American Academy of Neurology Guidelines on Transverse Myelitis:  Understanding the Complex Issues of Diagnostics and Nomenclature for Rare Neuroimmunologic Disorders
Sandy Siegel

We are publishing the patient summaries of the AAN Guidelines on TM.  These current guidelines build on the diagnostic guidelines that were developed and published in 2002 by the Transverse Myelitis Consortium led by the Johns Hopkins Transverse Myelitis Center.  These new guidelines focus on the differential diagnoses and a few treatment recommendations.  During an acute inflammatory attack, the guidelines recommend corticosteroids and then plasma exchange, if improvements are not observed from the corticosteroids.  In the case of recurrent episodes from NMO, the guidelines recommend the use of Rituximab as a long term therapy.  The focus of the article and guidelines concerns how a diagnosis should be considered when a person has an inflammatory attack in their spinal cord.  Various characteristics are presented as leading a clinician to suspect that the inflammatory attack is either multiple sclerosis, neuromyelitis optica or a spinal cord infarct (vascular cause).   

The guidelines describe when an inflammatory attack in the spinal cord could be MS, or NMO or a spinal card infarct.  The guidelines may be confusing to many of you who have received an acute transverse myelitis or idiopathic transverse myelitis diagnosis.  My goal with this article is to offer a lay person's perspective in an attempt to help better understand these guidelines.

The methodology employed in the development of the guidelines was a review of the published literature from 1966 to March 2009, with evidence-based classification of relevant articles.  The failure to include the entire experience from the Johns Hopkins Transverse Myelitis Center, which likely offers the most comprehensive case series on pediatric and adult transverse myelitis may be confusing for many of you.  Please refer to the meanings of 'evidence-based' in the guidelines for an explanation.   

I am most definitely not qualified to write an article critiquing the medical guidelines that were recently published by the American Academy of Neurology.  I have no medical training whatsoever.  Thus, this article is not going to offer a medical perspective on the issues presented in this article.  I will, instead, rely entirely on my expertise and experience as an anthropologist.  I have been a participant-observer of the medical community surrounding the diagnosis and treatment of transverse myelitis and the other rare neuroimmunologic disorders for the past 18 years. 

Anthropologists are experts in classification systems.  How people classify the world around them is a function of language and culture, and anthropologists are all about the study of language and culture.  Classification systems are also fundamental to physical anthropology or human biology. 

One of the all-time great accomplishments of humankind was Karl von Linne's classification of the plant and animal kingdoms. Linne' was a Swedish botanist who developed a taxonomy that organized all of the known plant and animal types based on a comparison of the similarities and differences of their characteristics. He grouped the categories based on the types of characteristics they shared and based on the characteristics that distinguished them from other groups. Ultimately, he defines a specific plant or animal based on an entirely unique set of characteristics. No other plant or animal possesses the same set of characteristics. Humans share characteristics with all other animals, a fewer number of characteristics with all other vertebrates, a fewer number still with all other mammals, and so forth. But humans have a complete set of characteristics that are unique to only humans, and which distinguish us from all other animal species.

The practice of medicine in the western world has a critically important classification system.  This system operates in the same manner as Linne's classification of plants and animals. Medicine classifies disorders and diseases based on a set of characteristics that are unique to that defined category. Each condition is defined as a unique category based on the presence and absence of various characteristics. While there may be similarities between certain classes of diseases or disorders, in order to be placed or defined in a specific category, the condition must possess a unique set of characteristics.  Defining a specific disorder or disease is critically important, because this classification process determines how the person is going to be treated; diagnosis determines treatment.

The disorders that we are concerned about in The Transverse Myelitis Association are the neuroimmunologic disorders of the central nervous system.  The disorders included in this broad category are acute disseminated encephalomyelitis, neuromyelitis optica, optic neuritis, transverse myelitis, recurrent transverse myelitis and multiple sclerosis.  These disorders can be characterized as inflammatory or immune mediated attacks at various locations in the central nervous system. Each of the neuroimmunologic conditions is characterized by a unique set of characteristics. While they are all categories of demyelinating attacks in the central nervous system, each can be distinguished based upon the location of the attack and whether the attacks are a monophasic or recurring event.

The classification of neuroimmunologic disorders is far from this straightforward, and the relationships between the disorders can be very complicated.  The diagnosis cannot be based on symptoms; there are many disorders that present with the same symptoms as each of these disorders, and some of these disorders are not even immune-mediated or inflammatory. 

