Fatigue and Transverse Myelitis
Randall T. Schapiro, MD
Director, The Schapiro Center for Multiple Sclerosis at the Minneapolis Clinic of Neurology and Clinical Professor of Neurology, University of Minnesota

Adapted from a presentation given at the 2004 Rare Neuroimmunologic Disorders Symposium

This article is about fatigue in transverse myelitis.  I have never really considered transverse myelitis a disease.  I have considered TM a symptom of some other condition; in much the same way as seizures end up being called epilepsy, if you are uncertain of the cause.  There are numerous causes of transverse myelitis.  These include:
 

1. Parainfectious - viral and bacterial
2. Postvaccinal
3. Autoimmune:  Lupus, Sjogren’s, Sarcoid, Multiple Sclerosis
4. Paraneoplastic syndrome
5. Vascular

Fatigue can be associated with any and all of the diseases associated with Transverse Myelitis.  Not every case of transverse myelitis, however, has fatigue associated with it.  I don’t know which causes are associated with fatigue and which are not; I am not sure that anyone has that answer.  Multiple Sclerosis is the prototype for fatigue in this disease group, so I am going to focus on the relationship between MS and fatigue.  I recognize that this case may not fit each and every person with their individual form of transverse myelopathy or myelitis.

Fatigue is the single most common symptom that we see in multiple sclerosis.  It is the most disabling symptom that we see in multiple sclerosis.  If you have a transverse myelopathy and not multiple sclerosis, and have fatigue, there is not a doubt in my mind that it is going to be very disabling and a significant problem.  It is seen in seventy-eight percent of the people with multiple sclerosis.  Nearly two-thirds of patients experience fatigue on a daily basis and it causes temporary disability in up to 75% of patients.  Fatigue interferes with physical functioning and with daily living.  It has an impact on overall mental health by reducing vigilance and cognitive function.  It can disrupt normal sleep patterns.  Fatigue is also intimately related to one’s sense of control over their illness.  Patients can feel that they have lost control over their disease and over their lives because of fatigue.  Fatigue frequently leads to unemployment, and consequently, Social Security has finally come to the conclusion that people who have MS or MS-like diseases can be disabled on the basis of their fatigue.  Fatigue is a criterion for disability.

Part of our problem in finding the causes and treatments for fatigue is that there are so many different kinds of fatigue.  Whether you have transverse myelitis or multiple sclerosis, you will have normal fatigue.  Everybody who works hard gets tired.  Sometimes when we work hard and get tired and have a disease, we tend to attribute the fatigue to the disease.  This fatigue can be just part of a natural pattern that occurs in all people.  We are thrilled when we see normal fatigue in one of our patients, because we are happy that they are able to go to work and work hard.   

We also see in transverse myelitis and multiple sclerosis a neuromuscular, short-circuiting type of fatigue.  It is fairly easy to understand.  The nerve is repeatedly firing until it blocks, because it is not healthy.  In the case of MS, there is the demyelination process, the axonal process, and the nerve process.  But it can be from other causes, as well.  You start out walking and you do pretty well.  Then you begin to get the neuromuscular fatigue.  It just doesn’t work any more.  Neuromuscular fatigue is treated with rest and graded exercise in order to build up capacity.

Deconditioning is a third type of fatigue.  People who have neurologic disease often do not get enough exercise and they become deconditioned.  They may wonder why they poop out when they try to do something; it is because they are just not in shape.   

A fourth type of fatigue is from depression.  If you are not sleeping well; if you are not eating well; if you are not feeling well; you may, in fact, be depressed.  With depression comes fatigue.  We have to understand this connection and then get the appropriate treatment for depression, as well.

The most common type of fatigue we see in MS is in a different category from what I have just described; it is a fatigue that we call lassitude.  It is an overwhelming tiredness that hits people for no particular reason.  When we talk about this type of fatigue, there may be some deviation for some people with transverse myelitis depending on the specific cause.  This fatigue must be a related to a neuro-chemical process.  A person can be feeling very well, not depressed, can be in shape and then just get so sleepy that they just have to take a break and take a nap.  After the nap, they feel better, and then a while later, they are back into the same cycle.  Lassitude, or overwhelming tiredness, is difficult to understand.

