AAN Meeting Presentations Highlight ALS Biomarkers, Risk Factors, Mechanisms

by Margaret Wahl

Biomarkers are a major focus of studies at the ALS Therapy Development Institute.

The 61st annual meeting of the American Academy of Neurology (AAN), held in Seattle April 25-May 2, 2009, included several ALS-related presentations.

Three concerned identification of biological markers (biomarkers), which indicate the presence or progression of ALS. Biomarkers are important for diagnosis of the disease and as a way to follow the effects of experimental treatments. They’re a major focus of MDA-supported studies at the ALS Therapy Development Institute (www.als.net) in Cambridge, Mass.

Additional presentations included descriptions of disease mechanisms, an analysis of smoking as a risk factor, and a possible new therapeutic avenue.

Neurofilament may correlate with ALS progression

Blood levels of a protein called “neurofilament heavy subunit” were higher, on average, in people with ALS than in the control (unaffected) group, in a study conducted by Kevin Boylan at the Mayo Clinic in Jacksonville, Fla., and colleagues. (Boylan directs the MDA clinic at that institution.)

The researchers measured neurofilament heavy subunit levels monthly for four months in 19 people with sporadic (nonfamilial) ALS and 19 people without ALS. Higher baseline neurofilament levels showed weak evidence of correlating with faster decline in ALS Functional Rating Scale scores over the course of the study.

The investigators said these preliminary results suggest that plasma neurofilament heavy chain levels may correlate with disease progression and that further study of these levels as a potential ALS biomarker are warranted.

Ferritin protein levels correlate with faster disease course, poorer survival

Muddasir Qureshi at Massachusetts General Hospital in Boston, and colleagues, found that levels of ferritin, a protein involved in iron storage, are correlated with survival and rate of disease progression in ALS.

Merit Cudkowicz, an MDA research grantee and director of the MDA ALS Center at Massachusetts General, was part of this research team.

The investigators measured serum ferritin levels in 90 people with ALS and 90 unaffected people and found the levels were higher in the ALS patients. When they followed a group of 99 ALS patients over the course of a year, they found that an increase in ferritin levels was associated with a more rapid decline in muscle strength in the arms and legs. Higher ferritin levels also correlated with reduced survival.

They say further study of the possible role of ferritin in ALS is warranted, particularly in relation to genetic variations.

Loss of skin elasticity goes along with ALS

Dematologist Harvey Arbesman of Williamsville, N.Y., and colleagues, found that skin elasticity was significantly reduced in 40 ALS patients, as compared to a control group of 30 unaffected family members.

Hiroshi Mitsumoto, an MDA research grantee and MDA/ALS Center director at Columbia University Medical Center in New York, was on the study team.

The researchers used a device called a Cutometer, which noninvasively measures the extent to which skin returns to its original position after pressure is applied.

The ALS and control groups were evaluated at baseline and three months later, with skin measurements taken on their arms and back.

At the start of the study, skin elasticity in the arm was significantly less in people with ALS than in the control group. Skin elasticity on the back was significantly correlated with disease progression in the ALS group, becoming less elastic as scores on the ALS Functional Rating Scale and respiratory capacity declined.

The researchers noted that the central nervous system and skin share the same embryologic origin and that many diseases affect both systems. They said further studies are needed, but that skin elasticity could be a valuable, noninvasive way to help detect ALS and assess disease progression.

Smoking correlated with increased risk of death from ALS

Exposure to tobacco smoke appears to increase the risk of dying from ALS, according to a study conducted by Valentina Gallo at Imperial College London and colleagues.

Out of 517,890 apparently healthy subjects who began participating in a European study 10 years ago, 118 have died from ALS.

Those listed as current smokers in the study died from ALS at twice the rate of people who never smoked, while those who said they were former smokers were 1.63 times more likely to die from ALS than those who never smoked.

Those who smoked more than 33 years were almost 2.5 times more likely to die from ALS than those who never smoked.

Small antibody sticks to ALS-causing protein abnormality

Raymond Roos at the University of Chicago and colleagues have developed a protein called a “single-chain antibody” that specifically sticks to one type of ALS-causing genetic abnormality. They say this protein has therapeutic potential against a type of familial (inherited) ALS caused by the so-called A4V mutation in the SOD1 gene. The A4V mutation causes the SOD1 protein to take on highly toxic properties in cells.

