Chemotherapy causes brain atrophy and demyelination

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Chemotherapy causes brain atrophy and demyelination

Postby cheerleader » Fri Apr 25, 2014 7:58 am

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 CNS 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.

for more information, with links to published research and specific chemotherapy outcomes:
http://ccsviinms.blogspot.com/2014/03/c ... rophy.html

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Re: Chemotherapy causes brain atrophy and demyelination

Postby erinc14 » Fri Apr 25, 2014 9:27 am

makes you wonder about all DMDs.
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Re: Chemotherapy causes brain atrophy and demyelination

Postby centenarian100 » Sun Apr 27, 2014 11:11 pm

Yeah...

mouse doctor talks about the neurotoxicity of bone marrow transplant (implied by increase in neurofilament)

http://multiple-sclerosis-research.blog ... brain.html

cognitive side effects are well known from cytotoxic therapies from the cancer literature.

Presumably, this would only apply to broadly cytotoxic drugs but not to drugs like rituxan, alemtuzumab, tysabri, interferons, and so forth.

aubagio and novantrone are potential culprits though.
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Re: Chemotherapy causes brain atrophy and demyelination

Postby cheerleader » Mon Apr 28, 2014 8:47 pm

100--
The research I put together is relatively new---we're talking delayed complications due to the interference with proginator cells and changes in the brain's metabolism years after chemotherapy. It might be worth it to check out the note. http://ccsviinms.blogspot.com/2014/03/c ... rophy.html

Chemotherapies cause brain atrophy and disrupt myelin---these side effects could be contributing to "MS progression" and increasing disability---which will be blamed on the disease progression.

I also quoted the mouse doctor write up in the article. He is very concerned about brain atrophy rates in bone marrow transplants.

Yes, there has been atrophy noted in other MS specific treatments---
like cyclophosphamide http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3002608/

And this is a consideration....
Currently approved immunoactive drugs can help control inflammation and relapses, but even powerful agents, such as Campath-1H or mitoxantrone, do not prevent the subsequent accumulation of irreversible disability and neurodegeneration.

http://www.direct-ms.org/pdf/Immunology ... bility.pdf
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Re: Chemotherapy causes brain atrophy and demyelination

Postby centenarian100 » Mon Apr 28, 2014 9:51 pm

yes. cytoxan could be a problem too.
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Re: Chemotherapy causes brain atrophy and demyelination

Postby Kronk » Tue Apr 29, 2014 8:38 am

I don't think it should be a surprise that chemotherapy causes these side effects as it is a toxic chemical. The theory is that it will PRIMARILY affect cancer cells, immune cells, and other fast replicating cell such as human hair. The discussion of how much impact it has on other tissue cells in the human body doesn't seem to be as well discussed. I will say that it is a critically important cancer treatment. A friend of mine from work has a severe form of cancer and was given 1 year to live 4 years ago. His quarterly chemo treatments have kept the cancer from spreading and he continues to live a normal life.

How it is used for MS is debatable... I think the only proven MS cure is when they use chemo to erase the immune system and build a new one from stem cells. I don't think i would support any other use of chemo for MS. A treatment would kill many of the EBV infected B cells, but if there are some left they will replicate, and you would soon be in the same situation. This is what is currently seen when using chemo in MS. The info Cheer has found should eliminate the "casual" use of chemo in MS as it may cause longer term damage.
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Re: Chemotherapy causes brain atrophy and demyelination

Postby HarryZ » Tue Apr 29, 2014 12:56 pm

I think the only proven MS cure is when they use chemo to erase the immune system and build a new one from stem cells.


Hi Kronk,

I think it's a bit premature to say this treatment is a proven "cure" for MS. While they have had some initial good success with a small number of patients, nobody knows at this time if the initial mechanism of what causes MS (totally unknown) has been affected. Changing a person's immune system is a very drastic measure that can have big risks...like dying!

