Acute Disseminated Encephalomyelitis

The primates who were the common ancestors of humans and apes lived in the trees.  That explains why we have eyes in front of our faces as opposed to the sides of our heads.  Depth perception is highly valued when your home is up in trees; not judging the distance to that branch could be a fatal mistake.  And how would you apply eye liner if you had to close one eye on the side of your head with the other eye located on the other side of your head.  Over a period of many many many generations, a phenomenal collection of both behavioral changes and physical changes took place among our ancestry that formed the foundation for our becoming human (Homo sapiens). 

We came down out of the trees to live on the savanna grasslands of Africa.  We likely came to the ground seeking food and because it is very scary and uncomfortable to sleep on a tree branch.  We were quadrupeds (walked on all fours) when we lived in the trees and when we first came down out of the trees.  Walking upright was more adaptive for our ancestors, allowing them to more easily see predators in the tall grass and eventually to be able to perform text messaging with one’s forearms while ambulating.  Bipedalism became all the rage and, over a long period of time, caused significant changes in the structure of the pelvis.  There was a considerable narrowing of the birth canal from our quadruped existence.  Most quadrupeds don’t feel the necessity to sign up for a Lamaze class. 

At the same time that our ancestors were walking upright and beginning to manipulate objects in the environment with their hands, which were freed up from locomotion, their behavior was also becoming much more complex.  These very early humans or hominids were becoming more and more intelligent; their brains were becoming larger.  Let’s see, brains getting much larger at the same time that birth canals are getting much smaller.  There must have been a fairly strong and rapid, in macro-evolutionary terms, selection for individuals who were born with smaller and less developed brains.  The selection must have been fairly rapid in evolutionary terms because infants with large brains would likely remove the mothers (and themselves) with the genetic traits for large and highly developed brains at birth from the gene pool.  The selection was for individuals who had smaller, less developed brains that would grow after birth. 

This change in the size of the head or the underdeveloped brain also meant that the offspring of these early hominids were going to be dependent for a much longer period of time.  It has always amazed me just how quickly most animals are up on their feet, eating and exploring their environment almost immediately after birth.  Human infants are totally dependent from the time of birth and for a very long time.  For those of you with a 24-year-old child living in the basement and self-actualizing with Madden on his xbox 360, you understand how humans have developed this dependency thing into an art form.  Luckily for these early hominid infants, at the same time that they were being born totally dependent for their survival, our ancestors were developing groups that would form the basis for stable social relationships over long periods of time.  These groups were also developing divisions of labor which allowed a woman to focus on caring for her infant while someone else, like Joe the hunter, went off to find them food. 

These humans were developing culture, a way of life that they were going to pass down from generation to generation.  Culture is learned and it is shared by a group.  Culture is taught by parents and the other members of the group.  Culture includes everything we know and all that we believe.  Over the many, many generations, our ancestors were developing so much more to learn.  For a long time, adults would tell us everything we had to know and we would memorize everything they passed down to our generation.  Eventually, the amount and complexity of this culture grew until there was so much information that we had to start writing it down.  Small groups could no longer handle teaching all of it on their own, so they developed public education, colleges, and professional and graduate programs.  Wow, my brain grew a whole centimeter while I was writing that; it’s a good thing that my really large head is balanced on top of my body; I’m not sure how my neck muscles would handle the weight otherwise. 

I taught physical anthropology and human evolution for four years at The Ohio State University.  I know that many of you don’t subscribe to this explanation of our evolutionary origins.  I respect your beliefs.  I suppose it is possible that fossils are just G-d’s chotchkes.  Every society has an explanation for how we came to be here; and every explanation is different.  This happens to be the one I subscribe to for who, what and why we are human.  I used to tell my students who totally didn’t believe any of this evolutionary stuff that I wasn’t interested in converting anyone to a way of thinking; they just had to memorize every single word that came out of my mouth and be able to regurgitate it on exams.  Hey, it wasn’t a debating class; it was a course on human evolution. 

Opposable thumbs are really cool, but what makes us human is our brains.  Since the practice of modern medicine in the nineteenth century, we have learned an incredible amount of information about human physiology.  It is amazing that this organ that is so central to who we are and how we function is so little understood.  Almost all of what we are and who we are is learned.  Talking about language is a good way to describe the important relationship between the physiology of the brain and the influence of culture.  Every human being has the capacity for language.  This capacity must be structured in our brains as some collection or wiring of neurons, but these are not specifically identified.  We know there are speech centers in the brain, because when they are damaged, people lose the ability to speak.  But that’s about as specific as we are about the physiology.  While the capacity exists for every human to speak, what we are speaking depends on the language you learn from infancy.  If you are born in Japan, you are going to learn Japanese and if you are born to Hopi parents, you are going to speak Hopi.  The ability or capacity to use language is biology and what language we speak is learned.  And speaking a language is more than the grammar and words we use to communicate.  Language structures the way we perceive and make sense of the universe around us.  Language creates categories that structure how we experience our world.  Language is a fundamental part of and inextricably linked to culture.