The gold standard for diagnoses and classification in the practice of medicine is a biomarker that is unique to a particular disorder.  The only one of the neuroimmunologic disorders that has a biomarker is NMO.  Most people with a NMO diagnosis have tested positive for NMO-IgG antibodies (aquaporin-4–specific antibodies).  While this biomarker has proven to be the most hopeful as a diagnostic test, it is also the case that not all people with a NMO diagnosis test positive for these anti-bodies.  There is a great deal of research and discussion in the medical community focused on understanding this situation, but the fact remains that there are people with NMO who are NMO-IgG negative and their diagnosis, as is the case for the other neuroimmunologic disorders, is based on clinical criteria.    

When you read that a diagnosis is based on clinical characteristics, what this means is that the criteria for diagnosis is based on observable features that are associated with what physicians and researchers believe are unique to a disorder.  Each of these neuroimmunologic disorders has been defined by a set of published diagnostic criteria. 

For example, in the case of TM, inflammation is identified in the spinal cord through examination of MRIs and/or the analysis of spinal fluid.  As was described in the TM guidelines, a vascular cause will be ruled out, and NMO and MS will be ruled out; there is no brain involvement or optic nerve involvement, there is no evidence of oligoclonal bands in the spinal fluid and the patient is NMO-IgG negative.  There is no unique biomarker for TM and thus, the diagnosis is really not conclusive or definitive.  It is a diagnosis by exclusion.  It is, however, the best we've got at the present time.  The criteria for all of the neuroimmunologic disorders are proposals and are being tested by clinicians and researchers around the world who apply these criteria to their own experience and case series to judge their effectiveness.  There are articles in the medical literature published fairly regularly that identify and discuss exceptions to all of the current diagnostic criteria for all of these disorders.  Thus, these categories are a moving target and can change based on newly discovered information and better understandings of all of these disorders.

Consequently, there is some amount of mayhem in the process, because if you talk to physicians who see the largest numbers of patients with these disorders, you will start hearing about all of the exceptions to the diagnostic criteria for each of these disorders.  Recently published ADEM diagnostic criteria define recurrent ADEM.  I've heard researchers and clinicians express the opinion that there is no such disorder.  I've heard other physicians express the position that ADEM is over diagnosed and that many of these cases are MS; after the massive brain attack no one goes back in to look to see if there are any new inflammatory attacks, and it could be possible that new inflammation and disability might be difficult to discern after the first massive attack. 

It wasn't that long ago that NMO was considered a subvariant of MS.  Mayo Clinic researchers have recently offered evidence that NMO is a different disorder from MS.  Mayo has also described a condition they refer to as longitudinally extensive transverse myelitis.  This is a demyelinating attack that is 3 vertebrae or longer in length.  It is believed that people with LETM are at risk to have repeated demyelinating attacks in their spinal cord and then receive a recurrent TM diagnosis or have repeated episodes of both TM and also optic neuritis and then receive an NMO diagnosis.  What is fascinating and not discussed at all in the medical literature, as far as I am aware, is that LETM does not apply to pediatric cases of TM.  Infants and very young children who get TM tend to be impacted high on their cords and their inflammatory attacks tend to be very long.  I am not aware of an infant or very young child having more than one episode of TM or getting NMO.  If it happens, it must be extremely rare.  So, the cases described by Mayo Clinic may be limited to other than these pediatric cases.  What could that possibly mean for the classification of these disorders?  NMO is a disorder that involves spinal cord and optic nerve involvement, but there are cases of NMO that also include brain lesions.  And then there are people who have repeated episodes of inflammation in their spinal cord who never have an optic nerve attack and also never test positive for NMO-IgG.  What does that mean and how are these cases different from NMO.  Remember, we don't know the disease mechanisms all that well for any of these disorders.

And in the case of TM, as is implicit in the TM guidelines, the significance or the existence of TM from the perspective of some researchers and clinicians is in doubt.  The thought is that once we start to exclude those with a TM diagnosis that is really vascular in cause or infectious or is really NMO or is really MS or is really from one of the rheumatic disorders, there are some odds and ends that are left which are just too confusing to think about.

None of these disorders is always a clear cut, slam dunk diagnosis based on the accepted and published diagnostic criteria.  And that is even the case if a patient shows up at one of the premier medical institutions that specialize in these disorders.  If someone shows up in a small community hospital in the middle of nowhere, their experience could be a challenge.