I think it will be quite some time before any long term results can be determined from this. In the meantime, MS patients seem to be in line to test very potent chemo drugs that have been used with cancer patients. Again, rattle the immune system to pieces and hope it does something for your MS. Now we are finding out these chemo drugs affect the grey matter negatively and who knows what will happen in the long run.
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Re: Chemotherapy causes brain atrophy and demyelination

Postby cheerleader » Tue Apr 29, 2014 2:29 pm

Kronk---the idea that wiping out the immune system w/chemotherapy and rebuilding it is a "cure" for MS has never been proven. It does tamp down inflammation in those in the RRMS phase, and may provide reduced relapses--but we still don't know if it actually stops MS progression in the long term. And sadly, brain atrophy has not been studied in the RRMS group. However, it has been studied in the SPMS group-

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.

Here's Dr. G--
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.blog ... brain.html

http://ccsviinms.blogspot.com/2014/03/c ... rophy.html
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Re: Chemotherapy causes brain atrophy and demyelination

Postby Anonymoose » Tue Apr 29, 2014 2:59 pm

Has the temporary nature of this atrophy been disproved?
http://www.washingtonpost.com/wp-dyn/co ... 00488.html
Chemo Temporarily Shrinks Brain Areas, Study Finds

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By Alan Mozes
HealthDay Reporter
Monday, November 27, 2006; 12:00 AM
MONDAY, Nov. 27 (HealthDay News) -- Chemotherapy promotes a short-term, but apparently reversible, shrinkage of key brain areas, new research shows.

These changes could explain the impairment of thinking, memory, and focus that many cancer patients complain of after treatment, a Japanese research team has found.

The changes are marked by a temporary dimunition of certain brain areas that help people concentrate, plan, problem-solve, execute, and remember. This shrinkage can bring on a general cognitive malaise often called "chemo-brain."



However, these reductions in brain matter were no longer evident three and four years after chemotherapy, the Japanese team reported Monday in the online edition ofCancer.

"These findings can provide new insights for future research to improve the quality of life of cancer patients," concluded a team led by Dr. Masatoshi Inagaki of the Research Center for Innovative Oncology, part of the National Cancer Center Hospital East in Chiba, Japan.

The current study both supports and contradicts prior research into chemo-brain.

For example, a study released last month by researchers at the University of California, Los Angeles, suggested that chemo-brain is linked to brain blood-flow changes that can endure for a decade or more.

The UCLA findings also suggested that anywhere from 25 percent to 80 percent of breast cancer patients who undergo chemotherapy are subject to chemo-brain. The condition is poorly understood and is often accompanied by a range of other chemo side-effects, such as gastrointestinal disturbances and weakened immunity.

Chemotherapy has greatly improved cancer survival rates in recent years, however.

So, to better understand the treatment's negative implications, the Japanese team analyzed three years of MRI scans from breast cancer survivors who received follow-up care at the Chiba hospital.

The women were between 18 and 55 years of age. None had experienced recurrent breast cancer or had a history of any other type of cancer. As well, none of the patients was still undergoing chemo at the start of the study, and none had a family history of dementia.

Over 100 patients underwent an initial MRI brain scan one year after cancer surgery. About half of this group had also undergone chemotherapy.

According to the researchers, patients who had received chemotherapy had smaller brain volumes in areas that control cognitive function, compared to those who had not been exposed to chemo.

However, imaging taken at the 3-year mark from 130 patients showed no remaining brain size differences whatsoever.

The authors stressed that cancer, on its own, did not explain the reductions in brain volume. Cancer patients often displayed brain volumes that were similar to healthy controls, they said.

Instead, the observed short-term changes seemed linked to chemo and not to malignant disease, they said.

Inagaki's group cautioned that their finding is just an observed association and does not confirm a cause-and-effect relationship between chemotherapy and brain changes. They called for additional MRI imaging to further investigate the issue.

Dr. Claudine Isaacs, an associate professor of medicine and the director of the Clinical Breast Cancer Program at Georgetown University in Washington, D.C., described the findings as "encouraging."

"The problem with chemo-brain is that it is often hard to tell what it is related to, because there are so many factors involved -- chemotherapy, the medication that goes with it, the fatigue, and everything else that goes along with a diagnosis of cancer," she noted. "They all play in together."