Human beings are just phenomenally complex on so many different levels.  Who we are as humans is a combination of biology and culture.  Anthropologists have studied every society on the face of the earth and have developed a list of cultural universals; those institutions and elements that we find in every society.  Some of these universals derive from our biological selves; what we have to do to meet our biological needs.  Every society has rules about how we procreate and every society has methods for acquiring food, but the specific rules are amazingly diverse.  In our society, it is frowned upon to marry a first cousin.  In other societies, this person would be the preferred marriage partner.  Likewise, what one society defines as a delicacy might be considered inedible or abhorrent to a different society.  Every society functions to define how our needs are met, but the ways devised are unique to their way of life.  And dare I say it; the differences are, for the most part, entirely arbitrary.  Cultural universals reflect basic human needs, but only some of them are rooted in our biology; most of them have nothing to do with meeting our biological needs.  Every society has adornment!  Every society on the face of the earth has a conception of how to decorate oneself so as to “look good.”  Every society has an eschatology; a system of beliefs about what happens to the spirit when our physical selves are no longer here on earth.  And, again, every society has devised a different description and explanation about what happens to the spirit.  And, by the way, every culture has some conception of humans possessing a spirit.  Our culture is learned.  How we learn is a process or function carried out in our brains and all of what is learned is stored in our brains.

Because of the way we are raised, we “feel” like our way of life is the right way of life and the natural way of life.  Our way of life, our way of thinking and believing, feels so natural that it feels as though it was programmed into the cells in our brains.  It feels this way, because that is the way culture works.  But if at the day of your birth you were adopted by a Kwakiutl family, you would be speaking Kwakiutl and feeling like the Kwakiutl way of life was the right way to think and believe and that all of the rest of the world was more than slightly dazed and confused.  Culture is entirely learned; none of our way of life or our specific language is programmed into our brains at birth.  There is no genetic basis whatsoever for our culture – our religious beliefs, our political activity, how our society is organized, how we define family, how we find a partner or any of the other important things we do as humans.  And amazingly, we feel and think this way about our own way of life even with CNN world news available twenty-four hours a day, almost universal access to the internet and cell phones, supersonic jets and the myriad of other technologies we use that have connected peoples from around the world in very intimate ways and have shrunk the planet earth into a much smaller place.  My way is still the right way of life; I just have to make this pronouncement sometimes in a whisper as opposed to screaming it at the top of my lungs while beating a big stick on the ground at my cave entrance.   If the world were filled with cultural relativists, it would be near impossible to have people behaving themselves, because there would be no definition for what the correct, appropriate, acceptable behavior was supposed to be.  And aren’t we doing a wonderful job of behaving ourselves now.

The anatomy of the brain is well understood.  I never went to medical school or studied anatomy so I don’t know all of the parts of the brain.  But I have no doubt that scientists and physicians know all of the structures of the brain; they know all of the different cell types and they know much about the biology and chemistry of the brain.  With all that they know, I don’t believe they have the slightest idea about what the biology is of a “thought” or the biology of a “belief.”  Well, that’s what the brain is about for all of us.  Everything we know and everything we believe is learned from early childhood.  We learn from all of the remarkable and unique experiences that we have in our lives.  No two people have the same experiences.  I am a completely unique individual because I learned my culture from my parents, grandparents, Captain Penny, Barnaby and Ghoulardi.  A great deal of what I have learned, I share with Jewish people of Ashkenazic descent who were orthodox and kept a kosher home and then married a Lebanese Catholic woman or that I share with people who grew up in Cleveland Heights and now live in Columbus or that I share with people who got married and had children or who went to college for long enough to be a brain surgeon but only have a degree in cultural anthropology.  There is a tremendous amount of life experience that belongs uniquely to me.  No one knows all of the same people that I do.  No one has had the same collection of life experiences that I have had.  And no one thinks about or makes sense of all of this experience in the same way that I do.  And all of what I have just described about who I am, what I am, what I think and what I believe is stored in my brain, in all of those neurons that basically all look alike and have the same cell structure and chemistry.  There aren’t any parts of the brain that are labeled, “the religious belief neurons” or “the political affiliation neurons.”

After an inflammatory attack in the spinal cord or brain, the damage to nerve cells does not repair very well as compared to other cells in our bodies, such as skin or bone cells.  This is particularly the case in adults.  It is possible that this inability to reproduce or repair was the evolutionary tradeoff for the incredibly complex function these cells perform in our brains.  They account for us being a unique individual, with a unique personality, with unique attitudes, thoughts and beliefs.  What would a person be, who would that person be, if the cells in their brain were entirely replaceable?  

What happens to those nerve cells from a massive and destructive inflammatory and demyelinating attack in the brain?  What happens to the person?  What happens to what they learned and what they know and what they believe and what they remember and who they are; what happens to their personalities and their individuality and their identity?  For most of you reading this article, you have an intimate understanding about how complicated these attacks are in the spinal cord.  There is often damage caused to myelin and nerves in the spinal cord, but the damage is often not completely across the cord.  Most people have some function below the level of the attack on the spinal cord.  Some of that function might be sensory, some might be motor; or there might remain bowel and bladder function.  And some people have very good recoveries after their attack and from very severe symptoms at onset.  What happens during this recovery, if in fact, myelin and nerve cells do not very effectively repair after being damaged?  What does it really mean for the spinal cord to go into shock and come out of shock?  We’ve been thinking about all of these issues in the context of a spinal cord, and these are remarkably complex issues with many more questions about the process than answers.

When a person has this horrible inflammatory attack in their brain, there must be similar damage to myelin and nerves, there must be the same kind of shock and recovery from shock and there must be the same type of very complex and incomplete pattern of damage to neurons.  Even for people whose brains have been assaulted by their immune system, many do experience a recovery.  The brain must be able to relearn what was lost and a part of the brain that was responsible for one kind of activity must be able to be assumed by a different part of the brain, because some people learn to walk, they learn to speak, and they get back memories.