Antibodies are proteins generated by the immune system, usually to ward off bacteria, viruses and other threats to health. Laboratory developed antibodies are widely used to diagnose diseases. Most naturally occurring antibodies have more than one chain and don’t enter cells, but laboratory-engineered antibodies with a single chain can enter cells and are sometimes called “intrabodies.” The investigators say intrabodies might be effective against various types of SOD1-related familial ALS.

Intrabodies potentially could be developed that would help in nonfamilial (sporadic) ALS too, because it’s been suggested that SOD1 protein abnormalities also may be present in this more common form of the disease.

’Splicing’ errors may be part of nonfamilial ALS

John Ravits at the Benaroya Research Institute at Virginia Mason Medical Center in Seattle, and colleagues, found that abnormalities in a cellular process called “splicing” were much more common in people with ALS than in people without the disease.

Before a protein can be made from a gene, a rough draft of the protein recipe is first created. The rough draft is made of RNA, which is similar to DNA, and contains sections that the cell splices out before a final protein recipe is made.

Abnormalities in the splicing process can cause disease, and they have been implicated in another motor neuron disease, spinal muscular atrophy. (ALS is a motor neuron disease.)

In nonfamilial (sporadic) ALS, a protein called TDP43 shifts from its proper place in the nucleus, where it normally participates in the splicing process, to outside the nucleus, where it forms clumps.

When Ravits and colleagues analyzed the nervous systems in autopsy samples from 12 people who died of nonfamilial ALS and 10 who died of non-neurologic causes, they found significantly more alternative splicing patterns, at least some of which are likely harmful, in the ALS samples compared to the samples free of neurologic disease.

They concluded that splicing abnormalities are probably part of the ALS disease mechanism.

Death of Spinal Cord Neurons in ALS Dampens Protective Mechanism

A vicious cycle of nerve cell damage and loss has been identified as a possible contributor to ALS. Identification of this pathway opens the door to targeting it with therapeutic agents.

Glutamate carries signals between neurons (nerve cells), and there may be too much of it in ALS.

In the cycle, damage to nerve cells (neurons) in the spinal cord results in the loss of an important protective mechanism, causing more neuron loss.

MDA-supported Yongjie Yang at Johns Hopkins University in Baltimore, with colleagues there and at other institutions, describe experiments in mice that clarify the relationship between loss of neurons and loss of the protective mechanism that clears away glutamate from the vicinity of the neurons. The chemical glutamate, when present in excess, is potentially toxic.

The relationship between these phenomena was previously shown in laboratory studies involving cells but not animals.

Jeffrey Rothstein, director of the MDA/ALS Center at Johns Hopkins University in Baltimore, and an MDA research grantee, coordinated the investigators, and Yongjie Yang at Hopkins received direct MDA support for this project. The investigators published their findings March 26, 2009, in Neuron.

Normally, glutamate, a chemical transmitter of signals between nerve cells, is released by a sending neuron, docks on a receiving neuron, and is then quickly cleared away by glutamate transporter proteins produced by neighboring nervous system cells called “astrocytes.” Loss of one of these glutamate transporters, known as EAAT2, is believed to represent a common mechanism for disease propagation in both familial and nonfamilial ALS.

Yang and colleagues showed that, in mice, when glutamate docks on a receiving neuron, neighboring astrocytes start producing a protein called KBBP, which in turn activates production of a glutamate transporter protein called GLT1. These mouse proteins exist under different names in humans; the researchers say KBBP in mice is identical to the human protein hnRNP K, and GLT1 in mice is called EAAT2 in humans.

When the investigators analyzed the results in mice of spinal cord injury, poisoning by the neurotoxin ricin, and an ALS-causing genetic mutation in the gene for the SOD1 protein, they saw a marked drop in both KBBP production and GLT1 production. They surmised that the damage sustained by the glutamate-transmitting neurons caused a reduction in glutamate signaling, which in turn caused a reduction in glutamate clearance.

They say their studies suggest an unfortunate “feed-forward” mechanism, in which loss of glutamate clearance may be the final blow in the demise of neurons affected by various types of insults, including ALS.

Perrin Named Head of ALS TDI

On May 1, the ALS Therapy Development Institute (www.als.net) announced that Steve Perrin, the Institute’s chief scientific officer, would also assume the role of chief executive officer. Maureen Lister was appointed president at the same time.

The ALS TDI and MDA, through its Augie’s Quest initiative, are collaborating on a three-year, $36 million drug-discovery effort in ALS.

