It is time to start talking about MS prevention and treat your relatives...

We’ve known since the 1980’s that the risk of MS among first-degree relatives (a genetically related child or sibling of a person with MS) is 2-5%. Initially, we did not know if there were factors, preventable or not, conferring either a higher or lower risk of developing MS. Because of this we tended to reassure these families with the knowledge that at least 95% of their offspring or siblings would not develop MS (excluding identical twins).  Accumulating evidence of genetic and environment risk factors for MS over the past 20 years strongly suggests that the risk of MS in certain family members may be considerably higher than the quoted 2-5%.  For this reason and the mounting evidence that the incidence of MS may be increasing in some population groups, we believe it is time to begin talking about MS prevention.

As a starting point, it is important to remember that the 2-5% risk of MS among first-degree relatives of MS patients is an overall average risk, not a particular individual’s risk.  To understand this better let’s consider an example of a theoretical disease that occurs in 1 out of 1000 people or 0.1% of the population. Overtime we may learn that 1 out of 100 first-degree relatives get the disease or 1%. This is useful information (i.e. a 10 fold increased risk over the general population) but perhaps not actionable. If we then learn that 25% of first degree relatives with a particular genotype and exposure to a particular virus develop the disease and only 0.2% of the first degree relatives without this profile develop the disease, you now have information that can be acted upon.

The situation with MS is approaching this level of understanding. To know the individual risk of MS in a first degree relative requires knowledge of the family member affected, when they were affected (younger or older age), environmental risk factors (read below) at different exposure ages, genetic background, the incidence of MS in the area the individual grew up in, and possibly an assessment of particular biomarkers (typically from a test done on a sample of blood, urine or spinal fluid) measured over time.  Knowing this information can allow clinicians to develop a risk profile for an individual. In fact, Dr. Philip De Jager and his colleagues at Harvard are working on the development of this type of platform. Based on the profile of an individual family member, it is likely that their risk of developing MS could vary from < 1% to as high as 25%. The actions this individual or their parents would be willing to take to minimize this risk of MS will obviously depend on both the risk of developing MS and, more importantly, the risk that their MS would be particularly severe. Future studies will hopefully allow us to assess both risks.

But what can we do at present without this multidimensional data to guide us? Since we cannot do anything at present about inherited risks, it is important to focus on modifiable risk factors.  It is our opinion that there is enough information currently available to help decrease the risk of developing MS among first-degree relatives by simply managing the following known risk factors:

1. There is significant epidemiological evidence that Vitamin D deficiency is associated with a higher risk of developing MS. This risk may begin even before birth based on evidence that MS is more common among children born in winter months when UV light exposure and 25-hydroxy vitamin D levels (25(OH)D) are at their lowest.  There is also significant evidence that vitamin D3 supplements in pregnant woman, young children, adolescents and adults are safe in doses much higher than currently recommended by the institute of medicine (IOM) or American College of Gynecology and Obstetrics (ACOG).  Although there are no controlled studies demonstrating that vitamin D3 supplements decrease the risk of MS or the level of 25(OH)D (this is what doctors measure in the blood when they check your Vitamin D level ) that must be achieved to decrease this risk, we do have some information to guide us. First, a woman planning pregnancy or pregnant with an unborn child that has a first degree relative with MS (either the mother herself, the father or a sibling of the unborn child has multiple sclerosis) and a 25(OH)D level less than 20 ng/ml (or 50nmol/lt) is Vitamin D deficient by all criteria and requires high dose supplementation with at least 50,000 IU per week of vitamin D3 or equivalent daily dosing (5,000 IU vitamin D3 or greater per day) with a goal of rapidly achieving a 25(OH) D level > 40 ng/ml (100 nmol/lt).  We recommend that pregnant woman with levels between 20 and 40 ng/ml (50 to 100 nmoles/lt), supplement with 4,000 to 6,000 IU per day of vitamin D3 to achieve these same 25 (OH) D levels (greater than 40 ng/ml (or greater than 100 nmol/lt) ) although many will require doses over 6,000 IU to achieve these vitamin D levels. Those with levels greater than 40 ng/ml (100 nmols/lt) prior to supplementation should take 2,000 IU of vitamin D3 during pregnancy. Once born the first-degree relative of an MS patient will continue to require vitamin D3 supplementation based on weight. If the average amount required for an adult is 5,000 IU (50 kg) then a 5 kg infant requires one tenth this dose or 500 IU of vitamin D3 per day. Of course, sunlight is also a source of vitamin D3 during the summer months but there is some evidence that sunlight exposure is no longer achieving the desired 25(OH)D levels. Therefore, it is important to maintain vitamin D3 supplementation unless it is demonstrated that you are able to maintain levels greater than 40 ng/ml year round.  The important point is to take enough Vitamin D3 supplement to maintain target levels greater than 40 ng/ml. To do this will require periodic blood tests to check 25(OH)D levels.