I have been consumed by these thoughts about our brains and our humanness and personalities and our memories and our identities since I met Al, Jessica, Rachel, Ashley, Barbara and Kevin.  My relationship with these people and their families has been so profound for me that the word profound really doesn’t do justice to what goes on in my own brain about these beautiful people.  I cannot say that they are all my friends because I’ve never met some of them.  But they consume my thoughts and draw my compassion from me as though they are magnets for my heart and mind.  There is just no other way to describe what is done to me by Al’s passion, drive and intensity, or the knowing smile in Ashley’s warm, engaging and engaged eyes, or Barbara’s earnestness and perseverance and persistence or Rachel’s insightfulness, sensitivity, anger and frustration.  Al, Jessica, Rachel, Ashley, Barbara and Kevin have forced me to think about “what is mind” and “what is brain.”  I honestly think about them every single day.  It doesn’t matter whether I am at work or with Pauline at the dinner table or playing golf with David and Aaron, or driving in my car, listening to Tori Amos; thinking about these people permeates my life current.  Their struggles have caused me great sorrow; their drive and optimism buoys my spirit, their daily challenges move my heart and deepen my compassion.  Their minds have totally blown my mind. 

I became involved in most of their lives through a family member, a sibling or parent, while they were in the hospital and while most of them were in a coma.  Al, Jessica, Rachel, Ashley, Barbara and Kevin have acute disseminated encephalomyelitis.  When we started The Transverse Myelitis Association in 1994, we were focused on TM and we really didn’t know very much about TM.  Over the years, we learned about neuromyelitis optica and acute disseminated encephalomyelitis and optic neuritis because you, our members, taught us about these disorders.  It has been such a fascinating journey.  You joined the TMA because you figured out the connection between all of these disorders before we did; that they are all immune-mediated or demyelinating disorders of the central nervous system.  By showing up, you forced us to think about what you were dealing with and what was going on with these other disorders.  That we became an organization focused on advocacy for people with ADEM, ON, NMO and TM resulted from the course of your journeys.  Believe me, most of the really insightful and brilliant directions we are going in have nothing to do with any purposeful decisions on my part.  I believe in some ways, you not only taught the TMA about the connections between these disorders, you have also forced the medical community to think about these disorders and their relationships in a way that they really weren’t focused on previously.

It has taken me a very long time to develop some very fundamental understanding about TM and NMO.  ADEM has been a mystery.  It is a very complex disorder and perhaps the least understood of these very rare neuroimmunologic disorders.  Most of what I have read and learned about ADEM has come from articles about ADEM in children.  In many ways, ADEM and idiopathic transverse myelitis in children seem to share a number of important features.

Acute disseminated encephalomyelitis is also sometimes referred to as postinfectious encephalomyelitis.  ADEM is more common in children and adolescents than it is in adults.  Most of the cases of ADEM, as is the case for TM, are monophasic.  And also similar to TM, there does not seem to be any higher incidence of TM among males or females, nor does there appear to be any higher frequency of this disorder among any particular ethnic group.  ADEM is an immune-mediated, demyelinating disorder of the central nervous system.     

ADEM is believed to be an autoimmune attack that is either triggered by a response to an infection or to a vaccination.  For this reason, ADEM is sometimes referred to as post-infectious or post-immunization acute disseminated encephalomyelitis.  In about 50-75% of pediatric cases, the attack follows a viral or bacterial infection; the attack and neurological symptoms often begin within a couple of weeks after the viral or bacterial illness.  There have been a large number of viruses associated with these infections, including but not limited to measles, mumps, rubella, varicella zoster, Epstein-Barr, cytomegalovirus, herpes simplex, hepatitis A, influenza and enterovirus infections.  ADEM seems to occur most often in the winter and spring.  Interestingly, this seasonal variation does not seem to take place in idiopathic transverse myelitis.  Less than 5% of ADEM cases follow immunization.  The association between the attack following an immunization has been temporal; the direct connection between a vaccination and the immune attack has not been established.  As in the case of TM, the cause of the auto-immune attack is not known; it is thought that there is an environmental trigger in a person that possesses the genetic predisposition for the auto-immune response.  There are different forms of ADEM and some of them are more severe than “typical” ADEM. 

The neurological signs from the inflammatory attack often begin with fever, headache, vomiting, altered level of consciousness, acute cognitive dysfunction, behavioral changes, and seizures in about a third of the cases.  The altered consciousness can range from stupor and lethargy to confusion to coma.  The inflammatory attack can go on for a few days or for a few weeks.  The most severe symptoms are ordinarily reached within the first week and the first 2 – 4 weeks are the most severe period for children.  ADEM is multifocal; the inflammatory attack occurs in the brain and it can also occur as optic neuritis and as transverse myelitis.  Thus, a child or adult with ADEM can have the symptoms of ON (i.e., impaired vision and eye pain) and all of the symptoms from an inflammatory attack in the spinal cord.  As is the case with idiopathic transverse myelitis, the symptoms depend on the severity and the level of the attack in the spinal cord; breathing may be impacted, bowel and bladder dysfunction, paralysis or muscle weakness, spasticity, paresthesias or nerve pain, as well as the other symptoms of TM.  It is common for the brainstem and the spinal cord to be impacted in ADEM.

