Acute Flaccid Myelitis: Understanding the Recent Outbreak – Q&A with Dr. Benjamin Greenberg and Dr. Teri Schreiner

With the recent increase in reports of children being hospitalized due to a respiratory virus, enterovirus D68, there have been many reported cases of acute myelitis from across many states in the US. Dr. Benjamin Greenberg from University of Texas Southwestern and Dr. Teri Schreiner from Children’s Hospital Colorado joined us for a podcast on the topic to share their experience. The podcast can be downloaded at https://myelitis.org/resources/update-on-outbreak-of-paralysis-in-us-acute-flaccid-myelitis/.

Drs. Greenberg and Schreiner respond to more questions from the community in this blog.


Post-infectious or Infectious Transverse Myelitis has been described before in the scientific literature. How are these cases of acute flaccid myelitis different?

Dr. Greenberg: The traditional description of transverse myelitis is inflammation of the spinal cord, but over the last 50 years, this term has been used when specifically describing immune mediated damage to certain parts of the spinal cord – specifically white matter. For years we used the term transverse myelitis and described it to patients and colleagues as an immune-mediated disorder, probably post-infectious leading to demyelination of the spinal cord white matter. What is being recognized now are the number of cases, specifically in pediatric patients, that target the gray matter, some of which may be the result of direct infection of spinal cord cells.

Dr. Schreiner: The cases of Acute Flaccid Myelitis (AFM) are distinct because of the pattern of spinal cord involvement. What we are seeing is that limbs of patients are weak and flaccid or limp, but not spastic. The MRI of these patients shows that only one part of the spinal cord – called the gray matter – is inflamed. Sensation is preserved in these patients, there is no difficulty with bladder or bowel function, and many patients have also noted difficulty with facial weakness, weakness of the muscles that move the eyes or muscles used for swallowing or speaking.

What is the treatment protocol for acute flaccid myelitis?

Dr. Schreiner: Unfortunately, none of the treatments that we use commonly for acute myelitis have shown much effect with Acute Flaccid Myelitis. We have used high dose intravenous steroids, IVIg and plasmapheresis. We have also tried an experimental anti-viral medication. None of these have had a discernable effect. As in TM, we believe that physical therapy remains a very important tool for recovery.

Dr. Greenberg: Treatment also has to be individualized to each patient. Most patients require supportive care including feeding and breathing support. Some patients may have swelling or inflammation in the spinal cord that could benefit from therapies such as steroids, IVIg or plasma exchange. These remain unproven in this cohort of patients.

Is the recovery similar to that from Transverse Myelitis?

Dr. Greenberg: So far, in my experience, the recovery is different. Patients with damage to the gray matter have a different pattern of weakness and different issues during recovery. They don’t respond to the same therapeutic approaches, but may benefit from specific interventions over time. For example, some patients may benefit from nerve transplant procedures in the setting of gray matter damage.

Dr. Schreiner: Among the 13 patients that we have seen in Colorado, the recovery has been slow to date. Most patients have improved slightly over time, but no one has returned to their baseline prior to AFM. It is important to note, however, that only 2 months have elapsed since onset of weakness in most cases. We may find that improvements continue over a much longer timeframe.

Does this always cause paralysis?

Dr. Schreiner: Weakness is a cardinal feature of these patients. The weakness may be in the arms, legs, face, oral or eye muscles. The weakness can vary from subtle to very severe.

Dr. Greenberg: We are tracking cases of total paralysis, partial paralysis and weakness of just one limb. The combinations and presentations have been quite variable.

Are there any restrictions to getting a vaccination when diagnosed with acute flaccid myelitis?

Dr. Greenberg: There are no specific contraindications. We tend not to vaccinate children when acutely ill in the hospital, but after discharge it is safe.

 Dr. Schreiner: If the child has received steroids during his/her hospitalization it may be prudent to wait a few weeks before vaccination.

Have there been myelitis cases reported in adults from enterovirus D68 infection?

Dr. Schreiner: California has reported seeing similar cases in adults. However, it is not known whether these patients have tested positive for EV-D68. Moreover, although EV-D68 is the suspected pathogen, we cannot say definitively that EV-D68 is causing the cases of paralysis.

Dr. Greenberg: There have been cases of myelitis in adults who have had enterovirus infections. We are working to confirm if it is the D68 subtype or others. Also, as noted by Dr. Schreiner, the relation to enterovirus D68 is a theory – substantiated by significant evidence, but remains to be conclusively proven.

In children and adults who have been diagnosed with Transverse Myelitis, will an enterovirus infection cause a recurrence of the disease?

Dr. Schreiner: We have no reason to believe that a patient previously affected by TM would be at any greater risk of AFM.

 Dr. Greenberg: I agree, based on our experience and the available data – no. The myelitis in the setting of enterovirus is VERY rare and we have not seen cases of recurrence.

What can we do to prevent acute flaccid myelitis?

Dr. Schreiner: Simple measures like washing your hands, coughing into your sleeve, and staying away from sick persons will help to prevent the spread of the virus.

Is the CDC currently monitoring these cases and is there a plan for the future?

Dr. Greenberg: The CDC has an active surveillance program underway and there is a collaboration among clinical centers in North America to explore these cases in detail. We are working to prove causation as best as possible and then focus on prevention and advanced therapeutics.

Dr. Schreiner: More information is available at: http://www.cdc.gov/ncird/investigation/viral/sep2014.html.