And then there are the cases of all of the rheumatic disorders.  People sometimes get a TM or NMO diagnosis before, during or after they have received a diagnosis of one of the rheumatic disorders, such as lupus, sjogrens or sacroidosis.  I remain entirely confused about whether these people have TM or NMO AND one of these rheumatic disorders or if the spinal cord and/or optic nerve inflammatory attack was a symptom of their rheumatic disorder. 

Making a good diagnosis is critical, because these disorders require different treatments.  For instance, it is believed that the MS drugs do not work for a person with NMO or recurrent TM.  These people are put on immune suppressants.  And if it is suspected that a person with TM or ADEM will not have another attack, they should not be given any of the immune modulating drugs or immune suppressants at all. 

The classification system for these neuroimmunologic disorders is complicated, and it is difficult at this stage of our understanding to draw bright lines of distinction with any degree of certainty.  I have come to appreciate and believe that the answers about one of these conditions are going to provide answers to all of these conditions; even if they are different conditions.

As there is no clear set of causes in all cases for all of these conditions, there is no understanding as to why one person is effected in one place in the central nervous system and not a different place; or why one person has one episode and another person has multiple episodes.  Is it possible that in TM or ADEM that the immune system corrects itself after the inflammatory attack, as opposed to what occurs in MS, NMO and recurrent TM?  How much does genetics account for the dysfunction in the immune system?  Could there be a genetic predisposition for the immune system to become deranged that is different for each of these disorders?  What role might environmental factors play in each case? 

It is just amazing how little is understood about the immune system.  Looking at the practice of medicine in 2012 as a participant observer, I'm going to make a guess that what is not understood about the immune system is far greater than what is currently understood.  And please keep in mind that even though you keep getting sent to neurologists, there wasn't likely anything wrong with your central nervous system until your immune system got ahold of it.  You likely have an autoimmune disorder – you aren't likely suffering from a disease of the nervous system.  I don't think medicine even accepted that the immune system could do these dastardly deeds until about the same time we invented Howdy Doody, Fury and Sky King.   

When Karl Linne' defined the different categories of animals, he did not know anything about genetics. If he had, he would have had a completely different and really wonderful set of characteristics that he could have used to define groups of animals and to distinguish them from other groups of animals. But he was limited by the then current understandings of biology. He could only use characteristics that he could observe and that he knew. It is not different today. Medical scientists can only use characteristics that they can identify and that they know. If there is no diagnostic test for it, it is not available for this definition. Today, physicians are using MRIs, CAT scans, lumbar punctures and various blood tests to observe the presence or absence of various characteristics. If they observe one set of unique characteristics, you are told you have one condition; if they see something else, you are going to get the diagnosis of a different condition.

One day, they are going to find new characteristics, and then they will better understand how to define these categories, and diagnose these conditions. I have no doubt in my mind but that the paradigm we are thinking about today will change. And I believe this, because we are thinking about them with such large gaps in our understanding about these conditions and about our immune systems.  I also have no doubt that someone, like Spock, will look back at how these disorders were diagnosed and treated and it will make his ears curl. 

A significant part of the transverse myelitis problem is due to diagnostic nomenclature.  There are nomenclature problems that arise in the general neurology community that exist from the way the term 'transverse myelitis' is applied, and there are problems that arise from the application of the term 'transverse myelitis' even from the clinicians and researchers who are trying to be precise about the application of diagnostic criteria.

In the general neurology community, transverse myelitis has become a diagnosis of a spinal cord problem that cannot be explained by trauma, compression on the cord or a tumor.  People call me who got a transverse myelitis diagnosis from a neurologist and then have Lyme disease or they had a spinal cord infarct or an AVM or they have tingling in their feet, legs and butt and every test known to humankind has come up negative … abracadabra … transverse myelitis.  As I understand it, the word myelitis has a meaning based on the concept of itis or inflammation.  And in this case, what is meant is inflammatory from what is believed to be immune-mediated or autoimmune.  Calling some of these conditions, or lack thereof, myelopathies would be more acceptable, but even the imprecision in these cases is somewhat disconcerting.  I haven't studied enough about medicine to understand what the pressures are in terms of giving a diagnosis; there must be some significant ones from what I am observing.  Clearly, some of the people I talk to don't have transverse myelitis. 