2. A recent meta analysis of 14 studies shows that being a smoker at any time increases the risk of MS by 50% compared to never smoking. This effect seems to be dose dependent (among and duration of smoking) and particularly strong in adolescence or early adulthood. Although smoking is on the decline there is a disturbing continued tendency for children, adolescents and young adults to experiment with smoking. It is extremely important for children and young adults who have first-degree relatives with MS to learn that any smoking must be avoided. This includes second hand smoke among other individuals in the household.  The American Lung Association has an on line program called, “Freedom from Smoking” that is a good starting point for individuals interested in achieving this goal. It is also adapted to both adolescents and adults.

3. More recent evidence suggests that obesity is associated with the risk of developing MS. This risk is particularly strong if you inherit HLA haplotypes (genes) associated with MS. Therefore, diets and exercise programs to improve aerobic fitness and decrease excess weight are important not only for MS patients but essential for first-degree relatives of MS patients.

Let us hope that by instituting these preventative measures we are able to not only decrease the risk of developing MS among your at risk relatives but also decrease the severity of the MS that may still develop in these family members. The next step will be the development of vaccines to control Epstein Barr Virus or mitigate the long-term effects of EBV infection.

-Ben Greenberg, MD, MHS and Rip Kinkel, MD

Benjamin M. Greenberg, MD, MHS
Director, Transverse Myelitis, Neuromyelitis Optica and Pediatric Demyelinating Disease Programs
Director, Neurosciences Clinical Research Center
Department of Neurology and Neurotherapeutics
Department of Pediatrics
UT Southwestern

“The main facts in human life are five: birth, food, sleep, love and death.”
― E.M. Forster

“I wonder why I don't go to bed and go to sleep. But then it would be tomorrow, so I decide that no matter how tired, no matter how incoherent I am, I can skip on hour more of sleep and live.”
― Sylvia Plath, The Unabridged Journals of Sylvia Plath  

Why do we so often forget how to sleep, as we grow older?  Even without a chronic disease like Multiple Sclerosis our lifestyles and the changes to our body with aging conspire to interfere with restful sleep. Ask any woman going through menopause about their sleep and you will hear frustrating tales of awakenings for a variety of reasons many unexplained.

Even well before the onslaught of middle age, our lifestyles become a hazard to sleep; we find ourselves with too little time between work and family responsibilities to take proper care of themselves. We stop exercising regularly, eat poorly, worry excessively and consume various drugs, some prescribed and others like alcohol and nicotine used to melt away our stresses and the burdens of feeling overwhelmed. Bad habits are formed early and persist. 

As the quote by Sylvia Plath (by the way she is not a good person from whom you should take advice regarding sleep) implies, from a young age we learn to burn the midnight candle too often and attempt to emulate those who never seem to require sleep. As people grow older they often develop strange beliefs or habits that actually worsen their sleep; some come to believe that they cannot fall asleep without the TV on or without a sleep aid and never attempt to adjust their sleep behavior. Often the problem is simply a result of a chronically disrupted circadian rhythm, yet the person insists it is simply impossible for them to fall asleep before 2 or 3 am. For people with MS, the problems with sleep are all too often blamed on the disease and simple measures are not attempted to control the insomnia before resorting to sleep aides or treatment of MS related symptoms perceived to be interfering with sleep.

The cure for insomnia in MS patients and the excessive daytime sleepiness that it creates begins with the doctor taking a good history and patient being receptive to changing their current sleep behaviors. First, without excessive daytime sleepiness there is rarely a problem that requires treatment. Some people just require less sleep as they grow older; fewer still never require much sleep, yet never experience problems with feeling excessive sleepy during the day. 

With this caveat in mind it is often useful to separate sleep problems into three categories: those associated with sleep onset insomnia, those associated with nocturnal awakenings and those without perceived insomnia or awakenings but clearly creating excessive daytime sleepiness.

Sleep onset insomnia (failure to get to sleep initially) is most often due to acute stressors, anxiety, depression (unipolar or bipolar), drugs (e.g. alcohol, stimulants including nicotine), eating large meals too late, pain, spasms when lying supine, restless legs syndrome or a disrupted circadian rhythm. These problems tend to be easy to identify and solve although they often require a willingness to change sleep behaviors (see list below). Medication to help with sleep onset insomnia is sometimes needed but only for short-term use. Long term use of medications to help with sleep should only be used after a complete evaluation.

The same problems associated with sleep onset insomnia may also be responsible for awakenings during sleep, although the list becomes even longer with the inclusion of nocturnal awakenings to urinate because of bladder dysfunction, the co-existence of other medical conditions that interfere with sleep (Diabetes, lung disease, congestive heart failure etc.) and nocturnal hypoventilation in more severely disabled MS patients.

