By Revere (Rip) Kinkel MD
Director of the UCSD Multiple Sclerosis Program
Fatigue associated with MS is one of the most complex symptoms to evaluate and treat. There are many reasons for this complexity but the ubiquitous experience of fatigue tops the list. How many of us with or without MS have NEVER experienced fatigue? Probably no one on earth. It seems that every peak and valley we achieve in life is accompanied by fatigue; when we are down and ill we experience fatigue, and when we reach the pinnacle of success and happiness our exuberance overwhelms us and leaves us fatigued. I once read that fatigue is the most common complaint of people presenting to their primary care physician. If fatigue is so universal it stands to reason that we can not all be describing the same symptom, and yet we use the same word for all our complaints: fatigue. It is said that the experience of fatigue in people with MS is qualitatively similar to the usual experience of fatigue but differs quantitatively in terms of the persistence and severity of the fatigue. While this is true, it still does not help with the evaluation and management of fatigue when it persistently interferes with your life.
So how do MS specialists help you evaluate and manage your fatigue under these circumstances? This topic is so complex that it is best for you to remember 5 important rules to help you over time:
1. Fatigue in people with MS is usually multifactorial. This means that fatigue is usually caused by a multitude of related or unrelated processes, not all of which are directly or even indirectly related to your MS. For instance, the fatigue may be 50 % caused by depression, 25 % caused by sleep disruption from chronic low back pain, 10 % caused by medication and 15 % caused by the direct effects of MS on the brain ( what we call primary MS related fatigue). It is the job of your MS specialist to help you figure out what factors are contributing to your fatigue and how to best treat it. In the example provided, treatment of the patient’s depression, elimination of the offending medication and improvement in sleep could go a long way towards improving the complaint of fatigue. On the other hand treatment with amantadine or modafinil for primary MS related fatigue would probably have little lasting benefit.
2. Fatigue means different things to different people. To some people fatigue means malaise or lassitude. To others it means the experience of being excessively sleepy during the day. Some are describing the experience of exertional weakness or mental fog or both. And some are describing a combination of fatigue experiences. It helps to be very specific when describing your complaint of fatigue. If fatigue means you are dragging your right leg after walking 100 feet and this requires you to rest before continuing, treatment may include a drug like ampyra to improve electrical conduction in your nervous system. If fatigue means you wake up feeling poorly rested and find yourself falling asleep easily during the day, then it is far more appropriate to assess your sleep quality to direct your treatment.
3. The causes of fatigue will change over time and must be re-evaluated frequently. This is probably obvious, but requires stating explicitly. I see many people with MS who benefited from amantadine or modafinil early in the course of their MS but eventually find that it no longer works or doesn’t work again when restarted. As you get older there are more and more opportunities for problems to develop that can contribute to fatigue. These may be unavoidable problems like other medical conditions (hypothyroidism as an example) or the addition of medications that cause fatigue. The list of medications causing or worsening fatigue is almost endless and one of the main reasons your MS specialist must continually reassess your need for certain medications.
4. There is never one treatment for fatigue. Treatment requires a multidimensional approach. If you expect to take a pill and eliminate your fatigue, you will be disappointed. Even in circumstances where the cause of fatigue is known and curable-- for instance, hypothyroidism--returning to normal after curing the hypothyroidism will require dietary modifications for the weight gain and an exercise program for the deconditioning. This is even more essential for chronic neurological problems like MS. Treatment should initially focus on the most treatable causes of your fatigue. This may include evaluation and management of treatable conditions (e.g. anemia), the elimination of unnecessary medications, improvement in sleep and treatment of depression. This should be accompanied by dietary modifications and a structured graduated exercise program with or without work and leisure activity adjustments during the day. People with MS should be regularly reassessed with the potential addition of medications to treat primary MS related fatigue, beginning with amantadine and considering modafinil or other stimulants if the amantadine is not effective.
5. Establish meaningful goals for treating your fatigue. It is rare that we totally eliminate fatigue in MS, so it is important to establish specific goals with your MS specialist and your family. This will help guide treatment recommendations.
#msfatigue #fatigue #multiplesclerosisfatigue #waystofightfatigue
A. Scott Nielsen MD, MMSc
Virginia Mason Multiple Sclerosis Center
This is a difficult question to answer because what is a "typical" case of MS?
The time from the first symptom of demyelination to presentation in a doctor's office is going to depend heavily on where in the nervous system the injury is occuring. For instance, if the injury is occuring in the pyramidal system (this is the circuit that involves strength and movement), then patients are much more likely to seek care early as opposed to a patient who experiences their first attack of MS (that produces symptoms) if it affects the sensory fibers (for instance, if there is a small area of numbness or tingling). This is particularly the case in young adults who may rationalize symptoms away as something minor because MS (or any chronic illness) is not supposed to affect us in our most productive years.
