Chemotherapy causes brain atrophy, demyelination and MS disease progression

While many MS specialists continue to explore chemotherapies and immunoablation for people with MS, the side effects of these drugs on the brain are rarely mentioned.

As we learn more about the long term effects of chemotherapy of the central nervous system, it is vitally important that people with MS are given the facts.

If you are being recommended to try any of these therapies, please discuss the side effects with your doctor.

Recent studies have now started to unravel the cell‑biological basis for commonly seen neurotoxic syndromes in chemotherapy associated central nervous system damage and have provided compelling explanations for delayed neurological complications, such as cognitive decline, progressive myelin disruption and brain atrophy.
http://www.ncbi.nlm.nih.gov/pubmed/20738009

1. Chemotherapy kills myelin and OPC cells--  Chemotherapies are known to affect healthy brain cells, causing them to die off long after treatment ends.   Studies have shown that months after exposure to common chemotherapies, oligodendrocytes and precursor cells continue to die, and the brain is unable to remyelinate.

This study is the first model of a delayed degeneration syndrome that involves a global disruption of the myelin-forming cells that are essential for normal neuronal function,” said Mark Noble, Ph.D., director of the University of Rochester Stem Cell and Regenerative Medicine Institute and senior author of the study. “Because of our growing knowledge of stem cells and their biology, we can now begin to understand and define the molecular mechanisms behind the cognitive difficulties that linger and worsen in a significant number of cancer patients.”
http://www.urmc.rochester.edu/news/story/index.cfm?id=1963

2. Chemotherapy changes the brain's metabolism--  Doctors have long-described "chemo brain"--a common and debilitating side effect of chemotherapy, causing cognitive fog and a loss of coping skills.  In fact, the brain's metabolism is altered.

Chemo brain phenomenon is more than a feeling. It is not depression. It is a change in brain function observable on PET/CT brain imaging."
With the help of special software, they were able to pinpoint differences in brain metabolism before and after chemo. They then correlated these with patient history and data from neurologic exams and chemo treatments.  The analysis reveals a statistically significant link between reductions in regional brain metabolism and symptoms of chemo brain.  Lagos says their findings show "there are specific areas of the brain that use less energy following chemotherapy".

"These brain areas are the ones known to be responsible for planning and prioritizing," she adds.
http://www.medicalnewstoday.com/articles/253277.php

3. Chemotherapy used in bone marrow transplant doubles brain atrophy in those with progressive MS.    Because of this, one neurologist is now cautioning his progressive MS patients.  The chemotherapy used in bone marrow transplant is likely to accelerate the disease progression in those with progressive MS.

The following study I was involved shows that when SPMSers are given chemotherapy they undergo increased neuronal loss, which is associated with faster progression on the EDSS and greater brain atrophy. The data speaks for itself. The picture below is what we call a survival curve of EDSS progressions and you can see that the MSers who had high serum levels of the neuronal toxicity marker neurofilament were much more likely to progress than those who did not have raised neurofilament levels. Similarly, brain atrophy rates in SPMSers were in the order of 2.1% per year in those who had a BMT compared to only 1.2% per year in SPMSers who did not have a BMT; the upper limit of normal for brain atrophy in healthy adults is generally accepted to be 0.4% per year. The bottom line is that if you have SPMS BMT is likely to accelerate your disease progression.
http://multiple-sclerosis-research.blogspot.com/2014/02/more-on-bmt-neurotoxicity-and-brain.html

4. Current information on Lemtrada (Campath/Alemtuzumab)
New claims are that treatment reduced cerebral atrophy in RRMS patients who were followed for two years---but earlier studies showed that this was not true in secondary progressive MS.  Treated patients were followed for 14 years past infusions---and cerebral atrophy and disease progression continued.  The FDA was right to deny Lemtrada in the US---sadly, the MS patients that are asking for this treatment to be approved have been given an incomplete scenario.

Unfortunately, this did not lead to a clinical improvement in the disability in these patients. In fact, their disability worsened with time at a rate of 0.02 EDSS points for each patient each year. Evidence for continued neurodegeneration in these patients was shown by progressive cerebral atrophy on follow-up MRI scanning. This particular group of patients who showed continuing disease progression had the highest inflammatory load prior to commencing alemtuzumab therapy. This group of patients were followed up with MRI scanning many years later (14 years post treatment) and did not demonstrate any increase in lesion load but did demonstrate further cerebral atrophy [Coles et al. 2006]. This was reflected in their EDSS score, the median being 7.5 (range 4.5–9) at latest follow up [Hill-Cawthorne et al. 2012].
http://europepmc.org/articles/PMC3629751

Campath 1H treatment was associated with a sustained and marked reduction in the volume of Gd enhancement, indicating suppression of active inflammation. Nevertheless, many patients developed increasing brain and spinal cord atrophy, T1 hypointensity, and disability. 
http://www.ncbi.nlm.nih.gov/pubmed/10489036



In fact, neurologists have known about chemotherapy causing brain atrophy for many years.  Here is a study from 2006--where neurologists followed brain atrophy after chemotherapy in preparation for a bone marrow transplant.  And they included a man without MS, being treated for cancer, to see how his brain did.  His brain atrophy doubled....just like the people with MS.

