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Re: Published Research - General Sleep and WED (RLS)

Posted: Sat Apr 27, 2013 2:07 pm
by cornelia
This is confusing research on iron and RLS: it seems that there is not that much wrong with our brain iron (to see on a scan at least).

Nat Sci Sleep. 2009 Dec 22;2:19-22. Print 2010.
Normal regional brain iron concentration in restless legs syndrome measured by MRI.
Knake S, Heverhagen JT, Menzler K, Keil B, Oertel WH, Stiasny-Kolster K.
Department of Neurology, Center of Nervous Diseases, Marburg, Germany.
Using a T2* gradient echo magnetic resonance imaging (MRI) sequence, regional T2 signal intensity (SI) values, a surrogate marker for T2 values, were determined in 12 regions of interest (substantia nigra, pallidum, caudate head, thalamus, occipital white matter, and frontal white matter bilaterally) and in two reference regions (cerebrospinal fluid and bone) in 12 patients suffering from moderate to severe idiopathic restless legs syndrome (RLS; mean age 58.5 ± 8.7 years) for 12.1 ± 9.1 years and in 12 healthy control subjects (mean age 56.8 ± 10.6 years). Iron deposits shorten T2 relaxation times on T2-weighted MRI. We used regional T2* SI to estimate regional T2-values. A T2-change ratio was calculated for each region of interest relative to the reference regions. We did not find significant differences in any of the investigated brain regions. In addition, serum measures involved in iron metabolism did not correlate with T2 SI values. We could not replicate earlier findings describing reduced regional brain iron concentrations in patients with RLS. Our results do not support the view of substantially impaired regional brain iron in RLS.


Re: Published Research - General Sleep and WED (RLS)

Posted: Sat Apr 27, 2013 6:31 pm
by ViewsAskew

Re: Published Research - General Sleep and WED (RLS)

Posted: Sun Apr 28, 2013 12:46 am
by badnights
It might be the method they're using to detect iron. The original studies sliced open dead brains. Other studies sampled spinal fluid and measured iron directly in it. This study is relying on indirect methods. (Iron deposits affect the T2 MRI signal, which affect the SI, which is measured. I have no idea what that means, but that's how I read it.)

Even more of an issue, perhaps, they don't say they compare WED brain to control brain (though they must have done so!?). It sounds like they compared selected regions of one brain against "reference" regions of the same brain. The selected regions are thought to be involved with WED, the reference regions are supposedly not involved. However, one of the reference regions is cerebrospinal fluid, which I think is known to be low in iron in WED patients - so comparing two regions that are both low would show no difference.

On the other hand, they seem confident in their conlcusion. I'd like to see the whole paper...

Did they test only medicated people?

Re: Published Research - General Sleep and WED (RLS)

Posted: Tue Apr 30, 2013 1:35 pm
by cornelia
First research (I think) done on relation RLS with glutamate:

Neurology. 2013 Apr 26. [Epub ahead of print]
Thalamic glutamate/glutamine in restless legs syndrome: Increased and related to disturbed sleep.
Allen RP, Barker PB, Horská A, Earley CJ.
From the Departments of Neurology (R.P.A., C.J.E.) and Radiology (P.B.B., A.H.), Johns Hopkins University, Baltimore, MD.
To evaluate possible abnormal increase in thalamic glutamate/glutamine levels for restless legs syndrome (RLS) indicating increased glutamatergic activity producing arousal that at night disrupts and shortens sleep.
1H MRS of the right thalamus was performed using a 1.5 T GE MRI scanner and the PROBE-P (PRESS) on 28 patients with RLS and 20 matched controls. The Glx signal (combination of mostly glutamate [Glu] and glutamine [Gln]) was assessed as a ratio to the total creatine (Cr). This study tested 2 primary hypotheses: 1) higher thalamic Glx/Cr for patients with RLS than controls; 2) thalamic Glx/Cr correlates with increased wake during the sleep period.
The Glx/Cr was higher for patients with RLS than controls (mean ± SD 1.20 ± 0.73 vs 0.80 ± 0.39, t = 2.2, p = 0.016) and correlated significantly with the wake time during the sleep period (r = 0.61, p = 0.007) and all other RLS-related polysomnographic sleep variables (p < 0.05) except for periodic leg movements during sleep (PLMS)/hour.
The primary findings introduce 2 new related dimensions to RLS: abnormalities in a major nondopaminergic neurologic system and the arousal disturbance of sleep. The strong relation of the arousal sleep disturbance to glutamate and the lack of relation to the PLMS motor features of RLS contrasts with the reverse for dopamine of a limited relation to arousal sleep disturbance but strong relation to PLMS. Understanding this dichotomy and the interaction of these 2 differing systems may be important for understanding RLS neurobiology and developing better treatments for RLS.