With that said, there have been some researchers who have looked into the time from first symptom onset to diagnosis. A group in Spain (Fernandez et al., Journal of Neurology 2010; 257(9); 1500-7) did just this and found that the mean time from first symptom to diagnosis is approximately 2.08 years, and the largest contributor to this delay was patients who waited an average of 19.2 months from first symptom to going to the doctor for the problem.
Since the diagnosis of MS is a clinical one (ie, we do not have a blood test--or any other test for that matter--that can definitely render an accurate diagnosis), there will be occasions where the diagnosis may be uncertain for quite some time. Since MS can be mimicked by other disease states (in particular, diseases that are treated with therapies different than the MS therapies), it is very important to "get it right" to the extent possible. While this can be frustrating for patients who struggle with the uncertainty of a diagnosis, it is too for the physician. Obviously, more research is needed to identify biomarkers of the disease that can help us diagnose sooner (and with improved accuracy). This is imperative as clinical trial evidence indicates that the sooner a person with MS is treated, the better the long-term outcomes.
A. Scott Nielsen MD, MMSc
Virginia Mason Multiple Sclerosis Center
By Revere (Rip) Kinkel MD
Director of the Multiple Sclerosis Program
Professor of Clinical Neurosciences
University of California San Diego
We spend so much time discussing alterations in sight and tactile sensations (e.g. pins and needles, burning sensations, electrical sensations, itching) in MS that we often forget that the other senses may be affected as well. I thought I would briefly discuss these for you today.
Acute hearing loss during the course of MS is relatively rare, although I suspect it occurs far more frequently than the reported 10 % incidence would suggest. Hearing loss at the onset of MS is even less frequent (1%) and often suggests another disorder masquerading as MS. Hearing loss may occur in isolation but is more readily associated with the multiple sclerosis when accompanied by other brainstem symptoms and signs such as vertigo, weakness or sensory disturbance on one side of the body, facial weakness or sensory disturbance sometimes opposite the affected side of the body, or incoordination of a limb. Unilateral hearing loss is more suggestive of an MS related cause, but MS may also rarely cause bilateral hearing loss. Many patients report symptoms such as tinnitus or fullness in the ear that may fall short of “hearing loss”, but still negatively affects auditory function and quality.
Hearing loss is almost always caused by inflammatory demyelination in the part of the brain called the brainstem where the auditory nerve (also called the eighth cranial nerve) enters the central nervous system, or in the auditory pathways within the brainstem. It is said that high frequency hearing loss is more common with involvement of auditory nerve entry zone and tract, whereas low frequency hearing loss is more common with involvement of the auditory brainstem pathways. When hearing loss occurs acutely in MS, it often recovers along with other symptoms of a relapse after treatment with high dose steroids. However, like other symptoms there are some people who recover very little and are left nearly deaf. Tests can be done to determine if the hearing loss is caused by a problem in the cochlea (the inner ear and therefore not caused by MS) or the brainstem (more likely related to MS) but these tests are rarely necessary in a person known to have MS who experiences hearing loss.
Altered smell and taste are reported more frequently in people MS (up to 2/3’s of people with MS may experience diminished smell perception and discrimination). Altered smell may even be a presenting symptom of MS, presenting either as diminished ability to smell (hypoguesia) or unpleasant abnormal smells (odors misinterpreted as smelling like gasoline, for instance). Rarely, patients will present with both altered smell and taste suggesting another problem such as a viral infection or a consequence of smoking. Altered taste can take many forms including inability to taste only sweet flavors, only sour or bitter flavors or both. The abnormal taste may affect only one or both sides and when it affects both sides the type of taste affected can differ on the two sides (i.e. sweet taste affected on one side and sour bitter tastes affected on the other side). In most situations people do not notice loss of taste when it affects only one side. Loss of or distorted smell is noticed with greater ease than loss of taste and often affects a person’s perception of smell as well.
The proportion of people with MS who experience a decrease in smell perception and discrimination increases with the duration of disease and is related to amount of demyelination (white spots on MRI) in the inferior frontal lobes and temporal lobes of the brain. Not infrequently the diminished sense of smell is associated with problems controlling emotions or behavior, staying on task, planning activities or thoughts and seeing them through to the end.
Both altered taste and smell have a large differential diagnosis. Common reversible causes of diminished smell include the common cold and other respiratory viruses, allergic rhinitis, chronic sinusitis, malnutrition and smoking. Other causes readily excluded by history, examination or imaging include head trauma, frontal lobe or suprasellar tumors, normal aging, Alzheimer’s disease and Parkinson’s disease. Diminished taste may also occur with common viral infections and with smoking but is particularly common with certain medications; for instance, most MS patients have noticed the bitter taste that occurs during the administration of high dose steroids to treat a relapse. Other correctable causes include vitamin B12 deficiency, zinc deficiency, and dry mouth either from medications or a disorder of salivary glands such as Sjogren’s syndrome.
So the next time someone tries to tell you that MS does not affect hearing, smell or taste pull out this blog and educate them. But never assume a problem affecting these senses is related to your MS without a thorough evaluation by your MS Specialist.
