Brain games

Low tech vs. hi-tech.

See the story on brain games:

- What do you think?

- What do you use?

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Recordings of LIVE Web TV

Recordings of LIVE Web TV: MS Town Hall Meetings and more at http://ustream.com/neurologique and http://www.neurologique.org and http://facebook.com/Neurologique

First Oral for MS: New idea, new leader

Congratulations Novartis AG (NVS), but more importantly:

Congratulations MS community.

As expected and anticipated, the FDA has granted priority review for Novartis's Gilenia (Fingolimod or FTY720) -- see:

http://neurologique.blogspot.com/2010/01/filing-and-timing.html

That leaves EMD Serono / Merck KGaA's Cladribine (Movectro/Mylinax) behind in refuse-to0file limbo. Of course, Gilenia leads Laquinimod (Teva), Teriflunomide (Sanofi-Aventis), and BG0012 (Biogen Idec).

So, let's countdown and wait for approval!

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

It's a tough time to have migraines

As if it's not bad enough having the pain of migraines, all these medical articles are coming out suggesting that people with migraines have a higher risk of heart attacks, stroke, claudication (peripheral artery disease), diabetes, hypertension, high cholesterol.

Migraines with aura were even associated with smoking.

So, how do we understand this paper: Bigal ME, et al "Migraine and cardiovascular disease: A population-based study"Neurology 2010; 74: 628-35. ?

Could migraine be an actual risk factor for these other problems?

Like always, let's look at several possibilities:

1. The association is incorrect -- this seems unlikely since multiple studies seem to show similar results, but there is always that problem of case ascertainment (how do you know who does and who doesn't have something).

2. The association is correct and there is something else that causes both the migraines and the other problems -- this is fairly likely.

3. The association is correct and migraines and cardiovascular disease/risk factors share a common genetic link (the genes contributing to them are close to each other in our DNA) -- this is also fairly likely.

4. The association is correct and migraines are caused by cardiovascular disease/risk factors -- so even though it seems that the migraines happened first, there could have been an underlying risk for the cardiovascular disease. This may be less likely since many people start having migraines very young and they don't (supposedly) have heart disease at that time, but couldn't there be something about their underlying genetic/environmental makeup that makes them destined for cardiovascular disease?

This is much more likely in the whole discussion of migraines and MS -- see:

http://neurologique.blogspot.com/2010/02/migraine-and-ms-lessons-for-ccsvi.html

Our analysis made WebMD and Medscape Neurology interested, see:

http://www.medscape.com/viewarticle/717267?src=emailthis

5. The association is correct and migraines cause cardiovascular disease/risk factors -- is it that the actual migraine disease process (inflammation on the covering of the brain [meninges]) causes cardiovascular disease? Alternatively, could it be that having migraines makes you more likely to have other (as of yet, immeasurable) habits that could predispose you to cardiovascular disease/risk factors? It would be difficult to explain the smoking association otherwise. Do we really think that migraine pathophysiology causes smoking? Couldn't it be that being a person with migraine (with aura) makes you want to smoke (maybe it relaxes you)? This is an example of how migraine can be associated with something but not cause it in the way we usually understand it.

So, we are stuck with more questions (as always), so what are our lessons?

Instead of focusing on how worried you should be about your migraines causing future health problems, you should take control over your own health and modify the cardiovascular risk factors that you can (you can't change age, sex or your family), such as smoking, blood sugar control, weight loss, cholesterol management.

The central principle of the Migraine and MS Team Approach Rule (M*STAR) is that YOU are the center of your own health team. That means you control your own destiny, but that also gives you great responsibility.

What can your doctors / neurologists learn from this?

When we see a patient with migraine, we should be sure to ask about cardiovascular risk factors and encourage you to modify them in order to maximize your potential and to work with you as a consultant for your M*STAR health team.

We need to keep this open dialogue among people with migraines and between people with migraines and their doctors. Don't forget your doctors probably have migraines too (especially neurologists and headache specialists). This is what My Grrr AYN (Migraine Association of Young Networkers) is all about.

Interestingly, establishing the association of migraine and cardiovascular disease raises the issue of our treatments and the potential for heart complications. Merck (MRK) is developing Telcagepant), a CGRP (calcitonin gene related peptide) antagonist, that we hope will be able to be used in people with migraines who have heart disease as well.