Graphic: Potential Causes of Fatigue

This graphic depicts the various causes of fatigue in multiple sclerosis; this would aptly apply to transverse myelitis, as well.  Moving clockwise around the graphic, physical health problems cause fatigue.  Fatigue is caused from not being able to sleep, perhaps because of legs jerking or bladder problems.  Everyone has normal fatigue; and people with MS and TM also have to deal with this fatigue.  Everyone also has to deal with psychological fatigue, and people with chronic disease have to deal with it in spades.  The environment also is a cause of fatigue; from physical, social, institutional and cultural barriers.  

Graphic: Fatigue in Patients with Multiple Sclerosis: Etiology

It is no wonder that fatigue is so common in these neurologic diseases.  It is common because we have the primary causes, the actual disease itself.  It is common because we have the secondary causes; the drugs that are taken, the deconditioning, the psychologic process.  All of these factors lead to fatigue.

Fatigue is the single most common and the most disabling symptom in MS.  Ninety-seven percent of patients report that they have fatigue.  It is described by up to half as their most disabling and worst symptom.  It is reported more than any other neurologic symptom in people with multiple sclerosis; more than balance problems, weakness, bowel and bladder problems or paralysis.  

When we treat fatigue, it takes a team approach to do it properly, and this is particularly the case when it is the severe kind of fatigue.  It takes an occupational therapist to understand the activities of daily living; how do you dress, eat, bathroom more efficiently, more effectively, more appropriately?  It takes a physical therapist to try to work out the neuro-muscular fatigue, decrease the spasticity, and improve the patient’s efficiency at functioning physically.  It takes the psychologist or social worker to work on the psychological aspect of the disease and the depression.  Finally, there is pharmacological therapy; we have drugs that we probably need to use in some people with these kinds of fatigue.

How does exercise fit into the equation regarding the causes and treatments of fatigue?  I am often told by many people with transverse myelitis and multiple sclerosis that when they exercise, they get tired and then they get fatigued.  So, what good is exercise, if it only gets one fatigued?  This was the prevailing thought for years; and then we began to learn something about exercise.  When I was in high school, a long distance run was a one mile run.  Roger Bannister was the first person to break the four minute mile.  He went on to have a brilliant career as a neurologist.  He developed an interest in neuromuscular disease.  Today, a marathon is a long distance run.  I couldn’t run a mile when I was sixteen years old, and now I can run ten miles without blinking.  How does that happen?  Well, we have to learn how to train; we have to apply the exercise appropriately.

In MS it was very hard to do until a skier came along; his name was Jimmie Heuga.  Jimmie motivated our learning about exercise and MS.  How do we exercise in MS?  We started to understand that you have to keep a balance between growth and overdoing it when it comes to exercise.  Training became important.  We began to understand the role of aerobic exercise in keeping oneself fit and less fatigued.  And we began to use an exercise prescription.  You have to know your goals; and your goals will determine the type of exercise you do. Then you have to know how hard to exercise (intensity); how often to exercise (frequency); and how long to exercise (duration).  Obviously, these are defined by individual circumstances.  If you apply the principles of training that we have learned in the past two decades to neurologic disease, you can use exercise to build endurance and to decrease fatigue.  But, if you just jump in and do it, it is destined for failure.

I would like to turn now to the pathophysiology of this very complex and poorly understood symptom.  Fatigue is present at all stages of MS and I suspect it is present in all stages of many neurologic diseases that involve the central nervous system.  It doesn’t correlate very well with disability level, with gender, or age.  Fatigue doesn’t correlate with the kind of MS one has (disease subtype) or how long they have had MS (disease duration).  Finally, it doesn’t correlate with MRI findings.  It is an amazing and difficult symptom.  Fatigue does have some relationship to depression and some relation to cognition.

Fatigue is biologically complex. Some neurologists believe that it all has to do with the central nervous system hormones that we call cytokines.  We really don’t know.  There must be a neuro-chemical relationship.  We don’t know this from any basic science studies, but it makes sense.  When we give people certain neuro-chemicals, it seems to have an effect on that kind of fatigue.  It obviously emanates from multiple levels within the neural hierarchy.  If we look at the metabolism and nerve conduction in the central nervous system, we see that it has some correlation with fatigue and increased energy demands secondary to neurological disability. 