"So, although this study is relatively quite small, it is a good attempt to look at ways -- with MRI, functional PET scans -- of trying to get a better handle on a real phenomenon in a structural kind of way," Isaacs said.

"But we need to be careful," she cautioned, "because we still don't have the perfect study yet. So we really can't tell patients exactly what the parameters are at this point."

More information

For additional information on chemo-brain, visit the American Cancer Society.
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Re: Chemotherapy causes brain atrophy and demyelination

Postby cheerleader » Tue Apr 29, 2014 3:15 pm

It doesn't look temporary in MS, anonymoose---
in the SPMS patients treated with Lemtrada, cerebral atrophy continued 14 years later---sadly, brain atrophy was not temporary for them. It also was not "pseudo-atrophy" related to reduced edema, since their disease progressed.
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].


Dr. G wonders if the neurotoxicity of chemo might be too hard on the damaged MS brain.
Check out the note for more....
http://ccsviinms.blogspot.com/2014/03/c ... rophy.html

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Re: Chemotherapy causes brain atrophy and demyelination

Postby Kronk » Tue Apr 29, 2014 4:10 pm

HarryZ wrote: Changing a person's immune system is a very drastic measure that can have big risks...like dying!


Very true, the mortality rate is 2% which is very high for a modern medical treatment.

I do believe it is a cure, because I believe MS is caused by EBV or VZV, but I think it is possibly a temporary cure. The problem I could see with the treatment is the fact that there is a VERY high chance you will be exposed to EBV again in future. Over 95% of the world’s population has it and it spreads very easily particularly through saliva. So if an underlying condition makes us more susceptible to EBV causing MS, it is possible we could get MS again.

There are many examples of this treatment being effective. Over 70% of people are symptom free after, and I don't think many experience disease progression post treatment. The individual in the interview below has been symptom free for over 6 years post treatment after a very aggressive start to MS.

http://www.cbc.ca/news/canada/ottawa/ot ... -1.1368173

http://www.mni.mcgill.ca/media/news/ite ... _id=219076
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Re: Chemotherapy causes brain atrophy and demyelination

Postby Anonymoose » Tue Apr 29, 2014 4:16 pm

Cheer,
I'd read the mouse doctor post on this and responses (and your page as well :) ). So many things are at play with brain atrophy in ms...it's hard to say it's just chemo, especially in progressives. Also to be considered is the difference in efficacy in halting/slowing ms between lemtrada and other single agents vs aggressive myeloablative chemo used for hsct.

I agree there are major risks involved with the chemo agents. I won't (yet) do a non-biologic as a single agent and I'm not ready to leap to hsct as I think it needs some tweaking still and more study of long term results. But for those who are suffering with aggressive disease, I say go for it if you feel inclined. In a heart beat, I would choose preserving physical function over guarding brain mass.

Hoping this will all be a non-issue in the near future.

Kronk,
If it is ebv, adoptive immunotherapy will save the day and keep us in true remission. Let's hope Pender is able to get things moving at breakneck speed! Until then, it's rituxan and antivirals.
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Re: Chemotherapy causes brain atrophy and demyelination

Postby centenarian100 » Tue May 06, 2014 11:53 pm

Cheer-I don't think that there is any reason to suspect that alemtuzumab is neurotoxic as it is not an anti-metabolite, alkylating agent, anti-DNA repair agent-it is specific to leukocytes.

Do you understand what I am saying? It makes sense that cyclophosphamide can be neurotoxic because it causes DNA injury which occurs in all cells but has a more dramatic effect in rapidly dividing cells. Hematopoetic stem cell transplant involves multiple cytotoxic drugs. alemtuzumab is a monoclonal antibody against CD52 which isn't present on neurons/oligodendrocytes, so there is no a priori reason to think it would be neurotoxic. Of course, any medication could have any side effect.

