apply the same principals in the study of another disease.  This will accelerate our progress understanding the entire spectrum of these diseases. 
Specialized centers focused on diagnosis and treatment of rare neuroimmunological diseases are being developed.  The development of specialized centers for the care of patients and for the study of these diseases is already underway.  The sharing of information between these centers will create the greatest opportunities for clinicians, scientists, and the people who have these diseases.  It is these multi-center, collaborative networks that will offer the most effective approaches to understand these diseases. 

Advances in neuroimaging and in selective immunotherapy will improve our ability to diagnose and treat the rare neuroimmunological diseases.  The use of modern imaging technology and the application of state-of-the-art scientific instrumentation and techniques is already paying dividends in our ability to diagnose and treat patients with these diseases.  In the near future, I expect that our improved ability to target specific components of the immune system using selective immunotherapies will allow for the safer and more effective treatment of patients with neuroimmunological diseases. 

Hopefully, I have been able to establish a framework for you to think about the neuroimmunological diseases as a spectrum of disorders that share important characteristics.  By devoting our energy and resources to a comparative analysis of these diseases, and by encouraging the development of other specialized centers, it is our hope that we will be able to gain a better understanding of these diseases.