Tired all the time: Could undiagnosed sleep problems be making MS patients’ fatigue worse?

People with multiple sclerosis (MS) might assume that the fatigue they often feel just comes with the territory of their chronic neurological condition.

But a new University of Michigan study suggests that a large proportion of MS patients may have an undiagnosed sleep disorder that is also known to cause fatigue. And that disorder – obstructive sleep apnea – is a treatable condition.

In the latest issue of the Journal of Clinical Sleep Medicine, researchers from the U-M Health System’s Sleep Disorders Center report the results of a study involving 195 patients of the U-M Multiple Sclerosis Center.

In all, 56 percent of the MS patients were found to be at increased risk for obstructive sleep apnea, based on a method of screening for the condition known as the STOP-Bang questionnaire. But most had never received a formal diagnosis of sleep apnea, and less than half of those who had been told they had sleep apnea were using the standard treatment for it. 

The authors also found that patients who were more fatigued were more likely to also be at elevated risk for sleep apnea – even after taking into account other factors that might have contributed to feelings of fatigue, such as age, gender, body mass index (BMI), sleep duration, depression, and other nighttime symptoms.

The research is based on patients’ answers from a sleep questionnaire designed by the authors, and four validated instruments designed to assess daytime sleepiness, fatigue severity, insomnia severity and obstructive sleep apnea risk. Medical records also were accessed with patients’ permission, to examine clinical characteristics that may predict fatigue or obstructive sleep apnea risk.

“We were particularly surprised by the difference between the proportion of patients who carried an established diagnosis of obstructive sleep apnea – 21 percent — and the proportion at risk for obstructive sleep apnea based on their STOP-Bang scores, which was 56 percent,” says the study’s lead author, Tiffany Braley, M.D., M.S. “These findings suggest that OSA may be a highly prevalent and yet under-recognized contributor to fatigue in persons with MS.” 

Braley, an assistant professor of Neurology and multiple sclerosis specialist at the U-M Medical School, conducted the study in collaboration with professors Ronald Chervin, M.D., M.S., and Benjamin Segal, M.D.  Chervin is the Director of U-M Sleep Disorders Center, and Segal directs the U-M MS Center.

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system that causes inflammation and damage of the brain and spinal cord. In addition to neurological disability, MS patients suffer from a number of chronic symptoms, the most common of which is fatigue.  Fatigue is also one of the most disabling symptoms experienced by MS patients.

Braley cautions that the design of this new study does not allow for demonstration of cause and effect – that is, the researchers can’t prove based on survey results that the patients felt more fatigued because they had a high score on a sleep apnea risk survey.  But, she says, “the findings should prompt doctors who treat MS patients to consider sleep apnea as a possible contributor to their patients’ fatigue, and recommend appropriate testing and treatment.”

The standard treatment for obstructive sleep apnea, called continuous positive airway pressure, or CPAP, involves a machine and mask device that applies a stream of air to the upper airway to keep it open during sleep. 

The patients in the study had an average age of 47 and had lived with MS for an average of 10 years. Two-thirds were female, consistent with the prevalence of MS in the U.S., and two-thirds were taking a medication to treat their MS. Three-quarters had the relapsing-remitting form of the disease.

Contrast Agent Linked with Brain Abnormalities on MRI

For the first time, researchers have confirmed an association between a common magnetic resonance imaging (MRI) contrast agent and abnormalities on brain MRI, according to a new study published online in the journal Radiology. The new study raises the possibility that a toxic component of the contrast agent may remain in the body long after administration.

Brain MRI exams are often performed with a gadolinium-based contrast medium (Gd-CM). Gadolinium’s paramagnetic properties make it useful for MRI, but the toxicity of the gadolinium ion means it must be chemically bonded with non-metal ions so that it can be carried through the kidneys and out of the body before the ion is released in tissue. Gd-CM is considered safe in patients with normal kidney function.