Re: Published Research - General Sleep and WED (RLS)

Posted: Tue Apr 30, 2013 3:19 pm
by rthom

Re: Published Research - General Sleep and WED (RLS)

Posted: Thu May 02, 2013 4:39 am
by rthom
Just an FYI, I'm not beng obtuse.

Re: Published Research - General Sleep and WED (RLS)

Posted: Mon May 06, 2013 8:39 am
by badnights
Board members may remember the hyperalertness/glutamate study requesting volunteers (discussed at viewtopic.php?f=5&t=8077&hilit=glutamate). The above post is, I think, the results of a pilot study. Based on those results, which are just now being published but were obtained probably a couple of years ago, they have gone ahead with the bigger study discussed in the above thread, which is still underway.

Re: Published Research - General Sleep and WED (RLS)

Posted: Mon May 06, 2013 9:11 am
by ViewsAskew
I'm always really tired when I see this and tell myself I'm come back when I'm awake and answer it better. That doesn't seem to happen.

They found out that people with WED/RLS do have differing amounts of chemicals in one of the major neurologic systems compared to people without WED. It's just more proof that our chemistry isn't the same as other people's and it may help them better understand why WED happens. This type of study opens up more avenues of research. Now that they know this, they can go study other things that will hopefully tell us a lot more. The short of it? Our alertness at night is related to a different system that they previously knew about.

Re: Published Research - General Sleep and WED (RLS)

Posted: Tue May 07, 2013 12:09 am
by rthom
No prob. I thought it looked like it was saying two opposite things. It's too bad they don't have an overview of their findings that was the "...for dummies" section on the bottom of these papers. lol :roll: :lol:

Re: Published Research - General Sleep and WED (RLS)

Posted: Tue May 07, 2013 3:11 am
by badnights
They're also saying that the dopamine system is correlated with PLMs, but not sleep arousals (which was known before), and that glutamate+glutamine levels are correlated with sleep arousals, but not PLMs (which is new). They point out that very few researchers have looked at the hyperarousal component of WED/RLS; these results indicate that there is a whole 'new' system to investigate that is involved in causing that hyperarousal. It gives a new direction for research, wihch is (imo) very important, to get people off the obviously-problematic dopamine bandwagon.

WED: an overload of glutamate in the brain?

Posted: Wed May 08, 2013 12:09 am
by erika13
Has anyone seen this new study out today?
EDIT by Beth: this is a plain-language summary of the research posted above: Postby cornelia » Tue Apr 30, 2013 7:35 am
First research (I think) done on relation RLS with glutamate: ... 134600.htm

Here is a link and I have copied it below too:

It found that glutamate (a neurotransmitter involved in arousal) was abnormally high levels in the brains of people with RLS.
The researchers went on to say, "We may have been looking at the wrong thing all along, or we may find that both dopamine and glutamate pathways play a role in RLS."
“If confirmed, the study's results may change the way RLS is treated.”

Restless Legs Syndrome, Insomnia and Brain Chemistry: A Tangled Mystery Solved?

May 7, 2013 — Johns Hopkins researchers believe they may have discovered an explanation for the sleepless nights associated with restless legs syndrome (RLS), a symptom that persists even when the disruptive, overwhelming nocturnal urge to move the legs is treated successfully with medication.

Neurologists have long believed RLS is related to a dysfunction in the way the brain uses the neurotransmitter dopamine, a chemical used by brain cells to communicate and produce smooth, purposeful muscle activity and movement. Disruption of these neurochemical signals, characteristic of Parkinson's disease, frequently results in involuntary movements. Drugs that increase dopamine levels are mainstay treatments for RLS, but studies have shown they don't significantly improve sleep. An estimated 5 percent of the U.S. population has RLS.