The real advance will be if treating and preventing migraines will actually reduce cardiovascular disease/risk factors.

In the meantime, remember ... an apple a day ....

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Revisiting the past: Neck pain in migraine

Medical media reporting confuses me sometimes.

Medscape Neurology reported on February 16th 2010 a study by Dr. Anne Calhoun looking at the percentage of migraine patients who reported neck pain and how that compares to those who have nausea.

See: http://www.medscape.com/viewarticle/717025?src=mpnews&spon=26&uac=88627FN

Is this surprising?

No.

Look to: Kaniecki et al. Poster presented at: 10th IHC; June 29-July 2, 2001; New York, NY.
Where they found that in a retrospective chart review of 144 patients with migraine, 75% reported neck pain with their migraines; 43% described bilateral neck pain and 57% unilateral (one-sided). 69% described the neck pain as "tightness" and 17% as "stiffness." The neck pain occurred 61% of the time in the prodrome (you just have a feeling that something isn't right and that a migraine is going to come on), 92% of the time during the headache and 41% during the postdrome (the yucky period you feel after the migraine).

In Cady et al. Poster presented at: 10th IHC; June 29-July 2, 2001; New York, NY, nausea is only present 63% of the time, while in Schreiber et al. Poster presented at: AHS June 21-23, 2002: Seattle, WA, nausea was present 70% of the time.

So, is anything new?

No.

We already knew this, as Dr. Calhoun pointed out: "...when we first presented these findings at the American Academy of Neurology meeting, the response from headache specialists was almost universal: vigorous nodding and assent,”

It is good, however to raise awareness to this and all the other common features of migraine, such as sinus stuffiness, pressure and drainage. Schreiber found prospectively in 2,524 patients without a prior migraine diagnosis that 82% of people reporting "sinus" headaches met the International Headache Society (IHS) criteria for migraines.

So, what does this mean?

1. Migraine is not just about the head pain and it is probably a lot more common than we think.

2. Not having a migraine diagnosis (yet) doesn't mean that your headaches aren't migraines.

3. Labels are important because they help with reassurance and they direct therapeutic options.

[see: http://neurologique.blogspot.com/2010/02/migraine-and-ms-lessons-for-ccsvi.html]

and ...

4. Take studies into their historical context. Maybe there really is nothing new under the sun.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Tragic Luger death: neurological lessons

I have been asked to weigh in on the potential causes of death of Olympic luger Nodar Kumaritashvili's.

As neurologists (and doctors in general), we think in terms of a differential diagnosis. We think in terms of what could potentially cause a given problem.

Here are some potential causes for his tragic death (at over 90 mph):

1) Subdural hematoma -- unlikely to kill so fast.
2.) Intracerebral hemorrhage.

3.) Epidural hematoma.

4.) Axonal shearing injury.

5.) Cervical (neck) fracture with damage to the sympathetic fibers to the heart.

6.) Voodoo death (death by fright) as we know he expressed fear the day before -- remember our discussion surrounding Michael Jackson's death:

http://neurologique.blogspot.com/2009/06/michael-jackson-voodoo-death-and.html

7.) Direct trauma to the chest -- stopping the heart.

For a full version of the interview I gave, please see:

http://www.associatedcontent.com/article/2708371/exact_cause_of_lugers_death_doctor.html?cat=70

Our hearts and thoughts are with the family of this great Georgian athlete.

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Daclizumab -- how does it fit in

Why did Facet Biotech Corporation (FACT) shareholder's reject Biogen Idec's (BIIB) unsolicited tender offer ($17.50)?

Maybe they were waiting for the release of the CHOICE data ($16.71).

The Lancet Neurology released Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta online in advance of print publication in April 2010

(http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(10)70033-8/fulltext#article_upsell).

So, how does the data on this subcutaneous (under the skin) anti-CD25 monoclonal antibody (which causes an increase in CD56bright natural killer cells) compare to data from other MS disease modifying agents?