However, in recent years, clinicians in Japan noticed that patients with a history of multiple administrations of Gd-CM showed areas of high intensity, or hyperintensity, on MRI in two brain regions: the dentate nucleus (DN) and globus pallidus (GP). The precise clinical ramifications of hyperintensity are not known, but hyperintensity in the DN has been associated with multiple sclerosis, while hyperintensity of the GP is linked with hepatic dysfunction and several diseases.

To learn more, the researchers compared unenhanced T1-weighted MR images (T1WI) of 19 patients who had undergone six or more contrast-enhanced brain scans with 16 patients who had received six or fewer unenhanced scans. The hyperintensity of both the DN and the GP correlated with the number of Gd-CM administrations.

"Hyperintensity in the DN and GP on unenhanced MRI may be a consequence of the number of previous Gd-CM administrations," said lead author Tomonori Kanda, M.D., Ph.D., from Teikyo University School of Medicine in Tokyo and the Hyogo Cancer Center in Akashi, Japan. "Because gadolinium has a high signal intensity in the body, our data may suggest that the toxic gadolinium component remains in the body even in patients with normal renal function."

Dr. Kanda noted that because patients with multiple sclerosis tend to undergo numerous contrast-enhanced brain MRI scans, the hyperintensity of the DN seen in these patients may have more to do with the large cumulative gadolinium dose than the disease itself.

The mechanisms by which Gd-CM administration causes hyperintensity of the DN and GP remain unclear, Dr. Kanda said. Previous studies on animals and humans have shown that the ion can be retained in bone and tissue for several days or longer after administration.

"The hyperintensity of DN and GP on unenhanced T1WI may be due to gadolinium deposition in the brain independent of renal function, and the deposition may remain in the brain for a long time," Dr. Kanda suggested.

Dr. Kanda emphasized that there is currently no proof that gadolinium is responsible for hyperintensity on brain MRI. Further research based on autopsy specimens and animal experiments will be needed to clarify the relationship and determine if the patients with MRI hyperintensity in their brains have symptoms.

"Because patients who have multiple contrast material injections tend to have severe diseases, a slight symptom from the gadolinium ion may be obscured," Dr. Kanda said.

There are two types of Gd-CM , linear and macrocyclic, with distinct chemical compositions. Since the patients in the study received only the linear type, additional research is needed to see if the macrocyclic type can prevent MRI hyperintensity, according to Dr. Kanda.

A simple eye test for multiple sclerosis

As you step outdoors into the bright sunshine, your pupils automatically contract. Scientists from the Australian Centre of Excellence in Vision Science (ACEVS) based at The Australian National University (ANU) are making use of how this ‘pupil reflex’ is connected to the brain as a potential new way of testing the severity of multiple sclerosis (MS).

Dr Eman Ali and her ACEVS colleagues have used an instrument they are developing to accurately measure the pupil responses of MS patients and have found that the pupils of MS sufferers respond appreciably slower. The finding opens the door to a simple and quick way of tracking the severity of MS over time: the slower the response, the worse the MS.

“Our instrument uses special patterns of flashing lights that the patient looks at for four minutes,” says Professor Ted Maddess, a vision scientist at ANU who is head of the ACEVS team.

“We use infrared cameras to measure light-induced changes in the diameters of both pupils, and with computer tracking we can measure the diameter to within a micrometre 30 times a second.

“We have just published the results of our study of 85 MS patients, and we find that in MS patients the pupil response is about 25 milliseconds slower than in our control group. Although the study is preliminary, we believe the test has good potential in individual patients because it can precisely measure the speed of their response to within a millisecond.

“So instead of an expensive MRI to track the condition, the new method gives an accurate readout after just a few minutes. That quick and easy test might, in the future, allow MS patients to be assessed on the spot and have their medication adjusted accordingly,” he says.