The man with non-Hodgkin lymphoma provided a clue. Because he didn't have MS, he should not have had any cerebral inflammation or edema. Yet, in the three months after he received the same treatment as the MS patients, his brain shrank at the rate of about 6 percent per year, a rate of atrophy similar to the MS patients.
http://journals.lww.com/neurotodayonline/Fulltext/2006/07040/Brain_Atrophy_in_Ms_May_Result_From_Immunoablation.11.aspx

We still do not fully understand the disease mechanism of MS.  While MS specialists continue to operate under the assumption that a faulty immune system must be annihilated ----we are learning that the true progression of MS can be linked to neuronal loss, or brain atrophy.  There is a terrible and tragic irony in the fact that chemotherapies, which are known to double brain atrophy rates, are being recommended to people with MS.

Please, share this information in the MS community.  For those who have already been treated with chemotherapies, there is hope of healing through diets high in antioxidants and phytonutrients and omega 3 oil supplementation. In fact, simple lifestyle factors like diet, exercise, UV rays and vitamin D are increasing blood flow to the brain are helping reverse brain atrophy in all of those with MS.

Know the facts, and be well,
Joan

A Single Step

There is a paradigm shift which is happening in our understanding of human health and disease.  More and more, researchers are looking at how our everyday movement is impacting our health.

There is a difference between supervised exercise training, physical therapy, and "lifestyle activity".  For years, people with MS have been encouraged to seek physical therapy.  But they have not been encouraged to simply move more.  For those with MS who are still able to take steps and walk, I'd like to offer some information, encouragement and cheerleading.

The MS activity paradigm is changing.  Here is a recent abstract on this topic:

Lifestyle physical activity in persons with multiple sclerosis: the new kid on the MS block.

Supervised exercise training has substantial benefits for persons with multiple sclerosis (MS), yet 80% of those with MS do not meet recommended levels of moderate-to-vigorous physical activity (MVPA). This same problem persisted for decades in the general population of adults and prompted a paradigm shift away from "exercise training for fitness" toward "physical activity for health." The paradigm shift reflects a public health approach of promoting lifestyle physical activity through behavioral interventions that teach people the skills, techniques, and strategies based on established theories for modifying and self-regulating health behaviors. This paper describes: (a) the definitions of and difference between structured exercise training and lifestyle physical activity; (b) the importance and potential impact of the paradigm shift; (c) consequences of lifestyle physical activity in MS; and (d) behavioral interventions for changing lifestyle physical activity in MS. The paper introduces the "new kid on the MS block" with the hope that lifestyle physical activity might become an accepted partner alongside exercise training for inclusion in comprehensive MS care.

http://www.ncbi.nlm.nih.gov/pubmed/24603882

What is the difference between exercise training and "physical activity for health"? 

Many of us may exercise and train at the gym or at home.  We lift weights, swim, do yoga, stretching----but then, for the rest of the day, we are seated.  Doctors and researchers are noting that people simply do not walk anymore.  And this is a problem.

There is a new movement many of you may have been reading about.  For those who are still able to walk, it may be in your best interest to see if this program is something you can incorporate in your life.

It's called the 10,000 Steps A Day Program.  Walking 10,000 steps is the goal doctors and the surgeon general would like us to have. 

 If you're just getting started, 10,000 steps a day probably seems enormous. Don't worry––it won't take long to reach it! According to research into activity levels, anything under 5,000 steps a day is considered to be a sedentary lifestyle, and it isn't until you reach 10,000 steps a day that you're considered to be "active".^[1][6] It is recommended that you begin walking as much as feels comfortable to you, then aim to walk in increments of 1,000 to 2,000 steps more each week until you're comfortably at 10,000 steps a day.^[7] There is nothing stopping you walking more than this each day, but the aim is to always make 10,000 steps.