In this study, participants wither received high dose Daclizumab plus interferon beta, low dose Daclizumab plus interferon beta or placebo plus interferon beta -- this reminds of the study design of the phase III AFFIRM study of Tysabri plus Avonex vs. Avonex alone. The endpoint in the 6-month phase II CHOICE study of new or enlarged Gadolinium enhancing lesion on brain MRI is different from the enfpoints in the AFFIRM (and other) studies. There was a mean of 4.75 in the interferon alone group and 1.32 in the high dose Daclizumab plus interferon group. This is a fairly active group of relapsing MS patients since there are so many new (or enlarged) Gadolinium enhancing lesions despite all patients being on interferon beta.

Although we are looking at slightly different MRI outcomes and certainly different time periods, let's look at a few of the Tysabri, Fingolimod and Cladribine trials:

2-year AFFIRM (Tysabri plus Avonex vs. Avonex alone):

Number of Gadolinium enhancing lesions:

0.1 vs. 0.8

Number of new or enlarging T2 hyperintense lesions:

0.5 vs. 2.4

1-year TRANSFORMS (Fingolimod/Gilenia [here low 0.5 mg dose only] vs. Avonex):

Number of Gadolinium enhancing lesions:

0.23 vs. 0.51

Number of new or enlarging T2 hyperintense lesions:

1.7 vs. 2.6

2-year CLARITY (Cladribine [here low 3.5 mg/kg dose only] vs. placebo):

Number of Gadolinium enhancing lesions:

0.12 vs. 0.91

Number of Combined Unique lesions:

0.43 vs. 1.72

Number of Active T2 lesions:

0.38 vs. 1.43

6-month CHOICE (Daclizumab [here high 2 mg/kg dose] plus INF vs. INF alone):

Number of new or enlarged Gadolinium enhancing lesion:

1.32 vs. 4.75

So, no matter how you look at it, the patients in the CHOICE study had more active MRIs (albeit, this is only a 6-month study).

So, were the FACT shareholders right in rejecting BIIB's bid?

What do you think?

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org

Migraine and MS: Lessons for CCSVI

Migraine and CCSVI have a lot to learn from each other.

Dr. Zamboni (and Dr. Zivadinov preliminarily) thinks that there is more CCSVI in people with MS than in those without Multiple Sclerosis.

[See our other blogs on CCSVI (chronic cerebrospinal venous insufficiency) at:

• http://neurologique.blogspot.com/2009/11/going-to-other-side.html
• http://neurologique.blogspot.com/2009/12/on-other-hand.html
• http://neurologique.blogspot.com/2010/02/ccsvi-does-it-hold-up.html

]

Does that mean that CCSVI causes MS or that fixing the CCSVI will fix/cure/treat the MS?

Well, does a recent study, to be presented at the upcoming AAN (American Academy of Neurology) annual meeting in Toronto, which raises the possibility that there is more migraine in women with MS than in those without MS, also mean that migraines cause MS or that treating the migraine will cure the MS?

No.

In the abstract (http://www.eurekalert.org/pub_releases/2010-02/aaon-mmc020210.php) to be presented by Dr. Ilya Krister, they found that by looking at participants in the Nurses' Health Study II, more people who were diagnosed with MS at the end of the 16-year study period had an initial diagnosis of MS than those who were not diagnosed with MS.

So, of the 116,678 women, 18,000 had an initial diagnosis of migraine, of which 82 went on to be diagnosed with MS by the end of the study; of the 98,678 without an initial diagnosis of migraine, 293 were diagnosed with MS by the end of the study.

This information has been picked up and spread around the internet by WebMD, U.S. News and World Report (HealthDay), MSN etc., but before striking fear in the 18 - 20 million American women with migraines, we need to analyze this further (in anticipation of the actual presentation):

This means that 15.427073% of the study population had an initial diagnosis of migraine, which is reasonable considering different prevalence rates depending on age (what is the age distribution in this study?) of approximately 18%. If someone went on to be diagnosed with MS, the prevalence of an initial migraine diagnosis was 21.866…% (which means that 78.133…% of the women who were eventually diagnosed with MS did not start out with a migraine diagnosis). Of the women who started out with an initial migraine diagnosis, 82 (0.455…%) went on to be diagnosed with MS, as opposed to 293 (0.29692535%) who were later diagnosed with MS and who did not have an initial migraine diagnosis.