Graphic: Fatigue in Patients with Multiple Sclerosis: Hypometabolism

If we look at these PET scans, it is evident that the people who do not have fatigue have a different type of scan from those people who do have fatigue.  This gives us some indication that there is a neuro-chemical process going on with lassitude; this overwhelming tiredness.  It is likely related to the pathologic alterations in MS; inflammation, demyelination, and axonal injury.  There is a relationship with depression and cognition, suggesting that common neural pathways and brain regions may be affected.  There is a probable association with reduced metabolism in the basal ganglia and frontal cortex.  Fatigue is aggravated by heat and it worsens at the end of the day. 

One of the issues we have to deal with is how do we measure fatigue?  How does Social Security tell whether you are tired or not?  So, we have fatigue severity scales. These scales are rough measures, because they are paper and pencil scales.  They offer limited insights into fatigue.  

The following are some examples of these scales so that you can get an idea of how we measure fatigue.  

The fatigue severity scale is a series of questions that you answer.  The patient rates each item from 1 (strongly disagree) to 7 (strongly agree).  The FSS score is a mean rating across all nine questions; the higher the score, the worse the fatigue.

My motivation is lower when I am fatigued.
Exercise brings on fatigue.
I am easily fatigued.
Fatigue interferes with my physical functioning.
Fatigue causes frequent problems for me.
My fatigue prevents sustained physical functioning.
Fatigue interferes with carrying out certain duties and responsibilities.
Fatigue is among my three most disabling symptoms.
Fatigue interferes with my work, family or social life.

The Modified Fatigue Impact Scale (MFIS) addresses physical, cognitive and psycho-social functions.  The different subscales allow us to look at fatigue in a broader way.

Physical Function Subscale; the patient rates each item from 0 (never) to 4 (almost always).  The MFIS score is the total of all ratings from 0 to 84.  The higher the score, the worse is the fatigue.

I have been clumsy and uncoordinated.
I have had to pace myself in my physical activities.
I have been less motivated to do anything that requires physical effort.
I have trouble maintaining physical effort for long periods.
My muscles have felt weak.
I have been physically uncomfortable.
I have been less able to complete tasks that require physical effort.
I have limited my physical activities.
I have needed to rest more often or for longer periods.

Cognitive Function Subscale

I have been less alert.
I have had difficulty paying attention for long periods of time.
I have been unable to think clearly.
I have been forgetful.
I have had difficulty making decisions.
I have been less motivated to do anything that requires thinking.
I have had trouble finishing tasks that require thinking.
I have had difficulty organizing my thoughts.
My thinking has been slowed down.
I have had trouble concentrating.

Psycho-social Function Subscale

I have been less motivated to participate in social activities.
I have been limited in my ability to do things away from home.

Another measure is called the Visual Analog Scale.  The patient can identify the extent to which they assess that fatigue has impacted their everyday function.

Graphic: Two Types of Wakefulness

Fatigue and sleep and wakefulness all seem to come together.  So, we look at the brain for our answers.  We recognize that there are different areas in the brain that have different roles in keeping us awake.  As you move to the front of the brain and to the left, there is more normal wakefulness.  As you move more deep into the brain, there is a different type of neuro-chemical aspect to our fatigue.  So, we have different kinds of activity going on with different neuro-chemicals in the brain.

We have pharmacologic management that we use to try to treat the fatigue that occurs in MS.  Most patients who have severe types of fatigue whether from chronic fatigue syndrome or MS or transverse myelitis, will require a medical and a non-medical approach to fatigue treatment.  Rehabilitative medicine will have a role as a treatment approach for fatigue.

Many years ago there was a doctor in Halifax, Nova Scotia who had MS.  He was a family doctor.  He used a drug for the flu called Amantadine.  It is an oral pill that you take to prevent the flu.  He was afraid he was going to get the flu, so he took Amantadine and his fatigue went away.  He thought that was strange, so he decided to do a study.  He went off of the Amantadine and the fatigue came back.  He went on the amantadine and the fatigue went away.  So, he went to Dalhousie University in Halifax, Nova Scotia and he set up a study with Dr. Jock Murray, a randomized, double blind, placebo controlled clinical trial on Amantadine.  Lo and behold it worked; a third of the patients got better with this medicine compared to the placebo.  The efficacy of Amantadine has been shown in four trials.  About a third of patients with mild to moderate fatigue report significant short-term improvement. 