http://www.wikihow.com/Walk-10,000-Steps-a-Day

For me, 10,000 step equals about four miles of walking.  How do I know this?  I've been using a pedometer for a couple of months now. Mine is a free app called Pedometer++ on my iphone.  But you can use any type of pedometer that works for you.  I was surprised at how few steps I had been taking!  Getting to 10,000 a day has taken a real, concerted effort for both me and Jeff.  Jeff is active, but he spends most of his day at his desk, writing music.  And I spend most of my time writing or singing.  We really have to go on longer walks every day to reach the 10,000 step goal.  We're parking the car further from the store, taking stairs, simply moving more during the day.  And we're finally reaching the goal.  Our son is home for spring break, and he has the same pedometer.  He walks about 12,000 steps a day, getting around his campus....but since he's been home with his folks, he's been sitting around more.  We all went on a long walk last night, and made our goals.

The truth is, most people, even healthy people, are simply not taking enough steps.  We've become a sitting society.

Sitting has been getting a lot of attention lately, to the point that there’s a new adage: “Sitting is the new smoking.” In addition to encouraging everyone to sit less, people are specifically encouraging exercises during TV watching and during work hours, with walking meetings and standing desks, as ways to decrease sedentary time.

“The real problem is that we are raising sedentary children,” said one of the researchers, Pamela Semanik, assistant professor of adult and gerontological nursing at Rush College of Nursing. “It’s so insidious in our culture.”

At her workplace, where people see the results of not moving, people have changed their ways, she said, adding that she has sold her car and reads medical journal articles on a treadmill.

The researchers in the current study said as many as 5.3 million annual deaths worldwide are related to insufficient activity.

http://www.latimes.com/science/sciencenow/la-sci-sn-sedentary-disability-20140219,0,7209026.story#ixzz2vshgBlk7

So, what to do?

I'd like to paraphrase a familiar quote.  The Journey of 10,000 steps begins with a single step.

Be encouraged!  Move more, to whatever extent you are able.  Get a pedometer, and follow your results.  And let me and our MS community know how you're doing!

We're all in this together,

Joan

Blood Matters

Seven years ago, when Jeff was diagnosed with MS, I asked his neurologist why his blood was hypercoagulated.  Why were his fibrinogen, c reactive protein, pro-thrombin and SED rates so high?  Why did he have all those tiny blood spots on his legs?  She replied that she didn't know, since it "had nothing to do with his MS."

But seven year later, we know that wasn't true for him, and it's apparently not true for other people with MS.

Blood matters.

After Jeff's diagnosis I went to the library and read medical journals online. I read Dr. Roy Swank's research, and saw he noted this blood vessel breakdown, as evidenced by what he called, "capillary fragility" on the limbs of his MS patients during their relapses, manifesting as blood spots called petechiae.  (see pic below.)   He saw hypercoagulation in their serum, too.    Dr. Swank knew it mattered.  In 1958, he saw what I was seeing on Jeff's legs in 2007.

Additional evidence that blood vessel fragility may be an important aspect of MS derives from Swank's study in which he concluded that MS is not confined primarily in or localized to the CNS: He observed small cutaneous hemorrhages in 77.4% of female patients observed repeatedly over a 5-9 year period. In 66.7% of these patients, the hemorrhages were spontaneous. `Biopsies of 5 spontaneous hemorrhages, where trauma could be confidently ruled out, revealed extravasated red blood cells infiltrating the deeper layers of the derma and the subcutaneous fat.' Swank goes on to state that `a number of patients have described petechial hemorrhages in large numbers after having their blood pressure taken both under and distal to the cuff.' He notes that the petechial hemorrhages are similar to sub- cutaneous hemorrhages seen in capillary resistance studies.   
Swank RL. Subcutaneous hemorrhages in multiple sclerosis. Neurology. 1958; 8: 497-498.

Jeff's hypercoagulation and petechiae were related to his MS.  Dr. Swank did not have the science of nitric oxide as EDRF in his time, but modern researchers have since connected hypercoagulation and clotting proteins as evidence of endothelial dysfunction and a break down of the blood brain barrier, and activation of the coagulation cascade.  This research comes decades after Dr. Swank's discoveries, but confirms what he saw as "blood vessel fragility."  We now know that endothelial dysfunction and a break in the BBB will affect the blood through out the body.  Once the coagulation cascade is activated, it is systemic.  And these extravasated red blood cells will leak and appear throughout the body.  Just like Jeff's petechiae--and the break in his blood brain barrier.

The disruption of integrity of the walls of brain blood microvessels rapidly activates the coagulation cascade. 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268209/

The coagulation cascade plays a major role in the development of an inflammatory response in MS.
http://circres.ahajournals.org/content/110/9/1157.extract#

Other researchers have noted hypercoagulation and high fibrin levels in the blood of pwMS for decades.  But these markers have been largely ignored.  Until recently.
Here's more on this research from the Gladstone Institute.