The Bugaboo of Fatigue

Why am I so tired all the time? I know, it goes with the paralytic territory, but like Charlie Brown and the football gag where he lands on his backside every time, I’m always shocked when all of sudden I feel like I just hit the wall at the Boston Marathon. It is infuriating that I have to stop my day, every day, to take a nap and recharge what batteries I have. A late friend of mine, actor/’writer Jim Troesh, a high quad, once told me that he was asleep more during the day than he was awake. Despite what I do, it seems like I’m getting there.

What’s really bothersome about fatigue, as opposed to, say, an infection or a wound that won’t heal, is its psychological impact. It is, in a word, demoralizing. We are taught from an early age in this go-get-‘em society that if you are tired when you shouldn’t be, you are a) lazy, a serious moral infraction, b) staying up too late watching TV, or c) in some way responsible for being so “weak.” This is hardwired into the brain, at least my brain. Napping is for retirees who have run out of juice. For the rest of us, it is an indulgence or luxury-or both, and from the workaholic Calvinist perspective, you are wasting your life away.

But why is this fatigue happening? And what can you do about it?

Let’s ask the experts.

Benjamin Greenberg, MD, MHS, Associate Professor, University of Texas Southwestern in Dallas, does research and provides care in the areas of mobility disorders and specifically, neuroimmunological disorders like transverse myelitis, neuromyelitis optica, encephalitis, multiple sclerosis and infections of the nervous system. Since I have transverse myelitis, he could explain at least my situation, if not that of a wide swath of the paralysis community.

Here’s why you are most likely to be abnormally tired, says Dr. Greenberg. By far the number one cause of chronic fatigue is sleep disturbances. You are most likely tired because you haven’t gotten enough sleep. You may think you are sleeping, but often you are only semi-conscious, wiggling around, waking up for brief interludes. Sleep has to be undisturbed for long periods of time to be restorative. Three trips to the bathroom in the night will throw you off. I myself have trouble sleeping because of general discomfort, specific muscle aches, and the fact that I wear a C-PAC mask every night. Just fiddling with that thing wakes me up two or three times a night. Spasms, neuropathic pain, anxiety, depression, and stress may also be factors.

The number two reason, especially for those with mobility disorders, is excessive energy output. You are burning a lot of fuel to move around while all or half of your body is immobile. According to Dr. Greenberg, for every common activity, from using the facilities to turning over in bed, you are using up to ten times as much energy as a non-disabled person. Ten times! It makes me tired just thinking about it. Take, for instance, a simple activity like transferring into a car. If you are non-disabled, getting in a car is merely plopping down on the seat. But the act of transferring involves the actual transfer itself, breaking down and putting the wheelchair someplace, and doing the reverse when you get out again. Do that eight to ten times a day – going to the doctor’s office involves at least four transfers – and it adds up.

Thirdly, many common medications can engender fatigue. I forgot to ask Dr. Greenberg for a list. Next time. And the right or wrong diet can have a blatant effect. And if you have a neuroimmunologic disorder, there may very well be an additional factor: residual immune-disorder effects on the brain leading to fatigue and depression. This is not a scientific certainty but a well-shared thought among medical researchers. Future research is needed.

Fixing the problem, or at least mitigating it, is essentially the reverse of those factors. Get 8-9 hours of pure sleep every night, and if not, there are a million experts out there to help you do it. Get serious about it. Don’t think you will “catch up” down the line. And be very careful with anything you ingest that can disturb your sleep: alcohol, recreational drugs, too much liquid after six, even light pepper-uppers like Focalin.

Though it may seem counterintuitive and you are probably sick of hearing this mantra, you pretty much have to exercise. Get into a vigorous exercise regimen like your life depended on it, because it probably does. Dr. Greenberg says to look at the energy you store in exercise as income and all of your daily activities as expenses. Build up those energy savings. You are sure to need them.

In my own case, exercise is the best antidote to sleep deprivation that I know of. Besides making me stronger and marginally less tired during the day, it helps relieve tight muscles, stress, depression, and feelings of self-inadequacy. I slack off like everyone else, but have no illusion that I can avoid it for very long. If you want to live well and sleep well and at least, in part, mitigate the bugaboo of fatigue, exercise is not a bad place to start.

Now it’s time to take a nap.

Screen Shot 2013-09-03 at 8.39.37 AM~ Allen Rucker contracted TM in 1996 at the age of 51, and was paralyzed from the attack at the T-10 level.  Allen published a memoir about his life after getting TM; “The Best Seat in the House.”  It is now available in paperback.  As his memoir so brilliantly conveys, Allen is on a journey.  That journey has taken him into a life as a speaker and an advocate for the transverse myelitis and disability communities.  Through his many speaking engagements, his appearance on the Montel Williams Show, and as a contributing writer for ABILITY and New Mobility Magazines, Allen is raising awareness about transverse myelitis.  He is the author and co-author of numerous books of humor and non-fiction. “The Sopranos Family Cookbook,” one of three books he’s written about the Sopranos, was a New York Times #1 bestseller.  Allen is the chair of the WGA Writers with Disabilities Committee.  He lives in LA with his wife, Ann-Marie. They have two sons. Follow him on Facebook and visit his website for more information.

This blog was originally published in the Life After Paralysis blog series on the Christopher and Dana Reeve Foundation website. Click here to view the original article.

 

What Drug Companies and the FDA Need from Us

If you are interested in learning more about clinical trials, how new drugs come to market and what this means for NMO, TM, ADEM, Dr. Benjamin Greenberg’s presentation at the 2013 Rare Neuro-immunologic Disorders Symposium shares what we need to know and what the future looks like!