By Lori Ann Kostich M.S. CCC-SLP
Mandell Center for Multiple Sclerosis Treatment and Research
What is Dysphagia?
Persons living with Multiple Sclerosis (pwMS) may experience changes in their ability to swallow. The act of chewing food (mastication) may become more difficult, the actual act of swallowing may become more difficult, or it may become more difficult to comfortably chew and swallow certain foods. PwMS may experience symptoms of increased coughing during meals (“It went down the wrong pipe!”), having to “think” to begin the act of swallowing (after chewing), difficulty eating some foods because of dry mouth or difficulty eating some foods because the consistency of the food is too hard to chew. These symptoms of dysphagia may “come and go”, much like the symptoms of tingling or weakness in the arms and legs, leaving the pwMS to experience “bad swallowing days”. Or, the symptoms of dysphagia may be consistent, occurring daily at every meal.
The act of swallowing is a complicated process. Food must be mashed in the oral cavity (mouth) in preparation for swallowing. A bolus (the ball of mashed food) must be formed prior to the act of swallowing so the food goes down in one neat ball, allowing the food to pass throw the larynx and pharynx (the throat) in an organized manner. Sufficient strength in the tongue base is needed to propel the bolus down the esophagus (pipe to the stomach), gravity is not enough. Three valves must open and close in a timely, coordinated manner to allow for smooth passage of the bolus to the esophagus. Breakdown in any of the components listed, or a change in timing of the movement of the component can lead to symptoms of dysphagia. Cranial nerve involvement (decreased innervation of the tongue and structures in the throat secondary to lesion placement) as well as muscle weakness can contribute to the breakdown.
Coughing is not always a negative symptom of dysphagia. Coughing is a defensive mechanism that the human body has to clear substances in our system away from somewhere it doesn’t belong. Coughing will occur when a person’s body senses that something inappropriate (saliva, mucus, food, liquids) is headed down the trachea (windpipe) towards the lungs. When coughing occurs, the hard expulsion is the protective part of the cough, blowing any bit of food or other item away from the lungs. The inhale of the cough is the part of the cough that requires care, inhaling too hard can pull the “bit of food or other item” just blown away from the lungs back into the lungs, resulting in penetration (the substance goes to the level of the vocal cords or above) or aspiration (the substance passes the vocal cords and goes into the lungs). Substances that move past the vocal cords into the lungs can cause respiratory infection (aspiration pneumonia). In the less impaired population, aspiration pneumonia is relatively infrequent, as the pwMS is up and moving around, helping the body can manage the substance. The risk of aspiration pneumonia increases when the pwMS becomes increasingly physically impaired. It is as the pwMS becomes less active that swallow function needs to be more closely monitored.
However, pwMS report unexpected, significant, frightening coughing episodes, which occur infrequently, but occasionally result in necessity of the Heimlich maneuver. These coughing episodes occur without warning, and may leave the patient fatigued for the rest of the day, or for several days afterward. These coughing episodes are scary for the patient, and any family or friends who witness the event. If one of these events occurs, the pwMS should contact the physician managing the care of the pwMS, to allow the physician to decide if the pwMS should come to the office to be examined and/or what follow up is appropriate.
What to do-Exercises
What to do-Compensatory Strategies
Bolus Control (Management of the food inside the mouth)
Oral management of food prior to the swallow (chewing) is important to maximize swallow efficiency and safety on all food consistencies and at all levels or fatigue. PwMS have been shown to have weaker lingual (tongue) strength and reduced rate of lingual motion on repetitive tasks, especially in the tongue base. How well the tongue works can affect how efficiently the food is moved around in the mouth while it is being chewed to a soft, mushy consistency prior to swallow. How well the tongue works is also important as strength and timing of lingual function is critical to initiating the swallow in a coordinated manner, leading to the bolus moving past the opening to the lungs and into the stomach safely. Decreased lingual strength or coordination can lead to difficulty swallowing muscle meats (beef, chicken, pork), lettuces, foods with skins (apples, grapes), small foods (peas, corn, rice, nuts etc) and foods of mixed consistencies ( soups, pizza, sandwiches with many different ingredients etc).
What to do-Exercises
1. Tongue sweeps- sweep the tongue around the outside of the upper teeth, from molar to molar. Move the tongue across the teeth from right to left, then back from left to right. Repeat 15 times (or work up to 15 times, this can be tiring). Why? Being able to move the tongue accurately and completely throughout the oral cavity is necessary to manage food as its being chewed. This is a range of motion exercise to targeting this function.
2. Repeat the tongue sweeps around the lower teeth. Work up to 15 repetitions.
3. Tongue –in-cheek- Push the tongue hard against the inside of the cheek (like trying to push a hoe through it. First on the right, then on the left. Repeat 15 times. Why? Same reason as the tongue sweeps, good tongue motion can help manage the food as it’s being chewed.