Perrin succeeds Sean Scott, who died of ALS this February. Perrin, who has a doctorate in biochemistry, came to the ALS TDI in 2007 from the Cambridge, Mass., biotechnology company Biogen Idec, where he was a principal scientist from 2000 to 2007.

Since he came to ALS TDI, Perrin has added new capabilities to the ALS drug-development pipeline and has assembled a research team of 30 full-time professionals to carry out dozens of projects.

Maureen Lister, a corporate operations and finance expert with experience in the biomedical and energy industries, joined ALS TDI in 2007 as chief financial officer. In 2008, she became chief operating officer and will continue to retain both titles, as well as additional responsibilities as president of the Institute.

by Bill Norman

A watercolor titled Pride of the Yankees is part of the MDA Art Collection. Painted by William Ross, who has ALS, the artwork captures the emotion of the moment when Lou Gehrig gave his farewell address in Yankee Stadium 70 years ago.

July 4 is a date that holds special significance not only for America, but for MDA and Major League Baseball (MLB) as well.

July 4 is the date in 1939 when Lou Gehrig, legendary first baseman and slugger for the New York Yankees, delivered an emotional farewell speech to 62,000 fans in Yankee Stadium, in the New York City borough of the Bronx.

After more than 13 years and 2,130 sequential games played for the Yankees, Gehrig, the “Iron Horse,” called it quits — not because he wanted to, but because he was feeling the paralyzing effects of ALS, the disease that would become known in time as “Lou Gehrig’s disease.”

Gehrig a tireless worker

ALS plays no favorites in the people it affects; even so, learning that stalwart Lou Gehrig had the disease was a shock to most who knew him. Born of poor German immigrant parents in New York, he was always among the largest and strongest of his classmates.

Although he eventually rose to fame in major league baseball, Gehrig first attended Columbia University on a football scholarship.

Even when baseball scouts saw Gehrig belting balls incredible distances, he wasn’t an overnight sensation. Author Ray Robinson wrote in his biography Iron Horse: Lou Gehrig in His Time (Harper, 1991), “It was always clear that Lou had not come to the major leagues as a born player. He was not a ‘natural’ in any true sense of the word. Only grim determination to succeed, plus his magnificent physique and stamina, had enabled him to make his way with the Yankees.”

Sportswriter Jim Murray called Gehrig “a Gibraltar in cleats.” Another writer described him as looking like a Percheron horse when running between bases. Yet another said he “carried around a body built along the lines of a railroad locomotive.” And his wife Eleanor recalled, “When he got into pro baseball, he was so muscle bound that he almost fell over his own feet.”

Gehrig had lifted weights as a boy and young man, which is how his 6-foot frame eventually came to weigh 200-plus pounds. When he first began playing baseball, fans called him “Buster,” for his batting prowess. Later, he became known as the “Iron Horse” for his endurance and perseverance, even when injured. When he was in his 30s, doctors X-rayed his hands and found 17 different fractures that he had endured while continuing to play.

‘Kind of an adult Eagle Scout’

Eleanor had him pegged. He was, she said, “sensitive, but not demonstrative, a huge but proper wallflower, maybe shy, maybe even square. Kind of an adult Eagle Scout, a 6-footer with strength, stamina and an unreal threshold of pain.”

Robinson wrote in Iron Horse of Gehrig’s “grim commitment” to baseball and noted that, “With chilling foresight [Babe] Ruth said he thought Lou might be hurting himself by forcing his body into Yankee pinstripes day after day.”

Ruth, a Yankees icon, was eight years older than Gehrig, but for several years they shared the stadium spotlight with their magnificent batting prowess. In 1927, when Gehrig was 24,Ruth batted .356 with 60 home runs and 164 runs batted in (RBIs). Gehrig hit .373 with 47 homers and 175 RBIs. In 1934, he won the batting Triple Crown with a .363 average, 49 home runs and 165 RBIs. He was named Most Valuable Player in 1936.

Ruth’s hitting power began to wane with age, and he slowed down as he became increasingly overweight. Gehrig was in his prime, just as rising star Joe DiMaggio, 11 years his junior, joined the Yankees and paired his power with Gehrig, as Gehrig had with Ruth. The Yankees were a sports steamroller.

The first warning signs of ALS

But Gehrig’s heroic performances were about to come to an end. He first began to feel the effects of ALS, even though he didn’t know what his ailment was, in 1938.