[youtube]http://youtu.be/lemEpjSGcj0[/youtube]

To view other videos from the 2013 Rare Neuro-immunologic Disorders Symposium hosted by the TMA, please click here.

UTSW TM-NMO-MS Nurse Wins the 2014 Excellence in Dallas-Fort Worth Nursing Awards

audrey-ayresWe are thrilled to announce that Audrey Ayres, clinical nurse at University of Texas Southwestern’s Department of Neuro-immunology was recently selected by the Dallas Magazine and presented the 2014 Excellence in Nursing Award. Audrey was selected as one of the 24 Awardees from 456 nominations. In her current role, Audrey provides care for adult and pediatric patients with Multiple Sclerosis, NMO, TM, ADEM and Limbic Encephalitis.  She is also the primary nurse for the Pediatric Demyelinating Disease Clinic for Children’s Medical Center.

Audrey completed her Bachelors of Science in Nursing at University of Texas Medical Branch in Galveston, Texas.  She began her career in the Surgical Intensive Care Unit at UTMB in Galveston. Later on she moved to Miami, Florida to work at Jackson Memorial Hospital in the Transplant and Cardiothoracic Surgical Intensive Care Unit. Then she returned to Texas and worked at Baylor University Medical Center in the Cardiovascular Intensive Care Unit and became the nursing educator for the CVICU and CCU. Audrey joined the Multiple Sclerosis Center and the NMO and TM Centers at UT Southwestern in February 2012.

Please join us in congratulating Audrey for her hard work, dedication and compassion for our community.  We are honored to know and work with you Audrey!

Click here to read more about the Award.

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Reported Cases of Polio- Like Illness and its Relationship to Transverse Myelitis

By Benjamin Greenberg, MD, MHS and Allen DeSena, MD – University of Texas Southwestern, Dallas.

News reports from California have recently come out identifying a series of patients, mostly children, affected by a polio-like illness with symptoms that can mimic transverse myelitis (TM). Naturally, these reports have raised questions within our community so we thought it would be important to address some of the concerns. First, it’s important to have some background.

The spinal cord is comprised of several different pathways and cell types. Connections from the brain descend in the spinal cord and ‘attach’ to neurons in the spinal cord that then project out to muscle groups. When a person wants to move their hand, their brain sends a signal down a pathway to a set of cells within their cervical spinal cord and form a connection (a synapse). The signal from the brain activates the neurons in the spinal cord, which in turn, propagates the signal to the muscles of the hands, leading to the intended movement. This pathway can be interrupted in many ways.

Polio is caused by a virus that specifically infects the cells within the spinal cord responsible for projecting out to muscle groups (the so called lower motor neurons). When these cells die the muscles they connect to cannot be activated. Classically, transverse myelitis causes damage to the wires that are responsible for connecting the brain to these lower motor neurons, leaving the connection from spinal cord to muscle intact, but interrupting the signal that was originally meant to activate the pathway. In clinic, we tend to describe this as “wire number 1 and wire number 2”. Wire number one goes from brain to spinal cord and wire number two goes from cord to muscle. Polio damages wire number 2 and traditionally, TM damages wire number 1.

The second issue that must be addressed is the mechanism of injury. In traditional transverse myelitis a “confused” immune system inappropriately causes damage to the spinal cord. When the immune system invades the cord there is no virus there to be fought off. In the cases of patients reported from California, a virus directly infects and kills the cells. Any inflammation in the spinal cord is responding to the virus. TM is often a missed diagnosis. Sometimes this occurs because of a lack of vigilance from medical personnel, but sometimes it is because the diagnosis is unclear.  In addition, the problem with diagnosing TM is that there is no single blood or spinal fluid test that definitively identifies TM.  In addition, the spinal fluid markers of inflammatory responses cannot differentiate between an autoimmune response and a response to an infection.

Sometimes people will read that a virus has been associated with TM, but these reports are difficult to interpret. The infection could have been the inciting event but the spinal cord injury was caused by a secondary autoimmune process after the infection, or the association could have been incidental in that the patient had previously had the infection but now has an unrelated process. Also there could actually be two processes causing the spinal cord injury – both an infection-related component and a separate inflammatory component. Finally, the patient could have tested positive for the infection even though they did not have the infection at all (a false positive).  Keeping these in mind, it makes it difficult to interpret many of the case reports regarding infection and TM.  In addition, we must always keep in mind that the viruses and pathogens we do actually know about (and can test for) are a fraction of those that exist in nature, there are likely hundreds and hundreds of viruses or virus subtypes (meaning we know several but not all in a certain virus “family”) that we are not aware of.

Although we do not know the intricate details of the cases in California, the clustering of extremely similar cases in a short time frame is more suggestive of a common infectious cause, likely a virus, that has a tendency to target the same and/or closely similar areas in the spinal cord and, thus, causing similar symptoms.

In a series of upcoming papers, our team at UT Southwestern and Children’s Medical Center has described differences among patients classically diagnosed as having TM. Some of these patients have evidence of damage to BOTH wire number 1 and wire number 2. We are using these features and others to differentiate patients relative to treatment options and outcomes. In California, the public health system has identified a series of polio-like illnesses, where only wire number 2 has been affected. Some of these patients may have originally been diagnosed with TM, but in retrospect this may have been an inaccurate diagnosis. While we do not have specific case details, this is not an unexpected event given the rate of misdiagnosis of TM.