The process involved in diagnosing the different neuroimmunologic disorders has been one of the more frustrating aspects of the work that I have been engaged in for the past 15 years.  The frustration began with Pauline’s nine hour episode in the emergency room trying to convince an emergency room doctor that she was not experiencing a case of psychic paralysis.  I am involved with a number of families on a weekly basis that are going through a difficult process of getting a loved one properly diagnosed with one of these disorders.  It is very easy to sit on the sidelines and wonder why these physicians can’t get this stuff right.  And the urgency and level of frustration is driven by the understanding that diagnosis is going to determine treatment and the treatments for these disorders need to begin to be administered as quickly as possible.  Lost time could result in greater permanent damage to the spinal cord or brain.  And then I think about the complexities surrounding the ADEM diagnosis, and my wild frustration settles into the very sobering reality about what an incredibly difficult job these physicians have to get this situation all sorted out properly.  And I need to add that not only is the guidance provided to these physicians about how to make this diagnosis a moving target; the very definitions of the categories of these disorders are moving targets, as well.  ADEM is the perfect case in point.

When a person presents with the symptoms of ADEM, the physician has to rule out that the child or adult actually has a direct infection of the central nervous system.  Keep in mind that most cases of ADEM are triggered by a preceding bacterial or viral infection.  The physician has to rule out that there is a direct infection of the central nervous system as opposed to an infection that subsequently triggers the immune system to go haywire.  As the immune attack is thought to be triggered by a bacterial or viral infection, it’s not like bacteria and virus may not be around; it is just not the bacteria or virus that is directly causing the damage in the spinal cord or brain.  If it is a direct infection causing the problem, the patient would be placed on an antibiotic and/or acyclovir; they would not want to quiet the immune system, in the process of fighting off an infection.  Thus, getting this complicated differential diagnosis correct is incredibly important and sometimes takes time. 

Then they have to figure out that this is ADEM and not MS or NMO.  TM may be the easy rule out.  There is no biomarker for either ADEM or MS, so all of these diagnoses are going to be based on clinical features and MRI and CSF analyses and none of these variables are definitive either.  Even with the blood test for NMO-IgG in the case of NMO, there are 30% false negatives and people can also have lesions in the brain with NMO.  And while oligoclonal bands are more common in the spinal fluid with MS, these bands are sometimes also present in ADEM.  If the physician determines that the event is immune-mediated, the acute treatments will be similar regardless of the cause.  However, getting these diagnoses correct is imperative, because the long-term treatments are going to be different between NMO and MS, and most ADEM cases are going to be considered monophasic at the outset. 

There is no scientific, randomized, controlled data on the diagnosis and treatment of ADEM.  This is also the case for idiopathic transverse myelitis and neuromyelitis optica.  Decisions about the diagnosis and treatment of these disorders are based primarily on the opinions of experts.  Since decisions will be based on clinical judgment, trying to connect people to one of these experts during this critically important time is a significant part of what I do for a hobby.
 
As noted, an ADEM diagnosis is determined by clinical features and results from MRI, because there is no specific biological marker for this disorder.  Often times, a person is placed on antibiotics and acyclovir (an antiviral medication) until the physicians can confidently rule out of an infectious cause.

Spinal cord inflammation is diagnosed in the same manner as idiopathic transverse myelitis.  Optic neuritis in ADEM is also diagnosed in the same manner.  The difficult and important differential diagnosis involves interpretation of the brain MRIs to distinguish ADEM from MS.  The brain stem is often involved in ADEM and spinal cord lesions typically extend over multiple segments of the cord.  It is possible that the MRI may be normal early in the course of the disorder and may have to be repeated.  The CSF shows evidence of inflammation but can also be normal.  Some patients have oligoclonal bands which is more often characteristic of MS.  In certain situations when no cause is evident, neither an infectious or immune-mediated cause is apparent, a brain biopsy may be performed.  Some physicians also recommend repeating MRIs on follow-up to be sure there are no new lesions which could change the diagnosis from ADEM to multiphasic ADEM or MS.

An important paper was recently published which proposes diagnostic criteria for ADEM in children.  The criteria are important for the purpose of arriving at better decisions about treatments and the criteria are meant to facilitate research on ADEM.  When physicians and researchers are designing and conducting studies and clinical trials, it is important that they are including patients that they all agree belong to the same disorder classification.  The authors of the study consider these criteria as operational and need to be tested and validated by future research.  They define child as under the age of 10 and adolescents as 10 until 18 years of age.  The following are the criteria developed by the International Pediatric MS Study Group (pp. S7-S8):

Monophasic ADEM

• A first clinical event with a presumed inflammatory or demyelinating cause, with acute or subacute onset that affects multifocal areas of the CNS. The clinical presentation must include encephalopathy, which is defined as one or more of the following:

* Behavioral change, e.g., confusion, excessive irritability

* Alteration in consciousness, e.g., lethargy, coma

• Event should be followed by improvement, either clinically, on MRI, or both, but there may be residual deficits
• No history of a clinical episode with features of a prior demyelinating event
• No other etiologies can explain the event
• New or fluctuating symptoms, signs, or MRI findings occurring within 3 months of the inciting ADEM event are considered part of the acute event
• Neuroimaging shows focal or multifocal lesion(s), predominantly involving white matter, without radiological evidence of previous destructive white matter changes:

* Brain MRI, with FLAIR or T2-weighted images, reveals large (>1 to 2 cm in size) lesions that are multifocal, hyperintense, and located in the supratentorial or infratentorial white matter regions; gray matter, especially basal ganglia and thalamus, is frequently involved