MS is a potentially devastating neurological condition affecting the myelin sheath of nerve fibres, leading to sensory disturbances and muscle weakness. Vision, speech, and walking are most often affected, and pain can occur. Puzzlingly, MS affects different people in different ways, but the condition inexorably gets worse with age and there is currently no cure. Some patients experience acute, inflammatory attacks while others don’t.

“MS is the most common neurological disability in adults, with about 12,000 sufferers in Australia,” says Professor Maddess. “Although it seems to be some sort of immune disorder, its cause is still obscure.

“There are many puzzling aspects to MS, and there are many theories,” he says. “But our main aim in this work was just to find a way of accurately monitoring the progression of the disease, a single measure that relates to the degree of disability. MRI is good for giving insight into the inflammation associated with episodic attacks, but it’s not so good at monitoring the chronic decline that’s always going on.

“If we can use our pupil measurements to monitor the decline, we might be in a better position to adjust medications, which often have unpleasant side-effects.”

The instrument to measure the pupil responses is the same one which has also been shown to be helpful in diagnosing vision loss in glaucoma, diabetes, and age-related macular degeneration. The device was developed by Professor Maddess together with Associate Professor Andrew James and other ACEVS team members. Under the name TrueField, it is being commercially developed by an Australian company, Seeing Machines, which plans to sell it as a multipurpose medical diagnostic instrument.

TrueField has already received American FDA clearance, and Professor Maddess is hopeful it might, after some more research, also find a role in monitoring MS. He believes it has good prospects of reducing the high treatment costs associated with the disease.

The paper by Dr Ali and colleagues, “Pupillary response to sparse multifocal stimuli in multiple sclerosis patients”, is available online in the Multiple Sclerosis Journal.

Molecular sensor detects early signs of multiple sclerosis

For some, the disease multiple sclerosis (MS) attacks its victims slowly and progressively over a period of many years. For others, it strikes without warning in fits and starts. But all patients share one thing in common: the disease had long been present in their nervous systems, hiding under the radar from even the most sophisticated detection methods. But now, scientists at the Gladstone Institutes have devised a new molecular sensor that can detect MS at its earliest stages—even before the onset of physical signs.

In a new study from the laboratory of Gladstone Investigator Katerina Akassoglou, PhD, scientists reveal in animal models that the heightened activity of a protein called thrombin in the brain could serve as an early indicator of MS. By developing a fluorescently labeled probe specifically designed to track thrombin, the team found that active thrombin could be detected at the earliest phases of MS—and that this active thrombin correlates with disease severity. These findings, reported online in Annals of Neurology, could spur the development of a much-needed early-detection method for this devastating disease.

MS, which afflicts millions of people worldwide, develops when the body’s immune system attacks the protective myelin sheath that surrounds nerve cells. This attack damages the nerve cells, leading to a host of symptoms that include numbness, fatigue, difficulty walking, paralysis and loss of vision. While some drugs can delay these symptoms, they do not treat the disease’s underlying causes—causes that researchers are only just beginning to understand.

Last year, Dr. Akassoglou and her team found that a key step in the progression of MS is the disruption of the blood brain barrier (BBB). This barrier physically separates the brain from the blood circulation and if it breaks down, a blood protein called fibrinogen seeps into the brain. When this happens, thrombin responds by converting fibrinogen into fibrin—a protein that should normally not be present in the brain. As fibrin builds up in the brain, it triggers an immune response that leads to the degradation of the nerve cells’ myelin sheath, over time contributing to the progression of MS.

"We already knew that the buildup of fibrin appears early in the development of MS—both in animal models and in human patients, so we wondered whether thrombin activity could in turn serve as an early marker of disease." said Dr. Akassoglou, who directs the Gladstone Center for In Vivo Imaging Research (CIVIR). She is also a professor of neurology at the University of California, San Francisco, with which Gladstone is affiliated. "In fact, we were able to detect thrombin activity even in our animal models—before they exhibited any of the disease’s neurological signs."

Quantity, not just quality, in new Stanford brain scan method

Researchers used magnetic resonance imaging to quantify brain tissue volume, a critical measurement of the progression of multiple sclerosis and other diseases.