The small new study, headed by Richard P. Allen, Ph.D., an associate professor of neurology at the Johns Hopkins University School of Medicine, used MRI to image the brain and found glutamate -- a neurotransmitter involved in arousal -- in abnormally high levels in people with RLS. The more glutamate the researchers found in the brains of those with RLS, the worse their sleep.

The findings are published in the May issue of the journal Neurology. "We may have solved the mystery of why getting rid of patients' urge to move their legs doesn't improve their sleep," Allen says. "We may have been looking at the wrong thing all along, or we may find that both dopamine and glutamate pathways play a role in RLS."

For the study, Allen and his colleagues examined MRI images and recorded glutamate activity in the thalamus, the part of the brain involved with the regulation of consciousness, sleep and alertness. They looked at images of 28 people with RLS and 20 people without. The RLS patients included in the study had symptoms six to seven nights a week persisting for at least six months, with an average of 20 involuntary movements a night or more.
The researchers then conducted two-day sleep studies in the same individuals to measure how much rest each person was getting. In those with RLS, they found that the higher the glutamate level in the thalamus, the less sleep the subject got. They found no such association in the control group without RLS.
Previous studies have shown that even though RLS patients average less than 5.5 hours of sleep per night, they rarely report problems with excessive daytime sleepiness. Allen says the lack of daytime sleepiness is likely related to the role of glutamate, too much of which can put the brain in a state of hyperarousal -- day or night.

If confirmed, the study's results may change the way RLS is treated, Allen says, potentially erasing the sleepless nights that are the worst side effect of the condition. Dopamine-related drugs currently used in RLS do work, but many patients eventually lose the drug benefit and require ever higher doses. When the doses get too high, the medication actually can make the symptoms much worse than before treatment. Scientists don't fully understand why drugs that increase the amount of dopamine in the brain would work to calm the uncontrollable leg movement of RLS.

Allen says there are already drugs on the market, such as the anticonvulsive gabapentin enacarbil, that can reduce glutamate levels in the brain, but they have not been given as a first-line treatment for RLS patients.
RLS wreaks havoc on sleep because lying down and trying to relax activates the symptoms. Most people with RLS have difficulty falling asleep and staying asleep. Only getting up and moving around typically relieves the discomfort. The sensations range in severity from uncomfortable to irritating to painful.

"It's exciting to see something totally new in the field -- something that really makes sense for the biology of arousal and sleep," Allen says.

Journal Reference:
R. P. Allen, P. B. Barker, A. Horska, C. J. Earley. Thalamic glutamate/glutamine in restless legs syndrome: Increased and related to disturbed sleep. Neurology, 2013; DOI: 10.1212/WNL.0b013e318294b3f6

Re: Published Research - General Sleep and WED (RLS)

Posted: Thu May 09, 2013 10:52 pm
by Chipmunk
If anyone wants the pdf of the full study, PM me with your email address.

I'm more excited about this research than any other I have read because all of it "fits" with my experience. I hope it leads to a new understanding of WED for all of us suffering from it.

Re: Published Research - General Sleep and WED (RLS)

Posted: Thu May 23, 2013 8:06 am
by badnights
Another study with puzzling iron information. This one tested RLS/WED patients with intravenous iron dextran. They note that it takes 1 to 6 weeks for changes to be noticed by the patients - this is useful for anyone considering trying IV iron. Over half the patients benefited, for periods as long as 22 months, with slightly more than half improving enough to stop medication for an average of about 4-5 months. But oddly enough, the level of ferritin in their cerebrospinal fluid did not rise as their symptoms improved.


Various techniques used to assess brain iron concentrations have demonstrated the presence of low iron stores in patients with restless legs syndrome (RLS). Previous open-label and randomized studies generally support the value of iron treatment for RLS symptoms. Only one of these studies assessed iron therapy response to changes in brain iron status. The current study was designed to assess the effect of iron therapy on RLS symptoms and on CSF measures of brain iron status.

Idiopathic RLS patients drawn from the Korean population received four weekly intravenous (IV) doses of 250mg low-molecular weight iron dextran for a total dose of 1g. One week after the last dose, any subject on RLS medication tapered off the RLS medications. Blood and CSF samples were taken to measure iron parameters at baseline and again, three weeks after the last dose. We have been following their response to the drug for two years after treatment.