* In rare cases, brain MR images show a large single lesion (>1 to 2 cm), predominantly affecting white matter

* Spinal cord MRI may show confluent intramedullary lesion(s) with variable enhancement, in addition to abnormal brain MRI findings above specified

Recurrent ADEM

• New event of ADEM with a recurrence of the initial symptoms and signs, 3 or more months after the first ADEM event, without involvement of new clinical areas by history, examination, or neuroimaging
• Event does not occur while on steroids, and occurs at least 1 month after completing therapy
• MRI shows no new lesions; original lesions may have enlarged
• No better explanation exists

Multiphasic ADEM

• ADEM followed by a new clinical event also meeting criteria for ADEM, but involving new anatomic areas of the CNS as confirmed by history, neurologic examination, and neuroimaging
• The subsequent event must occur 1) at least 3 months after the onset of the initial ADEM event and 2) at least 1 month after completing steroid therapy
• The subsequent event must include a polysymptomatic presentation including encephalopathy, with neurologic symptoms or signs that differ from the initial event (mental status changes may not differ from the initial event)
• The brain MRI must show new areas of involvement but also demonstrate complete or partial resolution of those lesions associated with the first ADEM event

To receive an ADEM diagnosis, the authors require that the patient have inflammatory brain involvement, i.e., encephalopathy.  The authors define three different categories of ADEM.  Monophasic ADEM is a one-time episode that can develop over a period for as long as three months.  They would consider any new or changing symptoms within this three month period as belonging to the one event.  They would also consider any symptoms that might occur during an oral steroid taper or within one month of the completion of the taper as also belonging to the single episode.  Recurrent and multiphasic ADEM episodes must occur more than 3 months after the initial event and more than one month after the completion of steroids.  Recurrent ADEM is defined as a subsequent attack that involves the same symptoms that occurred during the initial attack.  The MRI findings would be similar to the initial attack, and there would be no lesions, but there could be an enlargement of the lesions from the original episode.  Multiphasic ADEM is defined as an attack that involves new areas of the central nervous system from the initial or previous attacks.  There must be signs of encephalopathy, but symptoms and neuroimaging findings are in different areas from the initial attack.  There might be new lesions evident on MRI and there might also be evidence of partial or complete resolution of the lesions associated with the first episode.

The International Pediatric MS Study Group authors provide an excellent comparison across a number of variables for making the differential diagnosis between ADEM and MS (Table, p. S11).  ADEM more frequently occurs among younger age groups (<10 years) and there does not seem to be a higher incidence between boys or girls.  MS occurs more frequently in adolescents and the incidence is higher for girls than for boys.  A prior flu-like illness is very frequently the case in ADEM, while it is variable for MS.  Encephalopathy is required to arrive at a diagnosis of ADEM while it is rare in the early stages of MS.  Seizures are variable in ADEM and rare in MS.  A single event in ADEM can fluctuate over the course of 3 months, while in MS a discrete event is separated by at least 4 weeks.  Large lesions involving gray and white matter are frequently evident from MRI in ADEM and rare in MS.  MRI frequently shows enhancement in both ADEM and MS.  Over time, lesions typically appear to resolve in ADEM, while in MS, there is typically development of new lesions.  CSF pleocytosis (presence of a greater number of cells than normal) is variable in ADEM and extremely rare in MS (white blood cell count almost always <50).  The presence of oligoclonal bands in the spinal fluid is variable in ADEM and frequently found in MS.  The response to steroids appears favorable in ADEM and is favorable in MS.           

The authors explain that they expect that there will be specific cases that are exceptions to these criteria and through time with more research and better data, the criteria will change and be improved.  The International Pediatric MS Study Group authors explain, Clinical judgment by the treating physicians is critical to the management of patients whose diagnosis remains unclear and the proposed criteria are not meant to dictate treatment decisions in such cases (p. S11).

When children present with fever and evidence of inflammation, they are often treated with antibiotics and acyclovir until an infectious cause is ruled out.  In an article providing clinical practice guidelines for the management of encephalitis, the Infectious Diseases Society of America graded their recommendations for treatments.  The strength of evidence for a recommendation was graded as good, moderate or poor.  They also graded the quality of the evidence for the recommendation.  The highest quality evidence came from more than one properly randomized, controlled trial.  The next level of quality was from evidence derived from well-designed clinical trials without randomization, from cohort or case-controlled analytical studies, from multiple time-series or from dramatic results form uncontrolled experiments.  The lowest quality of evidence was from opinions of respected authorities, based on clinical experience, descriptive studies or reports of expert committees.

All of the treatments for ADEM are graded as the lowest quality of evidence; none of the treatments are confirmed from randomized, placebo-controlled trials.  Also, there is no good scientific data to determine an optimal treatment, including dose or duration.  Treatments are entirely based on experience and clinical judgment. 

High dose intravenous, corticosteroids for 3-5 days are the most often used first line treatment and they can be used concurrently with antibiotics and acyclovir.  The authors recommend Plasma Exchange (PLEX) in patients that are not responding to corticosteroids.  Intravenous immunoglobulin (IVIG) is then recommended in patients not responding to PLEX. 

The strength of evidence for the recommendation of corticosteroids and PLEX are graded as moderate.  The strength of evidence for a recommendation of IVIG is poor. 