A protein involved in blood clotting may be a new indicator to help detect multiple sclerosis (MS) lesions before symptoms arise. The presence of the clotting protein, thrombin, signals an early stage of the disease when the blood-brain barrier is breached and the brain’s immune response is set into motion. The research was presented at Neuroscience 2013, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health. 

The researchers found that thrombin, usually a beneficial protein involved in blood clotting, builds up in the central nervous system as MS progresses. Thrombin enters in the brain together with fibrinogen, another clotting protein when the protective barrier between the blood and brain becomes leaky. Thrombin converts the fibrinogen to fibrin which activates brain’s immune cells that break down the protective myelin sheath that surrounds neurons in the central nervous system. Because thrombin levels increase as the disease progresses, the researchers conclude that it could be used as an early detector of the disease. 
http://www.bioquicknews.com/node/1420

More researchers are noting this break in the endothelium, and detecting these microscopic bleeds in the MS brain.  At the ISNVD conference, Dr. Yulin Ge recently discussed how 7T MRI technology is allowing us to see tiny hemorrhages in the MS brain which occur before demyelination.  This further elucidates the microvascular connection to MS.
From his abstract at the ISNVD:

Being the most common demyelinating disease of the central nervous system, multiple sclerosis (MS) MS has a significant microvascular pathological component as a consequence of the perivascular inflammation. The role of vascular pathology in MS was suggested long ago. Now there is accumulating evidence of a primary vascular pathogenesis in MS. In vivo studies of vascular and hemodynamic impairment in MS may provide insights into the etiology and pathophysiology of MS and offer the potential metrics for assessment of outcome of the disease. 

Canadian microbiologists have recently published a paper on the iron around MS lesions, and link it to the vasculature and "chronic extravasation of hemoglobin", or microbleeds causing oxidative stress in the brain. 
http://www.ncbi.nlm.nih.gov/pubmed/24504127

Dr. Zamboni saw the parallels of venous disease of the legs and MS, and wrote about iron deposition and the inflammatory response in his 2006 publication,
The Big Idea: Iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1633548/

These researchers would tell you that blood matters.  When red blood cells enter brain tissue, there are serious repercussions--including oxidative stress, inflammation, iron deposition and an upregulation of clotting proteins.   Why does the blood brain barrier become leaky, and allow plasmic particles access into brain tissue? The exact mechnism is not known, but it appears to be related to endothelial dysfunction.  It may be venous hypertension, lack of shear stress, and hypoxic injury created by CCSVI which is compounded by environmental factors like diet, exercise, stress, UV rays, viral and bacterial infections and smoking.  We need more research.

MS researchers ignore this connection at the peril of their patients' brains---and lives.
I'll keep writing about it, until the day when neurologists understand the connection of the red blood spots I saw on Jeff's legs, the lesions in his brain and spine, and his MS diagnosis.
Joan

Obesity and birth control pills raise MS risk

Two new studies will be presented at the American Academy of Neurology's 66th Annual meeting in Philadelphia during April 26-May 3.
These studies shed more light on the vascular connection to MS.

One study looked at the connection between obesity and MS risk--

For the obesity study, BMI was calculated for 210 people with MS and 210 people of the same age and sex who did not have MS at ages 15 and 20 and at the time of the study. The study found that people who are obese at age 20 are twice as likely to later develop MS as people who are not obese.

This study is one of many recent studies finding the connection of higher BMI, obesity and increased risk of developing MS.  The researchers posit that higher levels of the hormone leptin may be promoting an inflammatory response.  They never once mention the cardiovascular connection of the heart and the brain.

Here is Dr. Ronald Cohen from the University of Florida on the relationship of obesity to brain health.  He discusses the link of increased BMI to reduced cerebral blood flow, reduced gray matter volume and increased white matter abnormalities.

When we looked at brain volume and gray matter volume specifically, we found that in this cohort of people without comorbid conditons, but with a range of BMI, what we found was increased BMI was related to reduced cortical or gray matter volume, suggestng that there are actual relationships between obesity and structural brain changes. Subsequent findings from other studies that were conducted along the way, just looking strictly at obese populations, indicated relationships between other markers as well. White matter hyperintensities were increased in people with morbid obesity, but even among people who were overweight or mildly obese, there were some relationships between white matter abnormalites.