At a Yankees game in Detroit, after hitting a single, he stumbled while running to first base. When he bent over to get his breath, he found it took almost superhuman effort to straighten back up. Gehrig dismissed it as a “cold” in his back and was quoted as saying, “I’ll shake it off. That’s what I’ve always done.”

But he was moving slower, and his swings didn’t have their former prodigious power. From his all-time high salary of $39,000, he took a $3,000 cut for his 1938 performance. He said it was just a bad year, and he’d do better in 1939.

In the winter of 1938, Gehrig went ice skating and lost his balance several times, falling to the ice. During spring batting practice in 1939, he missed 19 straight pitches, ones that in earlier times he’d have belted out of the county. In the locker room, he fell down when changing his pants.

The end of a streak

The first game of 1939 was on April 20. Gehrig, in his customary first-base position, appeared to have lost nearly all of his former catching, throwing and hitting abilities. Two weeks later, the Iron Horse’s 2,130-game streak came to an end.

“On that May 2 afternoon,” Robinson wrote, “the Yankee clubhouse … was like a graveyard. …[T]he melancholy grapevine had reached the players. Most of them spoke in whispers as they started to dress for a game they wished would never take place.”

But Gehrig insisted on playing one more time, on June 12 in a game against Kansas City. He lasted until the third inning. When he caught a line drive, it literally knocked him over backward.

Gehrig had been under the care of a New York doctor who was convinced the problem was gallbladder-related and prescribed a bland diet. The day after the Kansas City game, Eleanor arranged for Gehrig to be evaluated at the Mayo Clinic in Rochester, Minn., by Dr. Charles Mayo himself.

Diagnosis on his birthday

The Mayo Clinic physicians mailed their ALS diagnosis to Eleanor one week later; it arrived on Gehrig’s 36th birthday.

For a while, he continued to suit up and travel with the Yankees, but the end of his team involvement was in sight. When he made his historic July 4 farewell address, it probably came as a shock to many fans, but for Gehrig and those close to him, it must have seemed inevitable.

After Gehrig’s retirement, New York Mayor Fiorello La Guardia personally arranged for him to work at a desk job for the city, but it didn’t last long. His voice was growing husky; his hands trembled.

In the final months before his death on June 2, 1941, hundreds of friends, family, top sports figures, people in show business and others came by the Gehrig household almost every night, for dinner and to visit. But eventually, Gehrig took all his meals in his room. He had lost more than 80 pounds and didn’t want to be seen by the public. Every morning a doctor came by and “treated” him with an injection of vitamin E.

Eleanor Gehrig and Jerry Lewis in the 1950s.

When Lou Gehrig died, more than 1,500 telegrams from wellwishers flooded his home. Thousands of fans formed lines more than four blocks long to view his body in state. He and Eleanor (who died in 1984) are buried in Valhalla, N.Y., just a short distance from Babe Ruth’s grave. Soon after his death, Gehrig was inducted into the Baseball Hall of Fame.

Eleanor, MDA join forces

MDA was formed in 1950 and Gehrig’s widow quickly volunteered to serve as the Association’s national campaign chairman.

The late Robert Ross, MDA’s former president and CEO, worked closely with Eleanor Gehrig in the 50s and 60s. He commented in 2001, “The urgency she [Eleanor] conveyed to me in those early days about the need to defeat ALS is something I feel palpably to this day.”

Since its inception, MDA has spent more than $250 million in ALS research and services. Its programs share Eleanor’s unshakable conviction that ALS must be defeated, and Lou’s “Iron Horse” stamina to see the journey through.

This Independence Day, on the 70th anniversary of Gehrig’s farewell speech, Major League Baseball will conduct activities throughout the country to honor Gehrig’s memory and raise funds to support ALS research.

On July 4, MLB teams will wear 4♦ALS patches on their uniforms, and home teams will host on-field readings of Gehrig’s farewell speech during the seventh inning. Other MLB fundraising activities include raffling off luxury suites at the MLB home games, various in-stadium promotions and an online auction to be conducted after July 4, at mlb.com. Items to be auctioned off include first bases from each home game, in recognition of Gehrig’s position as first baseman.

The 4♦ALS effort will benefit four organizations: MDA’s Augie’s Quest, the ALS Therapy Development Institute (ALS TDI), the ALS Association and Project A.L.S.