From my own anecdotal experience, I am aware that for patients who present with the most severe symptoms, which may include coma, paralysis and the inability to breathe, some physicians have used Cyclophosphamide or Cytoxan (brand name) to quiet down the immune attack.  Cyclophosphamide is an anti-cancer drug and it is not identified as a treatment for ADEM in the Infectious Diseases Society of America guidelines.  Greenberg does, however, discuss the use of cyclophosphamide in the retrospective study involving 122 people with a diagnosis of idiopathic transverse myelitis at the Johns Hopkins Transverse Myelitis Center.    

The prognosis for most children with ADEM is good.  The recovery is usually a slow process lasting from four to six weeks and the majority of children with ADEM make a full recovery.  Between 60 to 90 percent are left with no neurological deficits.  Those children who do have residual symptoms are reported to have symptoms from transverse myelitis (the spinal cord inflammatory attack), recurrent headaches, and behavioral problems.  Interestingly, the location of lesions and the extent of inflammatory lesions do not appear to have any predictive value in regard to outcome.  Some physicians recommend that children receive follow-up MRIs for a period of up to five years to ensure that there is no new inflammatory activity after the initial ADEM attack; i.e., to confirm that the diagnosis is not MS. 
 
I have no idea whether my perceptions are influenced by selection bias.  It is quite possible that my observations are significantly skewed by who decides to contact me and under what circumstances, and therefore, I am exposed to more severe cases; people who are fully recovered are not looking for me.  Having acknowledged that possibility, it is my anecdotal experience that ADEM is more severe among adults and that the recoveries are more challenging than they are for children.   

Early in December, 2008, I received an email from Rachel’s mother.  She told me about her daughter who had ADEM and is 32 years old.  Rachel is living with her mother.  I also had a few telephone conversations with Rachel’s mom.  Then in the middle of December, I began corresponding with Rachel directly through emails.  Rachel’s ADEM attack occurred when she was 24 years old.  Rachel was in a coma for 9 months.  While we haven’t talked about the specific nature of her attack, Rachel must have experienced a severe inflammatory attack in her brain and spinal cord, and it is possible that she also had optic neuritis, as she has communicated about vision problems.  She has difficult symptoms from the damage in her spinal cord and she has certainly struggled with the residual symptoms from the inflammatory attack in her brain.  Rachel remains unable to speak.  She is working with a speech therapist and I have great hopes that I will have a telephone conversation with Rachel sometime in the not-too-distant future.     

Rachel has been on an incredibly difficult journey.  From my “conversations” with Rachel, I have learned that I am communicating with a person that possesses an amazingly vibrant, creative and adventurous spirit.   

I am going to share with you some excerpts from a few of the emails I have received from Rachel since we began communicating.  I am going to publish these emails as she sends them to me, because they reflect the enormous energy she must expend to get the words out and to get them typed on her computer keyboard.  She often expresses that she is totally exhausted at the end of her emails.  Rachel’s story is so incredibly compelling.  Getting to know Rachel has helped me to better understand the challenges that a person with ADEM has to manage during their recoveries and in their daily lives.  I am sharing Rachel’s words and a small part of her story, because I believe it is important to know about ADEM in the way that Rachel and Ashley and Al and Barbara and Jessica are teaching me about this truly horrible disorder.  Yes, ADEM is about the immune system and the nervous system and about many complicated symptoms, but ADEM is, first and foremost, about the human being that has it and the incredible changes and challenges it has caused in their life. 

2001 I woke up, I wanted to say something but I couldn’t, I couldn’t move my legs either, I looked down at my feet they were deformed I couldn’t stand up anymore I had a dream that I could grab my blue puffers jacket, my leopard print purse, and my blue back pac, I came to the hospital with those three things now I wanted them back.  I wanted to walk out of there into my silver beetle, listening to my house music but something was wrong, my body was stiff and I couldn’t say a word, what was going on.  I could still think; all of my memory hasn’t changed.  I even had a dream that I could talk. But this is really weird, all of my family looks the same but the hospital wasn’t where I checked into it, 9 months later, after I woke up from my coma the hospital was on the same street but not where it was before.  A park was directly across from the hospital and I don’t remember that building.

Am I dead or alive?  That thought runs through my mind at least everyday. It’s scary, I can’t explain it to anyone, everything looks the same, your life happened like it should’ve.  I remember my mother in law taking me to the emergency room, I remember staying overnight there and the dr. drew blood from my lungs, I remember my friend and her mom visiting me, my husband eventually came over and stayed with me for a couple of nights, the next thing I remember was meeting all my cousins, my aunts, uncles, and my grandparents, they were all in the family room at the hospital, I remember walking to my bathroom in my room and then I fainted. I guess that’s where I almost died, my mom came looking for me, she had me rushed down to emergency, then I woke up, I thought it was all a bad dream that I was stuck in, I couldn’t figure out the password to wake myself up from this dream, that is when I noticed everything was different.

No one understands and they r too lame for me to explain it with the board, I think I’ve tried to tell certain caregivers but they just brush it off, I can not get too deep with them, my friend would understand but he doesn’t live with me anymore, and he doesn’t email regularly so I haven’t told him yet,

Good news, I am alive but I think I am an angel, one lady, who works with my mom she was telling her mom, who is a rn, about me and all that has happened to me, she said u were sitting next to an angel.