And then there's all of the imprecision surrounding a spinal cord attack from ADEM, NMO and TM.  I'm not going to even talk about the rheumatic disorders because this part of the equation remains too confused to even conjecture about at the present time.  If you have a spinal cord inflammatory attack with an ADEM diagnosis, your doctor likely told you and the medical literature describes that spinal cord attack as transverse myelitis.  If you have a spinal cord inflammatory attack with an NMO diagnosis, your doctor likely told you and the medical literature describes that spinal cord attack as transverse myelitis.  There are lots of people who have a spinal cord attack as their first attack of MS and they are told that they have transverse myelitis.

The nomenclature is just horrible.  It is a fact that all of the symptoms of TM can be found in these other conditions. Spasticity, parasthesias, bowel, bladder and sexual dysfunction, fatigue, depression, muscle weakness or paralysis may occur from any of these conditions and the treatments for each of these symptoms, regardless of the condition, are going to be the same. From the perspective of symptoms, these conditions share many similar and important characteristics.  I have no idea whether the spinal cord knows whether it has been attacked by an inflammatory episode from one or another of these disorders. 

I've been doing this work for 18 years.  From my experience, I feel comfortable concluding that there are lots of people who have a spinal cord attack and they never have another attack anywhere else in the central nervous system.  Some of them do have other autoimmune disorders … if transverse myelitis really is an autoimmune disorder.  It is just so difficult for me to get my head around the idea that all of these people have AVMs or had a spinal cord infarct or had some direct viral or bacterial infection.  The infections get looked for and they aren't found.  Do all infections get tested for; I don't think so, we might not even know of all of the possible bacteria and viruses that are around.  There sure looks to be a disorder that is unique from these others.  Right now it is called either acute transverse myelitis or idiopathic transverse myelitis.  And to add to the confusion, both of these diagnostic categories refer to the same disorder.

We – and I mean everyone involved – need to either start calling the inflammation in the cord with ADEM, NMO and MS, inflammatory attack in the cord, or we need to start calling transverse myelitis by a different name and let the medical community use transverse myelitis for every spinal cord problem under the sun – until Spock shows up. 

The other beauty of a concept is conversion.  I often hear the medical community talk about how a TM diagnosis converted to NMO or MS.  Since we are talking about disorders or diseases, I have to guess that the only thing that converted was the physician's understanding about what was going on with the patient.  NMO was always NMO, even if it wasn't understood or known; same with MS.  Why is this clarification important?  Because patients are just amazingly confused about what they are being told about their bodies.  None of these people had transverse myelitis that transformed into NMO through some biological process.  They always had NMO.   They just didn't know it, because their doctor didn't know it.  The concept of conversion needs to be reserved for those people who are sent home from emergency rooms paralyzed and unable to urinate, because an emergency physician couldn't find anything wrong with them on an x-ray.

This nomenclature needs to be repaired.  Developing some clarity and precision in the use of language would be extremely important in helping patients better understand their diagnoses and what is happening to their bodies.  I am also suggesting that working on this terminology would be very helpful for the medical community which is currently just as confused as all get-out about a transverse myelitis diagnosis. 

It bears repeating that some researchers might not share my concern for clarifying the nomenclature surrounding the use of the term transverse myelitis, because they do not believe that acute or idiopathic transverse myelitis represents a unique disorder.  There are some very real and devastating consequences wrapped up in believing that transverse myelitis is not a unique diagnosis.  If transverse myelitis is thought to be not existent or is too difficult to define and understand, then we will never be able to make a case that there should ever be resources allocated to studying it.  If transverse myelitis is not considered a disorder, we will never be able to make a case to physicians that they should be interested in devoting careers to treating people with this disorder or devoting their careers to performing research on this disorder. 

There is so much that I don't understand about the practice of medicine or medical research or the entire sociocultural environment in which all of this activity transpires.  I am going to go out on a limb here, and make the following observations.  I don't believe that there is a medical center anywhere in the world that has gathered  enough information or conducted enough studies to reach a viable conclusion about any numbers of people who have any of these disorders, based on any of the existing diagnostic criteria.  I would also make the observation that based on what is currently known about any and all of these neuroimmunologic disorders, that however we are defining and diagnosing these disorders today is likely to change in the future and that drawing bright lines around any of these diagnoses only creates barriers to finding and accepting better ideas in the future.  What I am suggesting in Standard American English is that if transverse myelitis is being considered as not being a separate and distinct disorder from these other neuroimmunologic disorders, this conclusion is being reached, at the present time, on a speculative hunch, and not on any very compelling data.