“Major League Baseball is making a huge difference in the fight against Lou Gehrig’s disease through this July 4 effort,” said Augie Nieto, 51, MDA ALS Division co-chairman, and founder and chief inspiration officer for MDA’s Augie’s Quest. (Nieto received an ALS diagnosis in 2005.)

“Both in terms of public awareness and fundraising, the MLB contribution is significant and will have a profound impact on the spirits of people living with this devastating disease.”

To learn more about the 4♦ALS event, get links to press releases and set up your own fundraising Web page, go to www.joinmda.org/4ALS.

by Alyssa Quintero

Communication is a lifeline for MDA ALS Division Co-Chair Augie Nieto, and he continues testing new ways to stay connected with the world.

Although ALS has robbed Augie Nieto of his ability to speak, Nieto’s “voice” continues to be heard as he leads the charge toward finding a cure.

Nieto, MDA ALS Division co-chair and founder of MDA’s Augie’s Quest ALS research initiative, spends hours on the computer, communicating with people around the globe and working to raise ALS awareness.

With the aid of his alternative, augmentative communication (AAC) device, Nieto’s also able to answer questions during media interviews and other public appearances.

For Nieto, who received a diagnosis of ALS in March 2005, “communication is everything.”

“It means being able to interact with my family, friends and colleagues,” Nieto, 51, wrote via e-mail. “Communication is what makes us human, and it’s what gives me the desire to continue living.”

Finding new ways to do it all

In 2006, as ALS began affecting his upper body strength and speech, Nieto began working with Computer Dx owner Troy Jurgensen, based in Corona del Mar, Calif., to find alternative computer access solutions. (From the collaboration, Computer Dx, www.computerdx.com, launched a division dedicated to exploring communication tools and assistive technology solutions for people with ALS.)

For more than three years, Nieto has used a large, yellow trackball mouse to type with his feet. He currently types 40 words per minute. (For more, see “Let Your Feet Do the Talking,” March 2008. Go to www.als-mda.org/publications and select “back issues” from the left menu.)

In conjunction with the foot mouse, Nieto uses the Dasher program (www.inference.phy.cam.ac.uk/dasher) to type e-mails and other documents. Dasher is a free, downloadable text-entry interface that’s operated by continuous pointing gestures called “zooming.” It features energy-saving features like word completion and remembering commonly used words.

Following the philosophy of always staying a few steps ahead of ALS, Nieto and Jurgensen recently started testing an alternative computer access method — eye-tracking technology. After trying other eye-tracking equipment, Nieto began using the Dynavox EyeMax (www.dynavoxtech.com) in September 2008.

Changing from one communication access method to another should be gradual, so the person doesn’t feel overwhelmed, said Jurgensen.

“Our goal with Augie is that by the time he needs to make the change to using the EyeMax only, he will be very comfortable and proficient with it, as opposed to frustrated that he is having to learn something new … again.”

‘Eye’ toward success

Nieto’s been comfortable with the EyeMax from the outset, using it to generate speech, send e-mails, have video conferences via Skype (Internet phone access) and even write a book. But he hasn’t given up using the foot mouse with his desktop computer just yet.

“I know that at some point, I will no longer be able to control my foot, so I continue to use the DynaVox more and more to prepare for that day,” Nieto explained.

The EyeMax system has two parts — the Vmax speech-generating device (retail price is $8,420 for a dedicated/integrated version) and the EyeMax accessory ($7,000).

(Medicare only will fund dedicated, or speech-only, versions of communication systems, not integrated versions that also function as full computers. But virtually all such systems, including the Vmax, are available in dedicated versions that can be “unlocked,” or turned into integrated versions, usually for an additional fee paid by the user.)

When Nieto isn’t positioned in front of his desktop computer with the foot mouse, he’s on the move with the EyeMax mounted to his power wheelchair. The EyeMax includes an internal battery and draws from the same power source as the Vmax, making the device more portable and less cumbersome for the user.

Nieto uses the system about three to four hours a day, and hasn’t had any problems using it with his glasses. The EyeMax offers users multiple input methods, including dwell only, dwell-blink combination, blink only, and activation and selection with a switch. When Nieto is using the built-in EyeMax communication software, he prefers to make selections by blinking, and can type 20 words per minute.

Nieto recently finished work on his second book, Reciprocity Inc., writing for about three hours each day, sometimes using the desktop computer with the foot mouse and other times the EyeMax.

“It went very well,” Nieto wrote via e-mail. “The book should be published in the fall, and I could not imagine writing the book without the DynaVox product [EyeMax]!”