Sun 12/14/2008 3:16 PM
i went to brazil to help my friend with a fashion show. i went to fashion school right from h/s that’s what i did in London, and brazil.  i went via ny.

i went to live with my nonie, her house was cool, i had good memories there, i went back to school to become a hairdresser, i worked as a cocktail waitress, i met my husband there, i loved my nonie very much, she passed away on my winter break from school, i went back to London at the time she passed away

well I’m still in a wheel chair, manual,
i use a dynabox, a computerized talker
but i can do whatever anyone can do

i was hospitalized from November of 2000 until Feb. 2006, there were no computers in the california hospitals. so i missed out right when the computer age happened, i barely turned 24, when i went into the coma and i was 29 when i finally got out of the nursing home.

my mom and i were very close, i think that was why she has been at my side for the past 8 years.  She spends time listening to me or reading my spelling board. 

i had to live in the hospital for 6 years, i got sick in November of 2000. i still can’t speak, i spelled out for my husband i want a divorce. he just recently gave me a divorce in june of 2005.

if the dr. knew what the hell adem was they could have started rehabbing me right away, instead they just took care of me like the rest of the comatose patients.
all my muscles atrophied i am so mad the first thing i wanted to get out of those stinking diapers, and at the rehab center they potty trained me in 3 days i was wearing regular underwear, i am too young to wear an adult diaper.
the rehab hospital is full of mainly stroke patients, they keep them for 2 weeks, but me they kept me for a whole month, and it was still too short. i wanted them to teach me to walk again,

they should have never left me in that hospital for 6 years to just rot, i feel i was ready to walk out of there, but they just took care of me, no rehab

i wear an eye patch over my left eye and type with my left pointer finger only, i used to draw, write, with my right hand, but my right hand is curled in. i can’t write yet, i learned to use my left hand for most things.
i feed myself, brush my teeth, style my hair.
i like sweets, on my 25 birthday, my mom brought a power puff girls cake, but i could not eat any of it, they didn’t pass me for eating yet instead i had a stomach feeding tube, this sucks, i thought, so i had the speech therapist test me, and slowly i got to eat things now, i can eat everything, u just have to cut it up small. i can feed myself using my left hand. for 3 years i tried to eat by myself with the supervision of my activities director, i had a special spoon for my left hand, i dirty so many towels, and now i eat with spoons and forks like everyone uses.
brushing my teeth, i can do that as well. i stand up at the sink balancing, leaning up to the sink.
Dressing i can get myself dressed i can reach my feet so i sit down and put my right leg then my left leg through then i use my hospital bed to stand up and i pull my pants up, shirts dont work for me, i wear exercise pants i cant zip or button my clothes yet my bra and my top i just slide over my head i still need my tennis shoes put on, tied as well and i cant put on my socks yet
the people at my school call me the disabled diva,
i like it, i don’t mind, i like being labeled where i stick out from the older people who have had strokes.
i just got my power chair; trying to drive my chair, they put my control on the left side, but my muscles all atrophied, i can’t control my power chair very well, plus i don't have my 20/20 vision.
i would have never been able to type such a long email 2 years ago.
I’m tired i go to bed at 7 or 8

Sun 12/21/2008 2:16 PM

Sat 1/17/2009 10:48 AM
my recovery sucks!
i have too many components, and every therapist wants me to work on her thing throughout the day.
i just want my assistant to walk me more,
i have to c a hand therapist, she concentrates on my right hand, a speech therapist because i can’t talk at all, a social worker who i hope will get me into c a psychologist, a rehab doctor who taught my assistant how to stretch my feet, i had foot surgery 5 years ago at a childrens hospital, i love it there.
but my feet r still curled including my toes, so much so it hurts me to walk in socks
yesterday my assistant massaged each foot for an hour.
he found a knot in my right foot, i was looking at my reflexology book, and it was where the bladder pressure point is.
last nite i peed 10x, my bladder wasn’t emptying
i put on an adult pull up and i went to bed,
its a good thing i don’t have anyone to impress.
geez, i don’t know what i would have done.
but i woke up at 7am my bladder subsided.

My life sucks
when i wake up at 2am only to fight with my blankets for freedom and then i carefully get into my chair then i have to squeeze through the doorway, go all the way down the hall past the bathroom only to turn my chair around at the end of the hallway so i can park my chair on the left side, i can get in on my left side, but twice this journey’s taking me too long by the time i finally make i have already peed, then i get really sad knowing that this is a lifelong problem.

I’m still pissed off because the neurologist diagnosed me with adem while i was in a coma
they knew i had brain activity, couldn’t they have ordered the ot’s to work with me, set up a computer or something, i could have started my journal writing instead of laying in a hospital for six years amongst half dead people.
the image still haunts me

Sun 2/22/2009 12:14 PM
there r 3 of them, they r very close in age. the oldest is aaron, he is 32 and has a mild case of  c.p. he is literally a genius, he got a scholarship to u.c. berkley, but got sick and had to leave. he finished his education at s.j.s.u. and will b graduating in may, stuart is 30, they r all very liberal, we all like the same music, stuart practices brazilian jui jitzu, him and aaron like to work out, he has agreed to volunteer to meet me with aaron at gym, he is a model, so he doesn’t have a bunch of free time, he is also in a band, he introduced me to fred. fred is 30, and is also a genius, i went out to coffee with fred and aaron, fred is very organized, he carries around a p.d.a., i aspire to b like him when i can use both my hands, i want a p.d.a. so my emails will b more fun.  aaron and i saw a movie, aaron and fred r movie buffs.
fred and i will take an art class, and i will possibly take an exercise class, they have an exercise class that gears on balance, we all know, i have no balance so it prevents me from walking.
i hired fred, he is going to schedule all my appts and he has nutrition down
some people think i have cerebral palsy
at this point i have a lot of similarities with aaron.
we r both in a wheel chair, we both had to drink our coffee through a straw,
aaron can talk, his toes r curled like mine
and i was surprised he hardly used any napkins
but i feed myself with my left hand i used to b a right hander, i went through all stages of eating feeding tube, blended foods, now i can eat anything if it is chopped.
i learn to feed myself, i used to wear a bib but now i just use a bunch of napkins.