What to do- Compensatory Strategies
1. Double Swallow- The oral cavity (mouth) should be clear after each bite of food is swallowed. If it is not, a second swallow may be needed to clear all the food from the mouth.
2. Liquid wash- The mouth should be clear after each bite of food is swallowed. If it is not, a small sip of liquid may be needed to clear all the food from the mouth after the swallow.
Dry mouth can also affect management of the bolus in the oral cavity. Many medications that are frequently and successfully prescribed to treat other symptoms associated with MS (bladder/bowel dysfunction and some medications for depression) have dry mouth as side effect. Having reduced saliva limits the pwMS’ ability to keep the bolus moist inside the mouth and allow the bolus to flow smoothly out of the mouth towards the stomach. Add to this the possibility of some tongue base weakness and the act of swallowing can break down and coughing or having to swallow multiple times for each bite of food. A symptom like dry mouth can make eating foods like pasta, bread, rice, muffins, cookies, or doughnuts difficult.
What to do- DO NOT STOP TAKING PRESCRIPTION MEDICATIONS INDEPENDENTLY. Medications are prescribed to provide a benefit, to treat some issue. Unfortunately, some medications come with side effects. It then becomes a decision to be made by the patient and the physician whether to stay on the medication, discontinue the medication, switch to another medication, or manage the side effect. Dry mouth is a side effect that can be managed.
What to do- Compensatory Strategies
1. Adjust diet to eat foods high in fluid content (melons or other fruit, soups)
2. Add moisture or fluid (dunk breads in coffee/tea/milk, add gravy to meats, dunk meats in apple sauce, add copious condiments to hot or cold sandwiches, add jelly or butter to breads/muffins), to make the bolus less dry.
3. Bite – sip- chew- mash- swallow- This means take a bite of whatever food, take a small sip of liquid AT THE SAME TIME, chew and mash it all together, then swallow. The goal is to make the bolus in the mouth as mushy as possible. A mushy bolus will slide down better than a dry bolus.
Referral to a Speech Language Pathologist
Speech Language Pathologists evaluate, develop treatment plans and train exercises to reduce the symptoms of dysphagia (swallowing problems).Initial referrals should be made for an evaluation by a Speech Language Pathologist to be evaluated in an outpatient setting because some swallowing difficulties such as providing training to address dry mouth can be treated in the office setting. At that visit, the Speech Language Pathologist can request additional objective tests be performed such as a Modified Barium Swallow Study (MBS or MBSS) or a Fiberoptic Endoscopic Evaluation of Swallowing (FEES). Referral for a dysphagia evaluation by a speech language pathologist should be made when the pwMS:
Every pwMS with an EDSS of 7.5 or higher should have a yearly swallow evaluation.
What happens during a dysphagia evaluation by a Speech Language Pathologist?
During a dysphagia evaluation the pwMS will be asked a series of questions about what the specific problem with the swallow is, medical history, and what medications being taken. An oral motor examination will be completed, which means the SLP will look at how the structures in the mouth move (such as lips and tongue), how prompt the pwMS can produce a single dry swallow (with no food) and how strong the pwMS can produce a cough. Sensation (numbness) will be checked on the lips, tongue, and the inside and outside of the cheeks. The pwMS will then be asked to eat foods of various consistencies, such as water, pudding, soft fruit, crackers and or bread. The Speech Language Pathologist will watch the pwMS eat, and look for the potential reason for the concerns/symptoms the pwMS has. A treatment plan will then be developed that may include exercises (the tongue is a muscle just like the bicep, it can be exercised) compensatory strategies or follow up instrumental/objective evaluation (MBSS or FEES). The pwMS will be expected to apply the recommendations made by the Speech Language Pathologist and report if there is improvement in swallow function at home or in restaurants.
What is a Modified Barium Swallow Study (MBSS)?
A MBSS is an objective swallow study that evaluates a pwMS’ swallow by watching the swallow happen on moving x-rays that takes pictures of the swallow in real time as the swallow happenes. The pwMS will be asked to drink and eat different consistencies of food and liquid that have traces of barium or other substance that will show the organization and movement of the bolus as it moves through the oral cavity and into the throat (pharynx) during the swallow. The MBSS is run by a radiologist and a Speech Language Pathologist. The Speech Language Pathologist will be looking at organization of the bolus, lingual motion and motion of the muscles in the throat to try to identify the reason for the patient’s concern/symptoms. Unfortunately, since the MBSS is a “snapshot” of a series of single swallows, if significant coughing is the reason for the referral, it may not happen on the day of the MBSS which may be frustrating for the pwMS, it is important not to try to “create” the symptom. A report will be written and sent to the treating Speech Language Pathologist, who can then adjust the treatment plan as appropriate.
While participating in the MBSS, the pwMS should ask to see the pictures. Ask to have the screen turned, and have the images explained. Most Speech Language Pathologists are happy to do this and answer any questions, but do not always think to do so. Seeing how the food is moving through the mouth and throat, and being able to see where “breakdown” in the swallow can happen will make the swallow less of a mystery and less concerning.