This became even clearer when we used diffusion tensor imaging, a method by which we can measure the coherense of white matter. ... Those types of findings suggested that coherence of white matter decreased as a function of BMI as well. When we look at blood flow in the brain (this was from a study of heart failure and the relationship of obesity) what we find is that obesity and cerebral blood flow are negatively correlated and together relate to cognitive problems among people with heart failure. So that was another finding that links obesity with cerebral blood flow or another marker.
https://psychiatry.ufl.edu/files/2011/12/Cohen.Newsletter.Final_.pdf

The other study looked at the connection between birth control pill use and MS--

For the birth control hormone study, researchers identified 305 women who had been diagnosed with MS or its precursor, clinically isolated syndrome, during a three-year period from the membership of Kaiser Permanente Southern California and who had been members for at least three years before the MS symptoms began. Then they compared them to 3,050 women who did not have MS.

A total of 29 percent of the women with MS and 24 percent of those without MS had used hormonal contraceptives for at least three months in the three years before symptoms began. The majority used estrogen/progestin combinations.

Women who had used hormonal contraceptives were 35 percent more likely to develop MS than those who did not use them. Those who had used the contraceptives but had stopped at least one month before symptoms started were 50 percent more likely to develop MS.
http://www.eurekalert.org/pub_releases/2014-02/aaon-dob021214.php

It is scientific fact that obese women and women who take birth control pills have an increased risk of cardiovascular disease, stroke and venous thrombosis.  And obese women on birth control pills have an even higher risk--due to the increase of hypercoagulating factors in their blood.  Both of these factors create endothelial dysfunction.  Both of these factors reduce cerebral blood flow.

We evaluated the risk of thrombosis due to overweight and obesity using data from a large population based case-control study. Four hundred and fifty-four consecutive patients with a first episode of objectively diagnosed thrombosis from three Anticoagulation Clinics in the Netherlands were enrolled in a case-control study. Controls were matched on age and sex to patients and were introduced by the patients. All patients completed a standard questionnaire and interview, with weight and height measured under standard conditions. 

The associations of obesity with clotting factor levels were studied to investigate possible mechanisms. Obesity (BMI >/=30 kg/m(2)) increased the risk of thrombosis twofold (CI95: 1.5 to 3.4), adjusted for age and sex. Obese individuals had higher levels of factor VIII and factor IX, but not of fibrinogen. The effect on risk of obesity was not changed after adjustment for coagulation factors levels (fibrinogen, F VIII, F IX, D-dimer). The relative risk estimates were similar in different age groups and in both sexes, indicating a larger absolute effect in older age groups. 

Evaluation of the combined effect of obesity and oral contraceptive pills among women aged 15-45 revealed that oral contraceptives further increased the effect of obesity on the risk of thrombosis, leading to 10-fold increased risk amongst women with a BMI greater than 25 kg/m(2) who used oral contraceptives. Obesity is a risk factor for deep vein thrombosis. Among women with a BMI greater than 25 kg/m(2) the synergistic effect with oral contraceptives should be considered when prescribing these.

http://www.ncbi.nlm.nih.gov/pubmed/12624633

Obesity and birth control pills both affect the blood.  They increase the risk of clots, due to hypercoagulation.   They slow cerebral blood flow and increase white matter abnormalities. This is a vascular connection worth exploring!

There is another well-known condition that is increased in obese women and women on birth control pills.  Idiopathic intracranial hypertension--
This condition occurs when cerebrospinal fluid pressure becomes increased in the brain.  This can cause headaches, visual problems, and tinnitus.  It affects cerebral perfusion, and is related to hyper coagulation.
http://www.ncbi.nlm.nih.gov/pubmed/12878984

And some researchers have found connections in patients with both demyelination and IIH-

Three patients with IIH and MS
http://content.lib.utah.edu/cdm/ref/collection/jno/id/81
One patient with MS and IIH
https://www.webmedcentral.com/article_view/2544
IIH and transverse myelitis
http://journals.lww.com/jneuro-ophthalmology/Fulltext/2004/12000/Intracranial_Hypertension_Associated_With.14.aspx
IIH and inflammatory demylinating polyneuropathy
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC504474/

MS researchers need to remove their blinders and consider how cardiovascular health is affecting the brain.  Why does smoking worsen MS and increase progression?  Why does exercise improve MS progression and symptoms?  Why is obesity linked to MS susceptibility?  Why do transfats worsen MS?   All of these environmental factors are linked to endothelial dysfunction.   If researchers continue to focus on the immune system exclusively, they miss an incredible opportunity in understanding the complete aetiology of this disease.  

Surely, if lay people can see this connection--it should be obvious to them.
Joan