Imagine that your mechanic tells you that your brake pads seem thin, but doesn’t know how long they will last. Or that your doctor says your child has a temperature, but isn’t sure how high. Quantitative measurements help us make important decisions, especially in the doctor’s office. But a potent and popular diagnostic scan, magnetic resonance imaging (MRI), provides mostly qualitative information.

An interdisciplinary Stanford team has now developed a new method for quantitatively measuring human brain tissue using MRI. The team members measured the volume of large molecules (macromolecules) within each cubic millimeter of the brain. Their method may change the way doctors diagnose and treat neurological diseases such as multiple sclerosis.

"We’re moving from qualitative – saying something is off – to measuring how off it is," said Aviv Mezer, postdoctoral scholar in psychology. The team’s work, funded by research grants from the National Institutes of Health, appears in the journal Nature Medicine.

Mezer, whose background is in biophysics, found inspiration in seemingly unrelated basic research from the 1980s. In theory, he read, magnetic resonance could quantitatively discriminate between different types of tissues.

"Do the right modifications to make it applicable to humans," he said of adapting the previous work, "and you’ve got a new diagnostic."

Previous quantitative MRI measurements required uncomfortably long scan times. Mezer and psychology Professor Brian Wandell unearthed a faster scanning technique, albeit one noted for its lack of consistency.

"Now we’ve found a way to make the fast method reliable," Mezer said.

Mezer and Wandell, working with neuroscientists, radiologists and chemical engineers, calibrated their method with a physical model – a radiological “phantom” – filled with agar gel and cholesterol to mimic brain tissue in MRI scans.

The team used one of Stanford’s own MRI machines, located in the Center for Cognitive and Neurobiological Imaging, or CNI. Wandell directs the two-year-old center. Most psychologists, he said, don’t have that level of direct access to their MRI equipment.

"Usually there are many people between you and the instrument itself," Wandell said.

This study wouldn’t have happened, Mezer said, without the close proximity and open access to the instrumentation in the CNI.

Their results provided a new way to look at a living brain.

MRI images of the brain are made of many “voxels,” or three-dimensional elements. Each voxel represents the signal from a small volume of the brain, much like a pixel represents a small volume of an image. The fraction of each voxel filled with brain tissue (as opposed to water) is called the macromolecular tissue volume, or MTV. Different areas of the brain have different MTVs. Mezer found that his MRI method produced MTV values in agreement with measurements that, until now, could only come from post-mortem brain specimens.

This is a useful first measurement, Mezer said. “The MTV is the most basic entity of the structure. It’s what the tissue is made of.”

The team applied its method to a group of multiple sclerosis patients. MS attacks a layer of cells called the myelin sheath, which protects neurons the same way insulation protects a wire. Until now, doctors typically used qualitative MRI scans (displaying bright or dark lesions) or behavioral tests to assess the disease’s progression.

Myelin comprises most of the volume of the brain’s “white matter,” the core of the brain. As MS erodes myelin, the MTV of the white matter changes. Just as predicted, Mezer and Wandell found that MS patients’ white matter tissue volumes were significantly lower than those of healthy volunteers. Mezer and colleagues at Stanford School of Medicine are now following up with the patients to evaluate the effect of MS drug therapies. They’re using MTV values to track individual brain tissue changes over time.

The team’s results were consistent among five MRI machines.

Mezer and Wandell will next use MRI measurements to monitor brain development in children, particularly as the children learn to read. Wandell’s previous work mapped the neural connections involved in learning to read. MRI scans can measure how those connections form.

"You can compare whether the circuits are developing within specified limits for typical children," Wandell said, "or whether there are circuits that are wildly out of spec, and we ought to look into other ways to help the child learn to read."

Tracking MTV, the team said, helps doctors better compare patients’ brains to the general population – or to their own history – giving them a chance to act before it’s too late.