Twenty-five patients (age 55.2±9.3, 18 female) enrolled in this study without serious adverse reactions. Seventeen of the 25 patients (68%) showed moderate or complete improvement of all RLS symptoms after treatment based on the Korean-translated versions of the International RLS Severity scale (K-IRLS). Changes in the K-IRLS did not correlate significantly with changes in CSF ferritin. The response to IV iron could not be predicted by patients’ demographics, or by blood or CSF iron baseline characteristics. RLS symptom improvement started between one and six weeks after treatment and the treatment benefits lasted from one month to 22months. Fourteen patients, (56%) completely stopped all medications, for a mean duration of 31.3±33.1weeks. These results are comparable to those from a prior study with high molecular weight dextran.

Intravenous low-molecular weight iron dextran produced significant improvement of RLS symptoms in a majority of patients without any significant adverse effects. Serious anaphylaxis occurs with high molecular weight, but rarely, if ever, with this low molecular weight dextran. Given apparent comparable efficacy the low molecular weight and not the high molecular weight iron dextran, should be considered for RLS treatment. Although changes in CSF ferritin were seen following therapy, these changes were not related to clinical improvements.

Re: Published Research - General Sleep and WED (RLS)

Posted: Sat Jun 08, 2013 1:55 am
by erika13
Another fascinating study that's just been published on different protein levels in the cerebral spinal fluid of women with and without WED / RLS:

The Protein Profile of Restless Leg Syndrome
June 7, 2013 — A protein profile of people with restless leg syndrome (RLS) identifies factors behind disrupted sleep, cardiovascular dysfunction and pain, finds research in BioMed Central's open access journal Fluids and Barriers of the CNS. The research gives insights into the disorder, and could be useful in the development of new treatments.
It is not completely clear what causes RLS, also known as Willis Ekbom disease (WED), but in some people it is associated with iron deficiency in the brain, kidney failure, or low levels of the 'pleasure' neurotransmitter dopamine. It can also occur during pregnancy. It affects between 5 and 10% of the population and symptoms, which can range in severity, including sleep deprivation and decreased ability to work can lead to a reduction in quality of life. It is also a risk factor for cardiovascular disease.
Comparing the cerebral spinal fluid (CSF) of women with and without RLS, researchers from the US and Korea discovered there was a significantly altered level of six specific proteins with RLS. Dr Stephanie Patton from Penn State University who led this study explained, "Our results reveal a protein profile in the RLS/WED CSF that is consistent with iron deficiency, dopamine dysregulation and inflammation."
These proteins include a protein which transports vitamin D into cells and is involved in the regulation of dopamine levels, cystatin C -- a biomarker for pain found in people with sciatica and during labor, and a neuromodulator (PTGDS) known to be involved in sleep disturbances. Levels of apolipoprotein (Apo) A1 were lower with RLS and may be related to the increased risk of cardiovascular disease.
The importance of iron's role in RLS is highlighted by the presence of B-hemoglobin in the CSF of women with RLS, while levels of a glycoprotein (AGP) were reduced. AGP is involved in response to inflammatory damage and requires the presence of iron for it to be protective.
Dr Stephanie Patton continued, "Although a small study, this CSF protein profile is consistent with observed neuropathological findings and supports existing hypotheses about the biology behind RLS/WED, which could prove clinically important in developing new treatments."
Journal Reference:
1. Stephanie M Patton, Yong Won Cho, Thomas W Clardy, Richard P Allen, Christopher J Earley, James R Connor. Proteomic analysis of the cerebrospinal fluid of patients with restless legs syndrome/Willis-Ekbom disease. Fluids and Barriers of the CNS, 2013; 10 (1): 20 DOI: 10.1186/2045-8118-10-20

Re: Published Research - General Sleep and WED (RLS)

Posted: Sat Jun 08, 2013 2:19 am
by ViewsAskew
I just came to post the same study, Ericka! Thanks for being so thoughtful and proactive - we appreciate it.

I also thought this was very interesting. Most puzzles pieces are being found - not enough yet, but I'm hopeful that we're getting closer to figuring this out.