I can think of many great reasons as to why medicine might want to study transverse myelitis.  I am going to focus on only one of them.  Literally millions and millions of dollars have been spent on research on autoimmune disorders, from multiple sclerosis to rheumatoid arthritis to Crohn's disease.  Very little is understood about any of the autoimmune disorders.  Everybody and his brother talks about genetic predisposition and environmental influence as causes of autoimmunity.  Currently, very little is understood about the genetics and virtually nothing about the environmental factors.   Almost all of them involve multiple attacks.  Thus, once a person has one attack, they are at risk for repeated attacks by their immune systems on a particular part of their body, depending on the specific disorder they might have.  The best medical science can do for them at the present time is to put them on some kind of drug that 'dampens down' their immune system to either forestall the next attack or to lessen the severity of their next attack should they have one.  Being on an immune suppressant has its very obvious downsides, because the immune system plays a critically important role in our remaining healthy.  But when doing the cost benefit analysis, the immune suppressants trump the downsides to the drugs for most people.  None of these approaches repairs the immune.  The closest medical science has come to repair is to use drugs to kill off the immune system and then to regrow the immune system from stem cells.  The attempt to reboot the immune system doesn't repair either.  People who regrow their innate immune systems eventually develop the same autoimmune dysfunction that they had previously.  I'm not diminishing the importance of bought time, but this is no fix. 

If transverse myelitis is an autoimmune disorder, it is one of the few (along with ADEM) that involves the immune system becoming deranged just one time, and then going back to something other than entirely abnormal.  I won't speculate as to whether it is normal or not; just that it doesn't seem to attack the spinal cord again.  If I had endless amounts of money and was interested in understanding how to cure autoimmune diseases, I would sure want to learn as much as I possibly could about this autoimmune disorder that could represent an instance where the immune system 'corrects itself' after the one time attack.  We aren't doing a great job of trying to figure out how to settle it down.  And even when we do settle it down, we're keeping people on immune suppressants for a lifetime, and having to change these drugs throughout their lifetimes.  Is a more permanent repair possible?  I don't know.  But if transverse myelitis and acute disseminated encephalomyelitis are one time autoimmune disorders, I would sure want to understand what the immune system is doing in these cases, because as a model, it might offer clues for a more permanent repair for the immune system in the other autoimmune disorders.  I would consider the Manhattan Project on TM a worthwhile effort when weighed against the many millions of dollars that are being spent on finding new drugs that accomplish little more than forestall the next inevitable attack.

From my very anecdotal 18 years of experience, I believe that there is something unique going on with people who experience a one-time attack in their spinal cord.  It looks to be something different from what is currently being called MS.  It might be distinguishable from NMO.  It might be a different disorder from ADEM.  It might be different from optic neuritis.  Is it different from recurrent TM?  The overlap of clinical characteristics and the many exceptions to the clinical criteria make it very difficult for a cultural anthropologist who is interested in classification systems to observe distinct and definitive categories of neuroimmunologic disorders.  While we are developing some comfort with just how much we don't know and don't understand, I would hope that we aren't going to dismiss the existence of transverse myelitis on a hunch.   

My believing that acute or idiopathic transverse myelitis is a unique disorder is going to influence no one who matters – your physicians and the researchers who specialize in the rare neuroimmunologic disorders.  Being able to make this evidence-based case is critically important for Pauline and me.  If you have an acute or idiopathic transverse myelitis diagnosis, we think it is important for you, as well.  The only way we are going to make this case is to fund the research necessary to understand the disease mechanisms in idiopathic transverse myelitis, such that it is no longer idiopathic.  We need to be able to fund the research necessary to find a biomarker for acute transverse myelitis.  There are a lot of researchers who specialize in the immune system and in neuroimmunologic disorders who would be interested in doing this work.  We need to be motivated to raise the funds to make this happen.  If you are interested in making the case that what happened to you was important enough to understand, please make a donation to The Transverse Myelitis Association for the purpose of finding a biomarker for TM and for researching the disease mechanism for this very little understood disorder.

I'll conclude this article by imploring the medical community to change the name of the disorder, transverse myelitis.  Doctors are likely going to keep calling the inflammatory attack in the spinal cord from MS, ADEM and NMO, transverse myelitis.  For the sake of diagnostic clarity and perhaps to argue for the very existence of this disorder, it is time to change the name of this disorder from transverse myelitis.  It is also time for us to change the name of our association.  It is important that we make it clear that we are an organization representing the interests and advocacy for everyone who has one of the rare neuroimmunologic disorders.