Accelerated brain atrophy occurs in SPMS normally (and in RRMS as well), and alemtuzumab does not stop this from occurring. Whether or not alemtuzumab has a sustained effect on slowing brain atrophy in RRMS remains to be seen. Dr. G seems to be optimistic, but I am more skeptical. We will have to wait and see the extension phases of the randomized trials many years out.

To anyone who is curious, here is the link to the full text of the article cheer is referring to with campath in SPMS: http://www.neurology.org/content/53/4/751.full.pdf+html

Here is the discussion from the authors below:

This study shows that a single pulse of treatment with the humanized monoclonal antibody Campath 1H is associated with a major and sustained reduction in inflammatory MS disease activity as demonstrated by the suppression of Gd-enhancing lesion formation. No such reduction in activity was seen in the four untreated control subjects. Such a small control group cannot provide definitive comparative data, and indeed may by chance have had a lower level of enhancement during the pretreatment period. However, the baseline-treatment crossover design that we used has successfully shown a treatment effect on enhancing MRI activity using another agent, interferon β-1b,24 which was subsequently confirmed using the more robust parallel-group, placebo-controlled design.25 That both the treated and control group patients were blinded to the level of MRI activity throughout the study reinforces our impression that the reduction in Gd enhancement reflects a therapeutic effect.

In this analysis we have combined conventional MRI parameters (Gd enhancement and T2 lesion volume) with new approaches (hypointense T1 lesion volume, brain volume, and spinal cord area quantification) in an attempt to identify the effect of treatment on individual pathologic elements. These results should be interpreted with some caution due to the small numbers of control patients and the potential for measurement drift over time. However, all quantitative analyses were performed by the same experienced observer, in randomized order, without knowledge of patient identity or scan order, in an attempt to minimize the potential for bias.

We found no significant correlation between T2 lesion volume changes and clinical findings. This emphasizes the low pathophysiologic specificity of focal T2 signal hyperintensity, and is concordant with the weak correlations found between T2 abnormalities and disability in other studies.26-28 Although significant correlations between hypointense T1 lesion volume have been reported elsewhere,6 we found no overall correlation between hypointense T1 lesion volume and EDSS score changes. However, those with a sustained increase in EDSS score exhibited a significant increase in hypointense T1 lesion volume compared with those with stable disability. Furthermore, a moderate longitudinal correlation between the infratentorial T1-to-T2 ratio and EDSS score was identified. There is emerging evidence that those areas of high signal on a T2 sequence that are hypointense on a corresponding T1 image represent more severe structural loss.7 Therefore progressive loss of structure in functionally eloquent areas such as the brainstem and cerebellum might be expected to result in an increase in disability, as suggested by our results.

We also found a clear relationship between sustained increase in EDSS score and the development of cerebral (p < 0.009) and spinal cord atrophy (p < 0.01), although the significance of the latter is qualified by the smaller cohort of patients who could be analyzed for methodological reasons. Furthermore, those patients with a sustained increase in disability and brain atrophy had significantly smaller cerebral volumes at baseline. This finding suggests that an ongoing atrophic process is already more established in this cohort, and that loss of brain volume is predictive of subsequent clinical progression.

Those patients with a significant increase in EDSS score showed a much higher cumulative Gd-enhanced volume during the pretreatment period than the clinically stable patients. This indicates that although Campath 1H was able to suppress new lesion formation, it did not prevent the secondary consequence of inflammatory lesions that had already developed during the immediate pretreatment period. Increasing disability has been associated with higher Gd-enhancing lesion frequencies,28,29 and it is possible that inflammation might compromise repair mechanisms within demyelinated regions and thereby expose axons to the immunologic and biological consequences of persistent demyelination. Thus, even if inflammation is stopped, previously acquired extensive areas of damage may still undergo secondary degeneration with disease progression. Severe atrophy is likely to represent the final irreversible sign of axonal loss, leading to progression of disability.10 The recent interferon-β trials also suggest that suppression of active inflammation delays but does not prevent progression of disability,25,30 perhaps indicating ongoing axonal loss in established areas of pathology. A key issue in current MS research is to identify whether earlier intervention with therapies aimed at suppressing inflammation will delay or prevent later irreversible atrophy.31