This suggests that maybe women with MS have an earlier diagnosis of migraine – this can be for several hypothetical reasons, including that women who eventually get diagnosed with MS are more likely to go see a doctor as they may be having other early symptoms and when they see the doctor, they may be diagnosed with migraine at that time.

Looking at epidemiology alone also suggests that neurologists and especially headache specialists have a higher rate of migraine than the general population – in Neurology 2003;61:1271-1272, Evans, Lipton and Silberstein reported that 1-year and lifetime prevalences of migraine in the 220 respondents were as follows: male neurologists, 34.7%, 46.6%; male headache specialists, 59.3%, 71.9%; female neurologists, 58.1%, 62.8%; and female headache specialists, 74.1%, 81.5%.

The idea that migraine precedes the MS, and not vice versa assumes that MS comes on at a certain defined point, like a car accident, instead we believe that MS is diagnosed well after the disease process starts (even prior to the initial symptoms), so it could be that the women who had migraines and then went on to be diagnosed with MS, actually had the MS first.

Epidemiology and prevalence rates can be tricky – in a 1995 meta-analysis by Stewart et al. in the Journal of Clinical Epidemiology, 36.1% of the variation in prevalence estimates among studies was explained by case definitions/. Thus, the largest source of variation in prevalence estimates of migraine has to do with how you decide who does and who doesn’t have migraines. In the Nurses’ Health Study II, the definition of migraine was based upon the participant having gone to a doctor and that doctor having given them a diagnosis of migraine. This makes the data more difficult to interpret.

As some of you may know, a special interest of mine is the intersection between migraine and MS. With that in mind, we looked at a big series of neurology office visits by people with MS and found that neurologists underreported their patients’ migraines. A possible reason for this is that if a neurologist is less familiar with MS, she may focus on the disease process itself (the medications can be frightening) and not on the individual symptoms. This is why it is very important to write down three major issues you want to discuss with your neurologist at each office visit, so it will focus the visit on the symptoms and issues important to YOU.

Let’s delve deeper into the numbers in the press release of Dr. Krister’s study/ At the end of the study, 375 out of 116,678 women had an MS diagnosis. This makes a prevalence of 321.397835 per 100,000. This is extremely high and raises questions about the data. If we take the prevalence of MS in the U.S. as 450,000 and we assume that two-thirds of people with MS are women, then there are 300,000 women with MS in the United States out of a population of 154,938,000 women in the U.S. (2008 census of U.S. population is 303,800,000 of whom ~51% are women). This means that in the U.S. there are 193.61584 women with MS per 100,000 and if we took the very high number of 321.397835 per 100,000 as in the Nurses’ Health Study II, there should be ~497,967 women with MS in the United States!

So, how does this all related to CCSVI?

Well, looking at associations can be confusing and even looking at large numbers of people doesn’t always answer the question.

But we can keep trying, can't we?

P.S. Think about the name of a diagnosis that affects women more than men; young more than old; has a genetic component; normal appearing white matter may not be so normal; has white spots (T2 hyperintensities) on brain MRI in a quarter of people in some series; and involves inflammation on the meninges (covering of the brain, optic nerves and spinal cord).

Give up?

Clue: It's not MS.

It's migraine.

- Dr. Daniel Kantor, MD BSE

Medical Director

Neurologique

info@neurologique.org

www.neurologique.org

CCSVI: Does it hold up?

CCSVI: Fact or Fiction?

When I saw Robert Zivadinov, MD PhD 2 weeks ago he was excited. He may have even have a greater reason to be excited.

When they looked at the preliminary data (first 500 patients) from the University of Buffalo Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) study, they found that when the 10.2% of subjects in which results were border line were excluded, the percentage of affected MS patients rose to 62.5%, compared to 25.9 percent of healthy controls.

These are promising results, but remember a few things that we discussed on previous blogs:

http://neurologique.blogspot.com/2009/11/going-to-other-side.html

http://neurologique.blogspot.com/2009/12/on-other-hand.html

We need to prove the association (although 500 is a large number of patients) and then see whether association is equal to causation and then whether causation means that we can fix it after the fact.

I know it is hard, but patience is key ...

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

info@neurologique.org
www.neurologique.org