There is a virus that has been identified in some patients – a previously recognized cousin of the poliovirus – that may be the causative agent. It is also worth noting that this syndrome (viral damage to wire number 2) has been described with multiple viruses, including west nile virus. In the end, this is a reminder of the importance for improved diagnostic algorithms for patients and increased research into the world of acute paralyzing illnesses. The TMA and the UT Southwestern/Children’s Medical Center TM program will continue to monitor events and update our community.

News articles talking about this topic:

http://www.usatoday.com/story/news/nation/2014/02/23/polio-like-illness-california/5703827

http://news.yahoo.com/polio-disease-appears-california-children-074000774.html?vp=1

http://scopeblog.stanford.edu/2014/02/24/stanford-physician-leading-efforts-to-track-emerging-polio-like-illness-in-california-children

Are there guidelines for exercising when you have TM?

Many of my patients tell me that they don’t exercise because, “they don’t know what exercises to do.” This is a curious problem. On the one hand not exercising is a safe solution, after all, if you don’t know what the proper exercise is then maybe you will be hurting yourself if you push yourself to exercise, especially if you have a chronic condition like transverse myelitis (TM). On the other hand, if you don’t do anything at all, with or without TM, you are limiting your overall health. Over the years I have had many discussions with patients about this topic and have come to realize that the answer is difficult in part because getting regular exercise is hard work, fatiguing, time consuming, etc, for anyone, and often much harder for someone who has difficulty moving their body. Only 20.4% of adults in the United States actually met the federal physical activity guidelines in 2010. In fact, the CDC found that fewer than two in 10.

Americans get the recommended levels of exercise, and more than a quarter of U.S. adults do not devote any time to physical activity. Federal guidelines call for 150 minutes of moderate to vigorous physical activity every week, including two days of full-body strengthening.

Those guidelines are for the average healthy person, how does someone with TM interpret them? How much exercise does a person with TM need? There is clear evidence that the effects of TM can result in decreased endurance, pain, decreased walking stability, and make life tasks more difficult. In addition, there is rising evidence that exercise may have natural re-myelination capabilities.

However, the heterogeneity of the disease and the multitude of symptoms that accompany it make it difficult to determine concrete guidelines for exercise. As a movement scientist who studies exercise and its effects on walking and balance for individuals I have a vested interest in keeping up with the scientific evidence about this very topic. Based on the evidence that I am aware of most people with TM should prioritize physical exercise along with appropriate pharmaceutical medications.

It is important to have some flexibility in modifying the federal exercise guidelines to allow for more of an individualized plan. Changes such as exercising for shorter periods, planning rest breaks to allow for faster recovery from exercise bouts, and keeping core temperatures as cool as possible while raising your heart rate are all simple considerations that can make exercise more easily tolerated. The primary thing I suggest to my patients is that they should do whatever type of exercise they enjoy because the theory is that if you enjoy it you are more likely to prioritize it in your busy schedule. Since we don’t know exactly what types of exercise are most helpful to someone with TM, combining some aerobic and some strengthening exercise is ideal. Individuals with TM should be given more guidance on how to maximize their current energy levels and should seek out professionals such as occupational therapists (OT) who can provide concrete steps for managing or modifying daily tasks that have become more difficult. It is also important to consider the addition of technology, such as functional electrical stimulation, for strengthening the lower extremities or at least preventing further loss of muscle strength, and focusing more on the upper extremities for aerobic benefits, much of this can be learned from a good physical therapist (PT).

The health benefits gained from regular exercise are well known, from improving cardiovascular health, bone density, strength, cognition and emotional well being, to name a few. All of these should be a priority for people with TM but a primary problem still lies in convincing people to exercise, and to do it on a regular basis. For now, keep in mind that the evidence supports the idea that individuals with TM should be getting regular daily exercise. You can pick what that exercise is, keep it safe and enjoy it, your body deserves some movement time.

Kathy Zackowski, PhD, OTR
Kennedy Krieger Institute

Departments Physical Medicine & Rehab, Neurology
Johns Hopkins University School of Medicine

Fatigue and Transverse Myelitis: A Daily Fight With Exhaustion

One of the most common issues we hear about in our practice is fatigue.

“Doctor, by 10 am I am done for the day.”

“I don’t have the energy to do what needs to be done.”

“After work and on weekends, I just have to sleep.”

Fatigue is a pervasive issue in individuals who have been diagnosed with transverse myelitis and other rare neuro-immune diseases and often is responsible for large changes in lifestyle, family time and work schedules. It can be one of the most disabling issues that patients deal with, yet is often not addressed in an aggressive fashion. At our clinics in Dallas we take a three-step approach to dealing with fatigue.

  1. Understand the causes of fatigue in each individual (they are variable, but a few are most common).
  2. Directly deal with the underlying cause.
  3. Treat symptomatically if the underlying cause cannot be identified or treated.

What causes fatigue? A person’s energy level can be thought of like a household budget. Each person has a certain amount of money to spend in a day (their budget). Once the money is spent, that’s it – you are out of energy for the day, or you have to ‘borrow’, like using a credit card with a high interest rate (at some point you have to pay it back with a penalty). There are two ways to improve your spending: increase your income or cut unnecessary spending!