Sun 2/22/2009 5:31 PM
thanks to aaron, i felt comfortable being disabled
i know i will get better but not fully
i have the worst case of adem ever
no one has had a case so bad, all the other people with my disease, it is common to b in a coma, but the most i have heard is 2 weeks max, i was in a coma for 9 months
other people can talk, me i can’t
i have to relearn to write
I’m originally a right handed person,
but all my mucles have atrophied, my hand, my mouth, so i am learning to talk again, but all this therapy takes too much out of me. i get really tired with this disease. 

Sun 3/22/2009 10:33 AM
Fred is carer and aaron is his brother.
we all get along really well
Fred and I like art so we spend a lot of time at galleries, museums etc.
Aaron is a movie buff; he takes me to c a lot of movies
Fred got me into a rehab facility
I will b taking an adaptive swim class
It was Aaron’s birthday party last night so he threw a party
he knows a lot of successful people who have been disabled all their lives and who manage to study at berkley.
those people still make me sad because i think of how well off i used to b,
lets face it i have the worst case of ADEM EVER
my current disabilities r like some of theirs
it makes me sad to hear my friends say that if I i want to go to europe, i have to learn to walk first. i know that isn’t true but to do everything that i want to do, yes i better walk. i know it will b so hard for these people in a chair, but they don’t have the choice, in many ways i feel blessed.

Rachel signs her emails to me, lr love Rachel
I love you back, Rachel!
 
I have great hope for Rachel.  I have great hope for her future, because Rachel has great hope for her future!  Over the four or five months of communicating, Rachel is becoming more positive and her life is being filled with good people and healthy and interesting activities.  Rachel is most definitely getting better.  There is recovery from ADEM; even in adults who have incredibly difficult cases with very challenging long-term symptoms.  The recovery from spinal cord damage is difficult to understand, but we observe recovery from the damage all the time.  It doesn’t happen for everyone, but it happens for most.  The recovery from the damage done to the brain is so much more difficult to understand.  The brain is just so complicated.  It may be too complicated for us to ever really be able to understand.  Perhaps we just aren’t meant to understand the physiology of a thought or the physiology of a belief or the physiology of a memory.  But the brain recovers like the spinal cord recovers.  People do get better.  I think of Rachel, Ashley, Al, Jessica and Barbara every day and I’m pulling so hard for each of them.  I hope for them every day; that they are able to find themselves; all parts of their selves; and that they are able to return to the life that they want for themselves.   
 
Shortly after I began writing this article, I receive a phone call from a family with a husband/son/father who had been rushed to an emergency room.  It had been a couple of days since the beginning of his attack, and he was in a coma, paralyzed from the neck down and ventilator dependent.  I was on the phone with this family for the following three weeks, offering information, guidance and support.  This family went through the excruciatingly difficult process of standing by while the physicians were ruling in an ADEM diagnosis in order to decide the appropriate treatment course.  Just this past week, this gentleman passed away from complications of what was likely ADEM.  For the past few days, I have been on the phone with this family, listening, consoling, and grieving with them.  What this family is going through is painful and frustrating beyond words to describe.  They have a long and difficult emotional and spiritual journey ahead of them to find peace.  And that is what I hope and pray for them … just peace; I don’t think resolution will be possible. 

Please take good care of yourselves and each other.

Greenberg BM, Thomas KP, Krishnan C, Kaplin AI, Calabresi PA, Kerr DA, “Idiopathic transverse myelitis: corticosteroids, plasma exchange, or cyclophosphamide; Neurology, 2007 May 8;68(19):1614-7.

Benjamin M. Greenberg, M.D., M.H.S. “Central Nervous System Infections in the Intensive Care Unit;” Seminars in Neurology, 2008: Volume 28, Number 5, 682-689.

Lauren B. Krupp, Brenda Banwell, Silvia Tenembaurm and for the International Pediatric MS Study Group, “Consensus definitions proposed for pediatric multiple sclerosis and related disorders,” Neurology 2007; 68: S7-S12.

Timothy E. Lotze, MD, Donald J. Chadwick, MD, “Acute disseminated encephalomyelitis in children: Pathogenesis, clinical features, and diagnosis,” UpToDate (2009)

Timothy E. Lotze, MD, Donald J. Chadwick, MD, “Acute disseminated encephalomyelitis in children: Prognosis and treatment,” UpToDate (2009)

Allan R. Tunkel, Carol A. Glasser, Karen C. Bloch, James J. Sejvar, Christina M. Marra, Karen L. Roos, Barry J. Hartman, Sheldon L. Kaplan, W. Michael Scheld, and Richard J. Whitley,  “The Management of Encephalitis: Clinical Practice Guidelines by the Infectious Diseases Society of America,” Clinical Infectious Diseases 2008; 47: 303-327.