Search MBS/MBSS/Swallow Study on YouTube- a number of individuals have posted their own results for everyone to see.
What is a Fiberoptic Endoscopic Evaluation of Swallowing (FEES)?
A FEES is an objective swallow study to evaluate a pwMS’ swallow in real time by passing a camera through the nose, and “parking” the cameral at the level of the roof of the mouth (this is NOT the type of endoscopy where the camera is passed down to the stomach or into the lungs). The pwMS will be asked to eat and drink different foods of different consistencies of food and liquids. This is regular food, though the liquids will be tinted with food coloring to allow for better visibility to the camera. During this type of swallow study, the Speech Language Pathologist can watch the passage of the food and liquid through the video camera and see how the food moves over the back of the tongue and whether there is pooling or residue left anywhere in the swallow after the swallow. The Speech Language Pathologist is looking for any issues that would cause the patient’s complaints or concerns. This type of study is a “snapshot” of a pwMS’ swallow function, though it can continue longer than an MBSS due to the fact that there is no radiation involved. A FEES may be better suited to some patients who report that symptoms begin as a meal progresses, maybe as fatigue sets in. A pwMS should never try to “create” the symptom. The evaluating Speech Language Pathologist will generate a report that will be sent to the treating Speech Language Pathologist who can then adjust the treatment plan as appropriate.
When participating in a FEES evaluation, the pwMS should ask to see the pictures and the images of the swallow study. It helps in understanding what is happening during the swallow if the pwMS can see how the food is moving and where “breakdown” may be happening.
Search FEES on YouTube- there are studies posted for everyone to see.
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DePauw, A., Dejaeger, E., D’hooghe, B., and Carton, H. (2002). Dysphagia in multiple sclerosis. Clinical Neurology and Neurosurgery, 104, 345-351.
Klugman, T, and Ross, E. (2002). Perceptions of the impact of speech, language, swallowing, and hearing difficulties on quality of life of a group of south African persons with multiple sclerosis. Folia Phoniatr Logo, 54, 201-221.
Robbins, J., Coyle, J., Rosenbeck, J., Roecker, E., and Wood, J. (1999). Differentiation of normal and abnormal airway protection during swallowing using the penetration –aspiration scale. Dysphagia, 14, 228-232.
Stierwalt, J., Hancock, A., Lapointe, L., Apel, L., and Maitland, C., (2007). A longitudinal analysis of tongue function: Parkinson disease and multiple sclerosis. ASHA Convention Handouts 2007.
Tecfidera is a good treatment for relapsing MS; it is orally administered, tolerated well by most and significantly reduces relapses, new MRI lesions and residual disability; but it is not a risk free treatment and does require monitoring. This point became more than a hypothetical concern this week when Biogen Idec (the maker of Tecfidera) reported the first case of PML in an MS patient participating in one of their Tecfidera clinical trials.
PML (Progressive Multifocal Leukoencephalopathy), of course, is a dreaded complication of Tysabri therapy, a remarkably effective MS treatment also manufactured by Biogen Idec. There had been prior cases of PML in patients receiving fumarate esters very similar to Tecfidera (these are available in Europe to treat psoriasis), but in each case Biogen Idec suggested there was another potential explanation. It seems that the common thread tying all cases together is the continuation of treatment despite the development of persistently low lymphocyte counts. The most recent person with MS developed PML after 4 ½ years of low lymphocyte counts (ranging from 200 to 500). More importantly, there were no other potential explanations for PML in the most recent case.
So what information do you need to remember going forward if you are taking or planning to take Tecfidera?
1. Mean lymphocyte counts will decrease in the first year of treatment with Tecfidera by 30 % and then stabilize. Most reductions are minimal with lymphocyte counts remaining above 1000 but 6 % of patients will experience lymphocyte counts less than 500. The drop in lymphocyte count may be larger in those people who also received prior immunosuppressant therapy and prior immunosuppressant therapy likely creates a higher risk of PML . If you experience a persistent drop in Lymphocyte count below 500 (lasting more than 6 months), especially if you previously received immunosuppressant therapy (cyclophosphamide, mitoxantrone, methotrexate, azathioprine, alemtuzamab, Rituximab, mycophenolate, long term chronic steroids), you should discuss the pros and cons of stopping Tecfidera with your MS specialist.
2. You should have a baseline complete blood count (CBC) before starting Tecfidera, which is repeated every 6 months. This is already recommended. If Lymphocyte counts drop below 900 you should be monitored more frequently, perhaps every 3 months.
3. Lymphocyte counts will increase quickly (over a month) after stopping Tecfidera but may not return to normal levels.
What information do we need to learn about Tecfidera to minimize the risk of PML and other potential complications related to a low lymphocyte count?
1. What lymphocyte subsets are affected? There are many different types of lymphocytes with different roles and responsibilities. A prior study suggested that Fumaric acid esters preferentially lower CD8 positive lymphocytes. This would be important since research in HIV patients suggests that a strong cytotoxic response driven by certain CD8 positive lymphocytes against the virus causing PML protects HIV patients against PML. I plan to start testing these lymphocyte subsets in my patients on Tecfidera to help in decision making going forward.