Why do patients afflicted with transverse myelitis ‘spend’ their energy money so quickly relative to other people? If a person’s walking or balance was affected by the myelitis, then each step – each and every step – COSTS MORE. Just getting dressed in the morning, one can ‘spend’ the equivalent amount of energy that another person would use in half a day! Thus, by mid morning, our patients may be out of energy funds! Thinking about walking is exhausting and the rest of the world takes it for granted! Hence, we look at each patient to determine why one is running out of energy too soon in the day. Here are the most common causes:

  1. Disorganized, too little or interrupted sleep (you need 8 uninterrupted hours per night). Getting up to go to the bathroom, snoring, disordered breathing, untreated nighttime pain, disruptive bed partner, annoying pets, late nights are all a problem!!
  2. Poor walking mechanics cost you more energy! Why did the physical therapist yell at you to stand straight and move each leg slowly and purposefully? Because bad mechanics may allow you to go quicker, but costs a lot of energy over the long run. WEAR THAT AFO if you need it! The brace makes walking “energy” cost less, hence you have more energy later!
  3. Medication side effects. Look to see if your medication for pain or spasticity is actually affecting fatigue and consider a trial of a different medication or treatment option
  4. Depression. Low mood can present in a lot of ways, including a sense of fatigue. Discuss this potential with your care providers.
  5. Unnecessary steps. Perhaps you should put your clothes out the night before, instead of looping your bedroom twice, just to get dressed in the morning!
  6. Underlying medical issue. Checking thyroid, B12 level and/or iron level may be indicated. These types of concerns should be discussed with your health care provider.

Recognize that a lack of energy doesn’t just make you feel bad, but has been associated with lower scores on cognitive assessments (documented by our very own Dr. Lana Harder in research studies). So how do you fix it? Ensure that #1-4 above are examined and treated if necessary. Your energy budget can be increased with better sleep, better diet and regular exercise. While exercise is an ‘energy expenditure’, over the long run it pays dividends and increases your budget!

In the end, fatigue is common, but treatable. The key is understanding the underlying cause and developing a personalized approach to managing it!

Ben-small~ Benjamin M. Greenberg, MD, MHS

Depression and Rare Neuro-Immune Diseases: Q&A with Dr. Lana Harder and Angie Fayad

What is Depression?

Depression is a serious medical problem that causes a persistent feeling of sadness and loss of interest in activities. Studies have estimated that 6.6% of the U.S. adult population suffers from a depressive disorder, whereas about 2% of school-aged children and about 6 to 8% of adolescents in the United States have either major depression or other depressive disorders. While everyone may have occasional moments of feeling sad or “blue,” or a temporary period of sadness in response to stressors such as a major loss, a depressive disorder causes those feelings to continue for an extended period of time. Depression affects each person in different ways, so symptoms caused by depression vary from person to person. For some, depression can be very debilitating. Compared to the leading medical causes of chronic disability, depression is second only to heart disease in terms of its impact on daily functioning. Genetics, age, gender, and cultural background all play a role in how depression may affect each individual.

What does Depression look like?

Depression often affects how an individual thinks, feels, and behaves and can cause emotional, functional, and physical problems. Among the most pronounced symptoms is extreme sadness and loss of interests or pleasure that often interferes with daily activities and relationships.  Depression can also be a lethal disease, resulting in suicide in up to 15% of those severely affected. Anyone who expresses suicidal thoughts or intentions should be taken very seriously. Warning signs that someone may be thinking about or planning to commit suicide may include behaviors such as always talking or thinking about death, self harming behaviors, putting affairs in order, saying things like “it would be better if I wasn’t here” or “I want out” or a sudden, unexpected switch from being very sad to being very calm or appearing to be happy.

Although mood disorders, such as depression, can occur at any time in life, presentation of symptoms are likely to differ between adults and pediatric individuals. Adults with depression typically feel sad most of the day, experience increased fatigue, markedly diminished pleasure or loss of interest in activities, significant changes in sleep and/or appetite, and feelings of worthlessness or excessive guilt. Depression can also result in increased work absenteeism, short-term disability, decreased productivity, and a tendency to isolate oneself. Children or adolescents with depression may exhibit changes in sleep and/or appetite, and may look sad, withdrawn or tearful more frequently than they had previously. In other cases, they may be irritable, tired, listless, or uninterested in favorite activities. Children with depression may also report persistent boredom, problems at school and may complain of somatic symptoms such as stomachaches and headaches. In general, depression is an episodic condition in which an individual has symptoms for several weeks or months, which may then gradually resolve. Adults and adolescents may have recurring depression or a single episode. Variations in the course and presentation of depressive episodes can make diagnosing depression a challenge.

What do we know about depression and rare neuro-immune diseases like Transverse Myelitis? 

Little is known about the prevalence of depression among patients with TM.  Results of a recently published study revealed that 29% of pediatric TM patients experienced elevated depression symptoms according to parent report on standardized measures.  Based on survey data from a study conducted at a family camp for patients with CNS demyelinating diseases, pediatric patients with TM did not differ significantly from sibling controls in their endorsement of depression symptoms on standardized measures.  However, results showed that children and adolescents with TM reported these symptoms at a rate higher than the average population. Such results suggest that patients with TM may be at greater risk for developing symptoms of depression as compared to unaffected individuals; however, additional research is needed to more fully understand such symptoms in the context of TM.

Depression can adversely affect the course and outcome of chronic conditions. When depression is present in conjunction with chronic health problems or long-term conditions, studies have shown that these individuals experience greater reductions in health status. These reductions in health status are associated with poorer self-care, noncompliance with medical treatment, and disengagement from lifestyle and behavioral changes known to be protective in people with chronic conditions. If depression is suspected, it is recommended that you consult with your physician or a mental health care provider for evaluation.

What treatment options are available for individuals diagnosed with depression?