Nieto also appreciates that the system maintains calibration, even when he leaves the device’s eyegaze window and returns to it later. The device also works well in different lighting environments, he says.

Familiar software eases transition

In addition to using the EyeMax’s built-in communication software, Nieto still relies on Dasher for much of his text-input needs. Nieto’s comfort with Dasher has been crucial, Jurgensen said, because as his access method changes from the foot mouse to the EyeMax, the text-input software has stayed the same. The continuity has helped shorten the learning curve for the new equipment.

At this point in his transition, Nieto admits it’s easier to use Dasher with the foot mouse, but says it’s just going to take more practice with the EyeMax. And, Jurgensen is investigating a more specialized Dasher text-entry software that’s optimized for use with the Vmax software and EyeMax.

Unlike the EyeMax’s built-in communication software, Dasher doesn’t require a person to blink, dwell or activate a switch to make selections with their eyes, said Amy Roman, an augmentative communication specialist and speech-language pathologist based at the Forbes-Norris MDA/ALS Research Center in San Francisco.

Since Dasher is a zooming interface, Nieto simply passes his eyes through a letter box to select a letter to form words, phrases and sentences, explained Roman, who has worked with Nieto on his communication system.

The user chooses what to write by continuously zooming, which Roman says can be an advantage for eyegaze users who find blinking difficult or tiring.

In addition to Dasher, Nieto also uses the AlphaCore Midsize add-on software ($350), developed by Amy Roman, to quickly create sentences with the EyeMax. (This software only works with the Dynovox V and Vmax devices.)

“It gives me quick access to high-frequency vocabulary with a single selection,” Nieto wrote. “It also allows me to store phrases in various categories for easy access, and it lets me store photo and video albums so I can share favorite photos.”

AlphaCore implements a combination of alphabetized core words, keyboards, sentence starters and stored messages that help users gain access to rapid message construction, as well as seamless telephone, e-mail, IM, text messaging and Internet access with little navigation.

“This technology has given me the power of hope,” Nieto writes. “With my eyes, I can speak, send e-mail, watch TV, operate the computer and control my environment. I’m the preacher for technology tools that help people live versus preparing to die.”

Medicare will cover up to 80 percent of the cost for an AAC device, and MDA offers a one-time $2,000 grant for communication devices prescribed through its clinics. MDA also will provide $500 annually for repairs and modifications, including equipment/software upgrades. Be sure to visit a speech-language pathologist to find the communication system that’s right for you.

by Amy Labbe

In mid-March, Mark Wenzel, who has ALS, and his wife, Martha, were visiting friends when a mucus plug blocked Mark’s airway.

Mucus plugs became a problem for Mark Wenzel when his cough reflex diminished and he lost the strength to produce a forceful cough.

Something that most would simply cough away left Wenzel, 55, unable to breathe, and — due to a “perfect storm” of circumstances — unable even to signal for help. The result was a wave of panic as the minutes ticked by.

Because mucus plugs represent a very real danger, it’s imperative that individuals with ALS and their caregivers learn how to prevent and cope with them.

Perfect storm

Wenzel, who lives in Phoenix, received an ALS diagnosis in September 2002, and his cough reflex began to wane about a year later. In 2004 he opted for a tracheostomy.

Wenzel uses a pulse oximeter (a small device that clips onto a finger or toe) to monitor his blood oxygen saturation, and a Ballard closed suction system for suctioning secretions from his airway and maintaining ventilation.

But that day in March, Wenzel had left his oximeter at home. He was sitting with Martha and their friends on a patio, with a waterfall and pool nearby that masked the sounds made when the mucus began to obstruct his airway.

“It was a sunny afternoon, so I had sunglasses on, which hid the look of panic in my eyes from my friends sitting beside me,” he says via e-mail, which he operates by an eye-control system. “Fortunately for me, my wife glanced at me from where she was sitting and saw my gray color, and quickly moved to suction my airway. It was a close thing.”

Generally, Mark is on the pulse oximeter day and night, says Martha. But the device’s internal battery doesn’t hold a charge very long, so the Wenzels don’t take it with them when they leave the house, leaving Mark “more vulnerable when we are out.”

Additionally, Wenzel says, he was around “people who were unfamiliar with how quickly a serious problem could develop.”

Excess mucus and inadequate coughing

Mucus plugging occurs when bronchial secretions accumulate to the point that they obstruct airflow. If the cough is weak and the plug cannot be cleared, the situation can be deadly.