2. Are JC virus antibody test results helpful in determining risk of PML? So far there is no evidence that the JCV antibody results are useful as a risk factor in Tecfidera treated patients. Since many patients are known to harbor the harmless form of the JC virus despite negative JC virus antibody results, I have no intention of using this lab result to make treatment decisions on Tecfidera without further research.
3. How long does it take for PML to develop in patients on Tecfidera and how common is PML in patients on Tecfidera? The most recent case of PML was taking Tecfidera for 4.5 years and the prior European cases on fumaric acid esters were either on prolonged treatment or with prolonged lymphopenia (low lymphocyte counts). This is consistent with the experience in Tysabri treated patients where the risk of PML rises after 2 years of treatment, especially in those patients at risk. Based on the current world wide experience it is unlikely that the risk of PML in the first 2 years of treatment with Tecfidera will exceed 1 in 10,000 treated patients; a very rare risk. What is not known is whether the risk of PML increases over time in Tecfidera treated patients and assumes a higher risk profile with prolonged use.
4. Are there other potential complications of Tecfidera that are not apparent yet simply because not enough patients have been on the drug long enough. Biogen idec reports that there may be 70,000 to 100,000 patient-years of therapy at present (50,000 patients treated for 2 year each equals 100,000 patient-years of therapy), but the vast majority of patients have been on treatment for less than 24 months. Although patients with psoriasis have been treated with fumaric acid esters for decades, few of these patients stayed on long-term treatment. Therefore, we do not yet know the long-term risks of Tecfidera treatment and must remain vigilant in our monitoring over time. It is too early to tell if the incidence of serious adverse outcomes increases after more than 2 years of treatment.
The take home lesson is to learn and remember that there are potential risks with all treatments, both prescribed and homeopathic. It is the magnitude of the risk that is important and, so far, PML seems to be a rare outcome in people with MS on Tecfidera.
Blog written by Revere Kinkel MD and reviewed by A Scott Nielsen MD, Benjamin Greenberg MD and Deborah Backus PT PhD
This week has been very busy, beginning with an NMSS society sponsored program in Boston to introduce MS Fellows (those being formally trained to become MS specialists) to the unique issues and concerns of people with advanced MS. Following my opening remarks and those of David Rintell, a wonderful psychologist in Boston at the Partner’s MS program, we were treated to a panel discussion with 4 caregivers of people with advanced MS. Three of the caregivers were spouses of a person with MS and the remaining person with MS was cared for by her mother and sister-in–law.
The challenges and stresses of their day-to-day existence was palpable in their demeanors and their frequent pauses to fight back tears and collect themselves before proceeding with their monologues. Each described the immense difficulty of accomplishing what to us is considered the most mundane of tasks; rolling their loved one over in bed, sitting them up, transferring them to a chair, standing them at the toilet, balancing them upright while pulling down their pants to sit on the toilet, cleaning and dressing them. Each described in vivid detail how dressing and toileting alone consumed a minimum of 2 hours every morning of their lives.
Some of these caregivers did not qualify for personal care assistance because of their income level and never received any respite from their responsibilities; those that did qualify rarely experienced any significant respite or relief from their burden since they knew that no one could or would do as good a job as they are able to do. All of the caregivers acknowledged that their relationship with their loved one was no longer the same; as the disease advanced their loved one became dependent on them entirely and their prior partnership was no longer equal; changes in cognition and behavior often strained relationships further. Yet they persisted years on end caring for them, because they loved them. None could conceive of placing their loved one in a nursing home but all knew that a day could come when a nursing home was inevitable.
I myself found it difficult to fight back tears while listening to their descriptions of daily life. At the end of the session, I asked each of them what would make their lives better. All of them felt that they needed more skilled caregiver assistance and support. So let me throw out an idea that may help us reach this goal; besides lobbying state governments for broader qualification criteria for personal care assistants (PCAs), I think caregivers should use a website like ours to develop requirements for PCAs, create a pool of PCAs in your region meeting these requirements (MS certified PCAs) that can be shared for MS care and use this site to communicate with each other to provide support and advice. We already have a caregiver blog but I think the MS HealthAllies site that will launch in the near future will also help with this endeavor. (if you haven't already signed up for the MS HealthAllies beta test please do so here...Click Here To Sign Up For MS HealthAllies Beta Test
If you have any thoughts or ideas on this issue please share them with us.
Lastly, the next time you meet someone who cares day in and day out for a loved one in the home, regardless of whether they have MS, give them a big hug. This little bit of support and affection does really help.