Treatment for depression usually speeds the process of reducing symptoms as well as the chances of recurrence, and diminishes the time an individual may be at risk for consequences that may be associated with the depressive episodes (i.e., work or school failure, social withdrawal, or family conflict). There are two main groups of treatment for individuals with depression with well-documented evidence of efficacy: Psychotherapy and Pharmacotherapy (i.e., medication).  Additionally, recent research has found family psychoeducation, exercise, and social support to be beneficial for reducing some symptoms in individuals with depression. The care and quality of life for those with depression, regardless of particular treatment type, are optimized when there is open, collaborative communication between the patient/patient family and clinicians. It should be noted that suicide is a tragic and preventable consequence of severe depression and that a person who is at immediate risk for attempting suicide requires emergency evaluation and prompt treatment for depression.

Individual psychotherapy is generally recommended as the first line of treatment for individuals with mild to moderate depression. Psychotherapy is also helpful when ongoing stressors exacerbate the symptoms. Cognitive behavioral therapy (CBT) is a common therapy treatment option, as its effectiveness has been well established for treating depression. CBT can teach new skills to reduce some symptoms of depression, particularly the negative thoughts or feelings accompanying depression.

Pharmacotherapy: While psychotherapy may be sufficient to treat some individuals with depression, for others, symptoms do not improve significantly with psychotherapy alone. These individuals may benefit from medications. The most commonly prescribed antidepressants belong to a group of medications called selective serotonin reuptake inhibitors, or SSRIs. In most cases, these medicines begin to take effect after a few weeks. Medications should only be initiated, discontinued, or adjusted when a person is under the direct supervision of a trained clinician.

As noted above, if depression is suspected, it is recommended that you consult with your physician or a mental health care provider for evaluation.

REFERENCES

American Psychiatric Association (2000). Diagnostic and statistical manual of mental disorders (4th ed., test rev.). Washington, DC.

Bennett, D.S. (1993). Depression Among Children with Chronic Medical Problems: A Meta-Analysis. Journal of Pediatric Psychology, 19(2), 149-169.

Centers for Disease Control and Prevention. http://www.cdc.gov

Fayad, A. D., Holland, A. A., Greenberg, B. M., Graves, D., Desena, A., Hughes, S., & Harder, L. (2013, June). Self-report of attention and psychological functioning among pediatric transverse myelitis patients and sibling controls. Poster presented at the Annual Conference of the American Academy of Clinical Neuropsychology, Chicago, IL.

Harder, L., Holland, AA, Frohman, E., Graves, D., and Greenberg, B. (2012). Cognitive functioning in pediatric transverse myelitis. Multiple Sclerosis Journal, 0(0), 1-6.

Kaplin, A. (2013). Depression in TM. Transverse Myelitis Association, 5(2). https://myelitis.org/symptoms-conditions/depression/depression-in-tm/

Katon, W. and Sullican, M.D. (2010). Depression and chronic medical illness (Review article). Journal of Clinical Psychiatry, 29(2), 3-11.

Katon, W. and Ciechanowski, P. (2002). Impact of major depression on chronic medical illness (Review article). Journal of Psychosomatic Research, 53, 859-863.

Kovacs, M. (1997). Presentation and Course of major Depressive Disorder During Childhood and Later Years of the life Span. Journal of Health and Social Behavior, 33(3), 187-205.

Angie Fayad PhotoLana~ Angie Fayad, BA & Lana Harder, PhD, ABPP, University of Texas 

Southwestern, Dallas

Understanding Pain in Transverse Myelitis

– Q and A with Dr. Benjamin Greenberg, MD, MHS from the University of Texas at Southwestern in Dallas

Is pain a typical symptom in diseases like Transverse Myelitis (TM)?

One of the most common issues that patients afflicted with transverse myelitis experience is pain. It can come in many forms, but the most common is a burning or stabbing pain that occurs in an arm, leg or around the trunk. It is often described as a burning, aching or stabbing pain. When the pain occurs in the chest or abdomen it is often described as a squeezing sensation. Frequently the pain worsens with exertion, stress, heat or in the evening when trying to go to sleep. It is also frequently experienced in an area that had previous sensory changes.  This type of pain is often not present at the onset of TM, but develops in the weeks or months after TM.

What are the different types of pain?

Medically, there are many types of pain that affect human beings. These include nociceptive pain, phantom pain and neuropathic pain. Nociceptive pain includes pain that occurs in the setting of tissue injury, such as a cut, burn or broken bone. Phantom pain occurs in the setting of a lost limb and is a perceived pain when the brain no longer receives signals from a limb. Neuropathic pain occurs when there is damage to a part of the nervous system and after that event and normal sensation is replaced with uncomfortable sensations.

Why is neuropathic pain experienced in neuro-immunologic conditions?

As you might expect, neuropathic pain has a different cause, biology and treatment than nociceptive pain. When you place your hand on a hot stove, it hurts. It is supposed to hurt. A signal moves from your hand to your brain and is interpreted as pain. The wound is painful even during the healing stages. This process is there to protect animals from tissue injury. We are supposed to learn that placing hands on hot stoves is dangerous! The medications used to treat this pain include opiates (e.g. narcotics) because the brain’s pain centers express large numbers of opiate receptors. When opiate medications bind to these receptors it dampens down the perceived pain. As the medication wears off, the pain returns. In reality, the pain signals are always there – transmitted from the wound to the brain, but are ignored by the brain when opiates are present.