The third category, excessive daytime sleepiness without perceived awakening, is often the result of a primary or secondary sleep disorder (obstructive sleep apnea, narcolepsy, nocturnal myoclonus, periodic limb movements of sleep) although your sleep partner is often able to provide the key history of snoring, suddenly disrupted breathing or leg movements that interfere with their sleep! Nocturnal hypoventilation can also present with feeling un-refreshed, confused and anxious on awakening because of not getting enough oxygen during sleep.

As you have probably guessed by now, there is rarely one cause for your interrupted sleep and excessive daytime sleepiness.  MS itself is often associated with daytime fatigue, a similar concept, but patients rarely describe this “fatigue” as the kind of daytime sleepiness one experiences after a bad night of sleep. Instead, MS fatigue is usually described as malaise, lassitude or an inability to move or think further without rest, more often without the craving to sleep during the day. The difficulty in diagnosis arises when a person experiences both daytime primary MS related fatigue and excessive sleepiness from disrupted sleep.

So how should you manage your disrupted sleep? First, determine if your circadian rhythm is disrupted. This is usually obvious if you chronically find yourself unable to sleep until the middle of the night and then feel exhausted during the day because of the need to get up sooner than you would like. You will need to follow the advice listed below to improve your sleep hygiene but you may also need help in resetting your body’s clock; some people find success in resetting their clock by taking 3 mg of melatonin (an over the counter medication available at almost any pharmacy or supplement store) 2 hours before you would like to go to sleep. If this does not work after a week discuss the problem further with your physician. Rarely, a sleep specialist is needed to help people with chronic idiopathic (meaning unknown cause) insomnia. Next, you will need to adhere to the following steps to improve your sleep hygiene. This can be surprisingly difficult since many of us break these rules with regularity.

• Avoid long periods of inactivity during the day (example: sitting for more than 2 hours) if possible; get up and take a walk or walk somewhere for lunch if you are able; try to follow a strenuous exercise routine 5 days a week but no less than 3 days a week once cleared by your physician for this activity. You may benefit from working with a physical therapist or trainer to accomplish this goal

• If taking stimulants for fatigue (examples are modafinil (Provigil), amphetamines (Adderall), methylphenidate (Ritalin)) try to cut down or eliminate any doses taken after the morning. If taking other medications that interfere with sleep like medications for asthma, talk to you doctor about adjusting the dose or substituting another medication, if possible

• If taking away doses of stimulants increases your level of daytime fatigue, take a short nap during the day and adjust your activities (including work schedule) accordingly. This may require consultation with your physician and an occupational therapist to assist with activity adjustments.
  

• Relax in the evening at least an hour or two before bedtime. Meditation is helpful if you have difficulty unwinding or relaxing. Avoid rehashing issues, going through events of the next day or discussing a high tension topic just before bed

• Avoid caffeinated beverages 6 hours before sleep, avoid alcohol 4 hours before sleep, and avoid nicotine an hour before bedtime

• If you are getting up in the middle of the night to urinate more than once, especially if you have difficulty getting back to sleep, consume your required daily fluid intact between waking and 4 hours before bedtime. You should discuss this problem with your physician if the problem persists. We usually can find a way to eliminate this problem.

• Eat no more than a snack and perhaps a small amount of warm milk before bedtime; consume heavy meals at least 4 hours before bedtime

• Avoid strenuous exercise in the evening; light yoga, stretching and sex is fine

• Follow a bedtime routine and stick with it

• Go to bed when tired; when ready to sleep make sure the room is dark and at a comfortable temperature with comfortable bed clothing. If you are a light sleeper, ear plugs and eye masks can be helpful

• Use the bedroom only for reading, sleeping and sex; remove the TV or do not watch it when you are trying to fall asleep.

• If you are unable to fall asleep after 30 to 45 minutes, get out of bed (if you can) and read or do something relaxing until you are sleepy and want to attempt sleeping again. Do not stare into the dark counting sheep or getting frustrated with your inability to fall asleep.  Similarly, if you awaken at night and are not able to get back to sleep in a reasonable amount of time, read until you are sleepy again. If you are able to do so, get out of bed and go to a different room. You do not want to associate being in bed with being unable to sleep.
  

Lastly, if your problem with sleep or excessive daytime sleepiness is not easily managed with these adjustments or you are unable to follow through with these suggestions because of your MS or other medical problems, you will need to discuss these problems further with your primary care doctor or MS specialist.  Common additional solutions may require treatment of depression, treatments of bladder problems to limit nocturnal awakening to urinate and treatment of pain and nocturnal spasms. A good sleep history should be obtained; it is often advisable to obtain a polysomnogram (also called a sleep study) and possibly an MSLT (multiple sleep latency test) if there is any suggestion of a sleep disorder or if attempts at treatment the insomnia fail to cure your excessive daytime sleepiness.

“Suenos con los angeles”

-Rip Kinkel, MD