-Rip Kinkel, MD
I was reminded today at our weekly department grand rounds of an extremely important topic that MS specialists often forget; the benefits of folic acid supplementation in pregnancy age women. We spend so much time discussing the use of disease modifying therapies in pregnancy that we often forget about other equally common and well-known risks. It has been known for decades that folic acid supplementation in doses above 0.4 mg per day reduces the risk of neural tube defects such as spina bifida. What women often do not know is that by the time their pregnancy is confirmed, it is often too late to start this supplementation, since neural tube closure is an early event in embryogenesis (first 25 days). More importantly, at least 40 % of pregnancies are not planned in advance.
Why is this topic so important in woman of childbearing ages with MS? Well, one of the most common class of medications used to treat MS related symptoms are the anti-epileptic drugs (AEDs) such as gabapentin, valproic acid, carbamazepine, lamotrigine, phenytoin, primidone and topiramate. We use these drugs to treat MS related pain syndromes, migraine headaches, mood disorders and even the main disorder for which they were developed, seizures. This class of medication, particularly valproic acid, has been associated with a number of major congenital malformations (MCM) and, more recently, disorders affecting behavior and learning including autism spectrum disorders. The risk is even higher with use of more than one of these medications at a time. While most of the data supporting the association of certain AEDs with birth defects come from Epilepsy Pregnancy Registries, there is little reason to believe that this data would not apply to women using these medications for other indications.
The reason for the increased risk of birth defects is clear with certain enzyme inducting AEDs such as phenytoin, carbamazepine and the barbiturates (primidone and phenobarbital), all of which cause a reduction in folic acid levels. For valproic acid it has been suggested that the drug interferes with folic acid metabolism. Other more recently introduced AEDs such as gabapentin, lamotrigine, oxcarbazepine and zonisamide have no significant effect on folic acid metabolism and the data on MCM is mixed. Yet most epilepsy specialists recommend folic acid supplementation in all women taking these drugs.
So what should you do with this information if you are (a woman) women of childbearing potential regardless of whether you are on birth control? (Birth control can fail)
While the use of folic acid supplementation will not guarantee a child without birth defects, you can at least know you are doing something to reduce this risk. If you have daughters or grandchildren of childbearing ages, please pass this information along.
-- Rip Kinkel, MD
In order to maintain normal vision your nervous system has developed an extraordinary ability to keep viewed objects of interest focused on the central region of your retina, called the fovea, both at rest and with motion.
If your eyes are involuntarily moving to and fro at too great a speed (a symptom called nystagmus) while you are attempting to focus on an object, your vision will be degraded. Often this blurring of vision is accompanied by the illusion that the environment around you is moving.
We call this sensation oscillopsia and it is often accompanied by a loss of equilibrium. These problems are quite common in MS patients and often left untreated. The more severe forms of nystagmus in people with MS (called acquired pendular nystagmus) are easy for an observer to recognize since one or, more often, both eyes are constantly moving in a pendular or elliptical pattern. Subtle forms of acquired nystagmus or difficulty maintaining visual fixation with motion (caused by an impaired vestibule-ocular reflex) are more difficult for an observer to see, but can still significantly degrade vision and cause oscillopsia with motion (walking or driving or turning the head) or certain positions of the eyes (looking to one side or the other).
The goal of management is to reduce visual blurring or oscillopsia by slowing down the speed of the nystagmus or compensating for the abnormal eye movements. Those individuals with an impaired vestibulo-ocular reflex without spontaneous nystagmus (vision degraded only with head motion or movement) must maintain head and object (words) stability during tasks such as reading. General management of all forms of nystagmus begin with use of stabilized large print for viewing. Patients with markedly asymmetric nystagmus may benefit from patching the eye with the greater movement.
A number of medications are partially effective in slowing down the speed of nystagmus and improving vision. All of these medications are worth trying if your nystagmus is significantly affecting your vision.
Other forms of nystagmus in people with MS are less often associated with persistent degradation of vision or oscillopsia; but if treatment is required, I would recommend the same trial of medications.
For intractable nystagmus that does not respond to drug treatment there are several treatment options, but few of these options are tolerable or readily available in most communities. Optical devices (thick contact lens) that negate the visual effects of nystagmus (high-plus spectacle lenses in combination with high-minus contact lens) were pioneered by my former colleague in Cleveland, Dr. John Leigh, but were never well tolerated by most patients.
Several years ago I heard that electro-optical devices were being developed to measure and record the abnormal eye movements constantly and use real time image shifting technology to maintain object fixation. I am not sure where this technology stands at present, but it would certainly be an interesting technology to incorporate in the future development of “Smart Eye Wear” devices. Some investigators have used botulinum toxin injected into the extraocular muscles (those that move the eyes) to treat refractory nystagmus, but this effects normal movement of the eyes (causing double vision) and lasts only for a few months.
-Rip Kinkel, MD
ECTRIMS Meeting Boston MA
As I return to Boston for the start of the largest international MS meeting of the year, my thoughts have turned to the many wonderful resources that were and still are available to patients and their families in this area. From the many comprehensive MS Centers to the outstanding universities and research labs, Boston is truly an amazing place for people with MS. But one additional Boston area resource that is available in very few other locations around the country and often helpful to the many women with MS is a store in Brookline called Good Vibrations.