Amantadine is considered to be a first-line treatment for mild MS-related fatigue.  It is FDA approved as an anti-viral and anti-Parkinson agent.  Amantadine has a long history of being used for the treatment of MS-related fatigue; we have been using Amantadine now for almost twenty years.  It is clearly a neuro-chemical; a dopaminergic and a cholinergic medicine.  Generally, it is well tolerated.  Occasionally, it causes some side effects, such as nausea, dizziness and insomnia.  One of the side effects is called livedo reticularis, which may occur in 1-5% of patients following extended use.  It is a pattern of veins in your legs that look like spider webs.  If you didn’t know it is caused by Amantadine, you might think it was a circulatory problem.  Amantadine may precipitate or exacerbate psychotic symptoms.  Patients may become refractory to Amantadine with long-term treatment. Basically, it is an easy medicine to take.  We give it at one hundred milligrams, twice a day.  You should avoid taking an evening dose close to bedtime.  Overall, it appears to have a moderate effect on fatigue.

Another pharmacologic treatment is Pemoline or Cylert.  Pemoline should not be used as an initial treatment.  It is FDA approved for the treatment of ADHD.  Pemoline has been used for the treatment of MS-related fatigue.  This is a stimulant; the intent of this drug is that we can stimulate the brain.  Cylert is a drug that stimulates adults and it calms hyperactive children.  We have used Cylert for about the past twenty years carefully, because it has some abuse potential.  It may be useful for patients that do not respond to Amantadine or modfinil (Provigil).  A “Black box warning” on Pemoline in 1999 regarding the risk of hepatic failure has lead to a reduction in its use.  The FDA decided to survey people about liver disease and liver failure and found a few cases of liver failure.  They decided that this drug was unsafe.  Neurologists have used Pemoline for twenty some years and we never saw a case of liver failure. As a matter of fact, we never checked liver function.  We begin Pemoline at 18.75 mg per day, and then titrate to a maximum of 75 mg per day.  Due to its association with life-threatening hepatic failure, patient consent should be obtained prior to initiating therapy and liver functions should be monitored.  Patient discontinuation due to side effects is common.  The most commonly reported side effects include anorexia, irritability, insomnia and weight loss.  It should be discontinued if ALT (SGPT) is increased to a clinically significant level or signs of liver failure develop. 

Modafinil (Provigil) is considered to be a first line agent for the treatment of fatigue.  The FDA approved it in 1999 as a “wake promoting” agent for the treatment of excessive daytime sleepiness in patients with narcolepsy.  Modafinil has been found to provide effective treatment for MS-related fatigue in multiple trials.  In a crossover study by Rammohan, et al, MS patients treated with 200 mg/day modafinil for two weeks showed a significant improvement in fatigue versus placebo.  It was recommended by the “working group for Pharmacologic therapy in MS-related fatigue” as a first-line therapy for moderate-to-severe cases.  Data suggests that cytokine-induced fatigue following interferon injection may be mitigated by the use of Modafinil (Provigil).  It promotes wakefulness without generalized stimulation.

We initiate the therapy with 100 mg daily.  We may increase the dosage to 200 mg daily.  We administer the medication in the morning.  If a second daily dose is required, it is administered before 1:00 PM to prevent adversely impacting nocturnal sleep.  Interference with BCPs may necessitate use of alternative forms of birth control.  It is generally well tolerated.  The most commonly reported side effects include transient headache and nausea. 

Fatigue is present in many diseases associated with transverse myelopathy.  There is data about fatigue in MS, but there is not data about fatigue associated with TM.  There are many different kinds of fatigue.  When we treat fatigue, we need to identify the specific type of fatigue we are treating.  Measuring fatigue is an inexact science; the measures are very subjective.  Lassitude, the most common and significant fatigue in MS, remains a bit of a mystery.  It must have a neuro-chemical basis.  There are treatments for fatigue.  It is difficult to manage, but with a team approach and the three P’s, physical, psychological, and pharmacological therapies, we can, in fact, help most people who have fatigue with neurologic disease.