Neuropathic pain is different. Very different! While a person’s foot may burn at night, there is no flame near the skin! So why does the brain perceive pain? The answer has to do with the pain pathways to the brain and pain centers in the brain. When sensation fibers in the spinal cord are damaged by transverse myelitis there is often a loss of normal sensory input to the brain. As a result, the sensation networks in the spinal cord and sensory centers in the brain are left with incomplete input of signals. The brain is used to receiving billions of signals every second from our bodies. Temperature, vibration, pressure, movement, light touch and pain inputs bombard our brain constantly. Every square inch of skin includes thousands of nerve endings responsible for a multitude of signal types. If the pathways responsible for vibration are damaged in the spinal cord, then the brain receives an incomplete “sensory picture” about what is happening to the feet. The spinal cord is left to manage incomplete sensory inputs. As a result of these changes the spinal cord can lead to amplification of some sensations (in an unpleasant fashion) and the brain can “fill in the gap” of missing sensation with unpleasant sensations (burning, squeezing, stabbing pains).

Why does neuropathic pain get worse at night?

Many patients indicate that their pain is worse in the evening when trying to go to sleep. You may wonder why this occurs! If the theory of neuropathic pain is correct, specifically, that the brain “fills in gaps” you might expect for distraction to lessen this phenomena. Thus, while at work or busy, people may not experience the pain, but when less distracted, their brain may be free to ‘make things up’! Just as a person tries to relax, their brain kicks into gear and the pain intensifies. Neuropathic pain is not supposed to be there – no damage to the affected area exists. As such, the treatment for this type of pain would be expected to be different than the treatment for nociceptive pain (broken bones, wounds, etc.).

What are common treatments for neuropathic pain?

Treatment of neuropathic pain usually does not involve opiates. Often patients with neuropathic pain will indicate that the use of opiates ‘took the edge off’, but did not rid them of pain. As such, we usually use antidepressant or antiepileptic medications to treat neuropathic pain. Are patients depressed or seizing? NO! These classes of medications act on cells in the brain and spinal cord to dampen down the ‘made up’ signals that are interpreted as pain and as such are perfect for neuropathic pain. Examples include amitriptyline, pregabilin, gabapentin and carbamezapine. There are many other options that have been used in patients. Beyond medication, many patients will find benefit from topical anesthetics to reduce all sensory signaling, acupuncture and/or avoidance of pain triggers. A careful discussion with your physician is needed to discuss your pain, what it feels like, what triggers it, what has helped in the past and what medications might be indicated. Pain needs to be aggressively treated as it can worsen mood and energy levels. Often multiple agents need to be attempted so that an appropriate one can be found.

Ben-small~ Benjamin Greenberg, MD, MHS

UT Southwestern, Dallas, TX

Q&A with Dr. Allen DeSena: Intravenous Cyclophosphamide for Transverse Myelitis

What is cyclophosphamide?

Cyclophosphamide (a.k.a. Cytoxan) is a chemotherapy that has been more traditionally used for certain forms of cancer.  It actually works through one of its metabolites – it’s metabolized through the liver – to add a certain molecule to DNA.  In doing this, the cells are prone to dying, and it tends to affect the immune cells preferentially, so it has an immunosuppressive effect. The dose of cyclophosphamide varies depending on why it is used – usually at high doses for cancer and much lower doses for conditions like transverse myelitis.

Why is it used for transverse myelitis? 

Because of its immunosuppressive effect, and the prevailing theory that transverse myelitis is caused by an overactive immune system that has become “confused” by attacking its own spinal cord, these have led to the consideration of using it for transverse myelitis.  In addition, it has had some particular notable success in other autoimmune diseases, specifically systemic lupus erythematosus (SLE or called just ‘lupus’ commonly) and Sjogren’s disease.  Furthermore, these are two diseases that can rarely present with transverse myelitis also.

When do you consider using cyclophosphamide?

We will typically use intravenous cyclophosphamide after the patient fails to respond or has a poor response to intravenous steroids and/or if they fail less aggressive therapies such as plasma exchange or intravenous immunoglobulin.  We have used it for transverse myelitis and acute disseminated encephalomyelitis.  Furthermore, although there is a case report about a patient with neuromyelitis optica (NMO) responding well to cyclophosphamide, there are other reports of patients with NMO that have tended not to respond well to it.  So, we typically have not used it if we have either a strong suspicion of NMO.

Are there studies in which cyclophosphamide has been used for transverse myelitis?

There are several case reports and large case series of cyclophosphamide use.  Many of these, as mentioned above, discuss cyclophosphamide with SLE or Sjogren’s-related myelitis.  There is a large retrospective review of cyclophosphamide usage in transverse myelitis that showed suggestion of benefit in patients that had a more severe transverse myelitis (defined as being labeled ASIA A – which is a spinal cord injury classification in which the patients have complete sensory and motor loss and bladder/bowel function impairment).  The main limitation of this study was that the transverse myelitis patients were not all idiopathic, some were later diagnosed with NMO, MS, etc.  In addition, there was no benefit noted in this retrospective review with cyclophosphamide’s effect on patients with less severe transverse myelitis.  There have been no clinical trials with cyclophosphamide and transverse myelitis or acute disseminated encephalomyelitis.  A list of cyclophosphamide and myelitis articles will be included at the end of this article.

How quickly does cyclophosphamide work?

Cyclophosphamide does not work immediately.  It takes about 10-14 days to reach peak effect.  It will be out of your system in about a month.

What are the side effects?