Measurements of cerebral atrophy, spinal cord area, and T1 hypointense lesion volume represent important new approaches to the assessment of therapeutic efficacy. These techniques are objective, have high serial reproducibility, and are both simple and quick to apply. They can supplement the more traditional MRI measures and provide a means of assessing the impact of therapeutic intervention on destructive pathology and tissue loss.
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Re: Chemotherapy causes brain atrophy and demyelination

Postby cheerleader » Wed May 07, 2014 4:36 pm

I "get" what you're saying, 100.
The MOA for the monoclonal antibody drugs would predispose them to be less neurotoxic. CD52 is present on the surface on lymphocytes, but not stem cells. Yup. I get it. But there have been reports of peripheral neuropathy and myelitis, causing death in transplant patients following alemtuzumab-based therapy. http://www.nature.com/bmt/journal/v34/n ... 4538a.html

The point I was making is that in the CNS of someone with MS---the brain may be even more vulnerable to any amount of toxicity (or infections, for that matter--a known side effect of Campath) due to a weakened blood brain barrier. Brain atrophy and disease progression continued unabated in those with SPMS treated with Campath. Did the drug hasten this atrophy? Was it all just the disease progression? We don't know. But it sure didn't stop atrophy. (or reverse it, as my husband's treatment has accomplished.)
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Re: Chemotherapy causes brain atrophy and demyelination

Postby centenarian100 » Wed May 07, 2014 7:31 pm

cheerleader wrote:I "get" what you're saying, 100.
The MOA for the monoclonal antibody drugs would predispose them to be less neurotoxic. CD52 is present on the surface on lymphocytes, but not stem cells. Yup. I get it. But there have been reports of peripheral neuropathy and myelitis, causing death in transplant patients following alemtuzumab-based therapy. http://www.nature.com/bmt/journal/v34/n ... 4538a.html


I don't understand why you are posting that article. Infections are a known complication of multi-drug regimens for bone marrow transplant.

fludarabine and melphalan are also immunosuppressants and can cause neurotoxicity on their own

(sources: http://meetinglibrary.asco.org/content/96950-114, http://www.ncbi.nlm.nih.gov/pubmed/20182205)

The toxicity profile of alemtuzumab is well known-mostly infections, infusion reactions, and antibody mediated autoimmune diseases, especially autoimmune thyroiditis.

Neurotoxicity isn't a known side effect. I don't know why you are saying otherwise. Dr. G isn't implicating alemtuzumab in his article.

Not all chemotherapy is the same.

From the wikipedia article:

"Some newer anticancer drugs (for example, various monoclonal antibodies) are not indiscriminately cytotoxic, but rather target proteins that are abnormally expressed in cancer cells and that are essential for their growth. Such treatments are often referred to as targeted therapy (as distinct from classic chemotherapy) and are often used alongside traditional chemotherapeutic agents in antineoplastic treatment regimens"

Would you also say rituxan is neurotoxic? How about gleevec? Based on what?

The point I was making is that in the CNS of someone with MS---the brain may be even more vulnerable to any amount of toxicity (or infections, for that matter--a known side effect of Campath) due to a weakened blood brain barrier. Brain atrophy and disease progression continued unabated in those with SPMS treated with Campath.


I certainly agree that people with higher disability are more likely to have complications from alemtuzumab (especially infectious complications), and alemtuzumab is probably less effective or ineffective in people with SPMS-especially nonrelapsing SPMS.

Did the drug hasten this atrophy?


Who knows...but this certainly was not found in the head to head trial against Rebif in RRMS:

"A significantly lower rate of brain volume loss (atrophy) was noted with alemtuzumab compared to interferon beta-1a, as measured by change in brain parenchymal fraction (−0.867% versus −1.488%, P < 0.0001)."

source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593763/

I do agree that non-relapsing progressive MS is a different beast altogether.

But it sure didn't stop atrophy. (or reverse it, as my husband's treatment has accomplished.)
cheer


Has anyone actually documented a benefit of liberation on brain atrophy? Any case reports?
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