Normally, the moist lining of the lungs produces small amounts of clear mucus, which trap dirt and bacteria from the air. This mucus is slowly swept out of the lungs by tiny hairs called cilia, and is cleared from the body by the forceful expulsion of air from the lungs — a cough.

In ALS, however, several factors reduce cough effectiveness:

• Weak muscles in the abdomen make it hard to cough forcefully.
• Weak muscles in the throat impair closing the glottis, or top of the throat, in order to build up pressure inside the chest for a cough.
• Weak diaphragm muscles, or a chest wall that’s stiff from underuse, make it difficult to take a good deep breath to initiate a forceful cough.

The result of a weak cough can be the buildup of dangerous quantities of mucus, creating a life-threatening medical situation.

Trachs add to risk

Tracheostomy tubes increase the likelihood of mucus plug formation, says John Bach, a physical medicine and rehabilitation specialist at University Hospital in Newark, N.J., and co-director of the MDA clinic there.

“Mucus plugs affect anyone with very weak throat muscles,” he says, “but tracheostomy tubes cause mucus plugs even when throat muscles are not weak.”

This is because the tracheostomy tube often stimulates increased secretion production. A trach also bypasses the natural defense systems that filter and humidify the upper airway.

In addition, lack of airflow over the larynx can lead to reduced sensation in that area and decreased reflexes to cough or clear the throat.

In the clear

The only treatment for a mucus plug is to somehow get it out.

One mucus-removal method is to produce a cough, either with a manual assist from a caregiver or through the use of a cough machine.

An abdominal thrust is a way to manually assist a cough. The person with ALS takes a deep breath and holds it. The caregiver places a hand on the person’s abdomen and thrusts in at the same time as the person coughs. If the person can take in enough air at the outset, this maneuver supplies the extra force needed to clear the airway. (Note, ask your MDA clinic for a demonstration of this maneuver.)

A cough machine, such as the In-Exsufflator distributed by Respironics, first delivers an inflow of air, and then rapidly reverses the pressure to produce a cough. Adapters can be purchased that allow these machines to be used with tracheostomies.

Another way to remove mucus is to suck it out. Suction machines use a wand or catheter to capture secretions from the mouth or throat.

“It can be difficult sometimes to get the plug high enough to reach with the suction catheter,” Mark notes. “When this happens, we’ve found that tilting the chair back is helpful or, sometimes, going to bed to get horizontal is helpful.”

Pulse ox to the rescue

Bach says he always prescribes pulse oximeters for people with weak coughs and ventilation problems. The device can be programmed to issue an alarm when oxygen saturation drops below 95 percent. This allows a growing mucus plug or other respiratory problem to be handled before it becomes life-threatening.

“Normal is 95 percent or greater oxygen saturation,” Bach says. “If it falls below 95 percent, it means either hypoventilation or airway mucus plugging,” and failure to take care of the latter can lead to pneumonia, lung collapse, and respiratory failure.

A pulse oximeter painlessly measures a person’s blood oxygen saturation. It can alert a user to airway mucus plugging or other respiratory problems.

In the beginning, Martha Wenzel says, she and Mark used the oximeter primarily at night. If Mark’s oxygen levels drop below a pre-set level or his pulse rate becomes too fast, an audible alarm alerts Martha to the problem.

“The audible alarm is what makes it so helpful,” Martha says, adding that Mark has had many close calls, some due to mucus plugs, and “the pulse ox has saved him many times.”

Other prevention strategies

When a trach tube is in place, using a humidifier can lessen the number and severity of mucus plugs by partially substituting for the humidifying function of the bypassed upper airway.

Wenzel uses a humidifier attached directly to his ventilator to warm and moisten the air coming through the trach tube.

Thinning the mucus offers another route for helping to prevent a plug. The first step is to keep well hydrated. From there, some physicians recommend over-the-counter expectorants such as guaifenesin (i.e., Mucinex), which thin out secretions and make them easier to cough up. Papaya, pineapple or lemon juice in water also can thin mucus. Surfactants, or wetting agents such as saline, loosen up mucus and help the lungs inflate more easily. Ice cream lovers beware: Some people find that dairy products seem to thicken their mucus.

Although there’s nothing that can definitively prevent a mucus plug, knowing what to expect and being prepared for the eventuality can turn a potentially life-threatening situation into one you can handle.