The main side effects we see are nausea, vomiting and loss of appetite around the time of the infusion, although we give medications to help prevent this.  One of the concerning side effects during the infusion is an increased risk for hemorrhagic cystitis – a term for bleeding from the wall of the bladder into the urine.  This occurs because one of the metabolites of cyclophosphamide irritates the cells in the bladder wall, but cyclophosphamide is usually given with a medication called MeSNa (2-mercaptoethane sulfonate Na), which binds up that metabolite and dramatically reduces the risk of this complication.  There is always a concern for an infusion reaction too, but, again, this is rarely seen.  Patients are at an increased risk for infections after an infusion, but these are rare.  For this reason, we typically recommend only common sense-type precautions such as regular hand-washing, avoidance of people known to be sick, and avoiding sharing drinking glasses and similar such things.  We also may see some mild hair thinning at the doses we use, but profound hair loss is very rare.  In addition, we can see changes in the blood counts after it reaches peak effect, and we typically recommend some blood work about 2 weeks after the cyclophosphamide is completed.  In a large study of patients on regular cyclophosphamide doses over many months, the incidence of infections were about 20%, but the incidence of infections requiring a hospital visit was only about 8%.  These were patients getting regular cyclophosphamide infusions over many months, whereas in TM we typically only give one dose.  Theoretical long-term side effects are potential risks for future malignancies (cancers), infertility (both for men and women).  Nearly all of our safety data for cyclophosphamide comes from studies of its use in cancer, and patients are getting much higher doses of it for much longer.

What have you seen with cyclophosphamide in your experience? 

It is difficult to give percentages about responses to cyclophosphamide for either transverse myelitis or acute disseminated encephalomyelitis, but we have seen a few patients that appeared to have achieved more significant recovery following their cyclophosphamide infusion than we would have otherwise expected.

Do all medical centers and hospitals have access to this medication?

Most hospitals and centers that see children with transverse myelitis likely do have access to this medication; however, some neurologists and other specialists may not be as familiar with it as in some other places and may be hesitant to offer it as a next option.  We would always encourage families with children or other family members with either TM or ADEM to ask their doctors about other medication and treatment options should there continue to be significant neurologic deficits after standard treatment has runs its course.  The decision to use Cytoxan has to be individualized to each patient’s situation. The TMA is also a great resource for helping to direct families to the medical centers with the most TM and ADEM experience.

References

Ammouri W, Mezalek ZT, Harmouche H, Aouni M, Adnaoui M, and Maaouni A.  “Myelitis Complicating Systemic Lupus Erythematosus: Successfully Treated with Corticosteroids and Cyclophosphamide.” South Med J.  2009; 102; 744-745.

Bichuetti DB, Oliveira EML, Boulos FC, and Gabbai AA.  “Lack of Response to Pulse Cyclophosphamide in Neuromyelitis Optica: Evaluation of 7 Patients.” Arch Neurol.  2012; 69; 938-939.

Birnbaum J and Kerr DA.  “Optic neuritis and recurrent myelitis in a woman with systemic lupus erythematosus.”  Nat Clin Practice.  2008; 4; 381-386.

Carter D, Olchovsky D, Langevitz HYP, and Ezra D.  “Simultaneous deep vein thrombosis and transverse myelitis with negative serology as a first sign of antiphospholipid syndrome: a case report and review of the literature.” Clin Rheumatol. 2006; 25; 756–758.

Gadze ZP, Hajnsek S, Basic S, Sporis D, Pavlisa G, and Nankovic S.  “Patient with neuromyelitis optica and inflammatory demyelinating lesions comprising whole spinal cord from C2 level till conus: case report.” BMC Neurol; 2009; 56.

Greenberg BM, Thomas KP, Krishnan C, Kaplin AI, Calabresi PA, and Kerr DA.  “Idiopathic transverse myelitis: Corticosteroids, plasma exchange, or cyclophosphamide.”  Neurology; 2007; 68; 1614-1617.

Krishnan C, Kaplin AI, Graber JS, Darman JS,  and Kerr DA.  “Recurrent transverse myelitis following neurobrucellosis: Immunologic features and beneficial response to immunosuppression.” J NeuroVirol; 2005; 11; 225–231.

Misra AK, Mishra SK, Eigen AC, and Tourtcllotte WW.  “Successful immunosuppressive therapy for HTLV-I associated myelopathy.”  J Neurolog Science.  1994; 122; 155-156.

Neumann-Andersen G and Lindgren S.  “Involvement of the Entire Spinal Cord and Medulla Oblongata in Acute Catastrophic-Onset Transverse Myelitis in SLE.” Clin Rheumatol; 2000; 19; 156–160.

Rheu CW, Lee SI, and Yoo WH.  “A Catastrophic-Onset Longitudinal Myelitis Accompanied by Bilateral Internuclear Ophthalmoplegia in a Patient with Systemic Lupus Erythematosus.” J Korean Med Sci.  2005; 20: 1085-1088.

Strauss K, Hulstaert F, Deneys V, Mazzon AM, Hannet I, De Bruyk M, Reichert T, and Sindic CJM.  “The immune profile of multiple sclerosis: T-lymphocyte effects predominate over all other factors in cyclophosphamide-treated patients.” J Neuroimmunol. 1995; 63; 133- 142.

Takashima H, Smith DR, Fukaura H,  Khoury SJ, Hafler DA, and Weiner HL.  “Pulse Cyclophosphamide Plus Methylprednisolone Induces Myelin-Antigen-Specific IL-4-Secreting T Cells in Multiple Sclerosis Patients.” Clin Immunol and Immunopathology .  1998; 88; 28–34.

Allen_FinalAllen DeSena, MD, MPH | James T. Lubin Fellow | Department of Neurology, University of Texas at Southwestern, Dallas, TX