As the name suggests, some may call this a sex shop but it is unique among enterprises of this nature with it’s attention to the needs of women (as well as LGST couples) and it’s focus on education. The staff are provided with extensive training and I’ve never heard of customers feeling uncomfortable with either the location or the store atmosphere. I’ve even heard of mothers and daughters visiting the shop together. Their emphasis on education is remarkable with a staff sexologist, Carol Queen PhD, available. In a world where the management of sexual dysfunction seems confined to improving erections in men, and medical doctors are still of little help to women with sexual dysfunction, it is good to know that there are resources available to women with these problem.
There are Good Vibration stores also available in San Francisco, California although I have no personal knowledge of these stores. If you know of similar resources available in your community, please comment so we can post this information for other patients and families.
So with the ECTRIMS meeting now underway, take some time out to visit Good Vibrations if you live in the area and you think this may help. After all, a healthy sex life has been shown to benefit fatigue, pain, sleep disruption, mood and well being.
I will now return to the meeting and provide updates later this week or next week on new management strategies that may be of benefit to you now or in the near future.
308 Harvard St
Brookline, MA 02446
-Rip Kinkel, MD
Here is My Question:
I have RRMS. I don't want to take medications. What's the biggest risk if I don't?
Disease modifying therapies (DMTs) for MS are 1) expensive, 2) associated with a variety of side effects and potential safety risks, and 3) are partially effective. With this understanding, your question is one I hear frequently in clinic. The major risk of deferring DMT for relapsing-remitting MS is an increased likelihood of clinical relapses in the future that can disrupt your day-to-day function, and short- and long-term disability. Let me explain…
We have a great deal of natural history data on MS (this is information on the average experience of patients with MS who were not exposed to therapy). This information is available to us because it wasn’t until the mid-1990’s that we had our first approved DMT for clinical use. What we have learned is that patients with early and frequent clinical relapses are at a higher risk of developing walking disability (for instance, the average individual with greater than 5 clinical attacks in the first 2 years of MS will need a cane to walk by 6 to 7 years into their disease course; while the average patient with 0 or 1 clinical attack will need a cane by the 20 year mark). We have also learned that the initial MRI brain scan after the first clinic event of MS can tell us about the likelihood of disability in the future—the more scars of MS that are seen on this first scan, the greater the probability for disability sooner rather than later. Keep in mind that these numbers reflect MS patients who did not have DMT options.
At the time of this blog post, we have ten FDA-approved DMTs, with more being reviewed. In nearly every case, these therapies have repeatedly shown effectiveness in 3 main measurements: 1) less clinical relapses or attacks compared to placebo, 2) reduced number of new, enlarging, or enhancing scars on the brain MRI scan, and 3) a reduction is short-term disability compared to placebo.
Critics have long pointed out that the DMTs are not cures, are expensive, have variable safety risks, and have not been proven to make a difference in the long-term. While it is true that all DMTs are partially effective—meaning that the data does not show that they cut down new relapses, MRI lesions, and disability by 100%—they have recently demonstrated effectiveness in the long-term. In 2012, a paper was published in the journal Neurology that presented long term follow-up data on the first approved DMT called betaseron. This 21-year study followed the originally randomized study participants (an early treatment group that was randomized to betaseron from the beginning, and a late treatment group that comprised individuals that were originally randomized to placebo but were given the opportunity to take betaseron after the initial clinical trial ended 3 years later). This paper showed that there were more people alive from the early treatment group 21 years later compared to those in the late treatment group. You can read more about this at http://msj.sagepub.com/content/19/5/522.full. This study confirmed our suspicions that DMT does help in the long term and does underscore the need to treat early rather than waiting—because there appears to be a window of opportunity to alter the course of the disease for the better.
Many of the barriers to initiating a DMT for relapsing-remitting MS patients have been removed. There are financial and co-pay assistance programs in place to make DMTs affordable for patients, risk mitigating protocols for DMTs, and experienced MS clinicians that can help you in choosing a reasonable DMT that can fit your goals and lifestyle, and outline a plan to make sure the medication is doing what we expect it to do and make it tolerable for the patient.
While the majority of my patients ultimately decide to start a DMT after considering this information, some choose to defer treatment. That is certainly each individual’s prerogative. Before making the decision, everyone should recognize the fact that we do not yet have a therapy that can reverse or repair tissue damage already incurred due to MS inflammation, nor do we have a therapy at the moment that reverses sustained disability. What we are left with are DMTs whose purpose is to get in front of the disease and impact it for the better, and hopefully avoid significant disability in the future.
The medical information and opinions on this site are provided as an information resource only, and are not to be used or relied on for any diagnostic or treatment purposes. The information and opinions expressed do not create any patient-physician relationship, and should not be used as a substitute for professional diagnosis and treatment. Please consult your health care provider before making any healthcare decisions or for guidance about a specific medical condition.