No Time for MS
Aug 20, 2019 Amy Paturel
As soon as 39-year-old Amy Fire sits down to take a breath, her 2-year-old son, Phoenix, hops into her lap. “Mommy, I want a snack,” he announces. A minute later, her 6-year-old son, Fenris, strides into the room. “Mommy, can you read me a book?”
Like many parents, Fire is used to juggling a few dozen balls simultaneously. The mother of two is also a PhD-level scientist.
“I like to stay busy,” she says, citing the built-in cabinets she fabricated from scratch while she was seven months pregnant with Phoenix and completing her thesis. Her latest project: working alongside her husband, Kaolin, at Grabango, a company that’s developing a checkout system to allow people to walk into a store, grab the items they want, pay and leave—all without stopping at a cashier.
Amid this busyness, Fire is also navigating multiple sclerosis (MS), a degenerative disease that attacks the fatty myelin sheaths that protect nerve cells and allow them to communicate. With MS, the patient’s immune system damages the healthy nerves in the brain and spinal cord. Like a fraying electrical wire, nerve cells with damaged myelin can short-circuit, causing a constellation of troubling symptoms ranging from blurry vision to trouble with balance and speech.
In Fire’s case, MS means she can’t count on her legs to do what they should. When she walks, they often give out. And if her kids play too roughly with her, they might knock her down. She also suffers from periodic fatigue, numbness in her left hand and occasionally feeling off-balance.
To prevent the neurological disease from progressing, Fire gives herself injections and, when it’s time for her thrice-weekly shot, both boys run into the room to watch. “They think it’s the coolest thing,” she says.
This is the changing face of MS, a disease that once sentenced women and men to wheelchairs and robbed them of their livelihoods, their independence and their chance to have a family. Scientists still don’t understand what causes the disease or how to definitively stop it from progressing—and many people suffer for years undiagnosed or misdiagnosed. But with advancing technology, refined diagnostic criteria and more than a dozen treatment options, there is hope.
Women are two to three times more likely to be diagnosed with MS than men, primarily between the ages of 20 and 50. Some are preparing to start a family or career, while others are in full swing, managing busy work schedules and households.
“Women are more susceptible than men to autoimmune diseases like MS,” says Nancy Sicotte, MD, director of the Multiple Sclerosis Program and the Women’s Guild Distinguished Chair in Neurology. “There are a lot of theories as to why they are disproportionately affected—hormones may play a role—but the bottom line is, we just don’t know yet.”
Fire has the most common and unpredictable form of the disease, called relapsing-remitting MS, where symptoms shift, striking various areas of the body. They can also spontaneously disappear (remit) or recur (relapse). Left untreated, relapsing-remitting MS can develop into secondary progressive MS, in which patients experience worsening symptoms without periods of remission.
Like many MS patients, Fire suffered for years before doctors delivered a definitive diagnosis. Her symptoms began in 2000 when she was an undergraduate at the University of California, Berkeley. They were minor, almost unnoticeable without the benefit of hindsight. But, by 2011, when she and Kaolin frequently went on 6-mile walks, her legs would often just give out.
“It was like a bunch of wet clothes were on the ground and my legs were kind of stuck in them,” Fire says, “and when I rubbed my legs together, it felt like they were coated in oil.”
During one of their weekly walks, her husband said, “I hope it’s not MS,” recalling an acquaintance with MS whose legs didn’t function well.
When a doctor at UC Berkeley’s student health center referred her to a neurologist, Fire underwent her first MRI, but it was clear. “The doctor said to return if my symptoms didn’t resolve on their own, which they always did, but then they would come back,” Fire says.
We are not just trying to stall disease progression, we’re also trying to predict what their disease process will look like 10, 20, even 40 years down the line,” —Marwa Kaisey, MD
Those persistent and vague symptoms led to a frustrating series of misdiagnoses. One doctor said the numbness in her hand was carpal tunnel syndrome and told her to wear a brace. Another said she was suffering from neuropathy and repeatedly tested her for diabetes. None of them mentioned the possibility of MS.
“Unfortunately, no single test can diagnose MS,” Sicotte says. Instead, clinicians rely on a complex mix of clinical symptoms, imaging tests and spinal fluid analyses to make an educated and informed assessment about whether a patient has the condition.
Physicians get it wrong about 15-20% of the time.
That’s one reason Sicotte, chair of the Department of Neurology at Cedars-Sinai and founding director of the Neurology Residency Program, trains residents and practicing neurologists to review MRIs themselves rather than relying on radiologists who may not be well-versed in the signs of MS. She notes that improved diagnostic criteria do no good if physicians don’t know how to apply them.
Lesions to the central nervous system can occur up to 10 times more frequently than a new symptom. So, even if a patient doesn’t notice a new attack, she can accumulate nerve damage while waiting for answers. On an MRI, those lesions show up as bright white spots. “The image lights up like a Christmas tree,” Fire says.
The problem is, other conditions—such as diabetes, hypertension, stroke and even migraines—also produce ominously festive MRIs. Therefore, doctors like Sicotte look for bright spots of a specific size, shape and location.
“MS lesions have a distinctive oval shape, a bit like a football,” Sicotte says. Almost all MS lesions have a vein running through the middle because the immune system’s fighter T cells lock on to small vessels where the blood runs more slowly. From there, they can break through into the brain or spinal cord and cause an inflammatory attack on myelin that appears as the lesions visible on MRI scans.
More than a decade after Fire’s first MRI, doctors referred her to a neurologist. “The neurologist reimaged my entire spine and said, ‘It’s textbook MS,’” Fire says. “After I was diagnosed, I went over the old UC Berkeley records again and I saw the doctor’s note. She suspected MS.”
Irritated with the misdiagnoses, Fire was also disappointed with herself. “If I had carried my records through, somebody would have picked up on it sooner,” she says. The same week she was diagnosed, her husband was laid off and, as Fire was driving around a curve in the middle of the desert, she hit a ditch and totaled her car. “It felt like a metaphor for my future,” she says. Her body, like her car, was beyond her control.
Even though the neurologist cautioned against reading about MS online, Fire saw stories about people diagnosed with an aggressive form of the disease who were in wheelchairs at age 29. Nearly every story linked MS with a poor quality of life and early death. “I wondered if having a family was in the cards for us,” she recalls.
Regrettably, when patients like Fire are first diagnosed with MS, they often see outdated information and think their future is being erased. “They have a real fear that the trajectory of their disease will lead them to a wheelchair,” says Marwa Kaisey, MD, a neurologist and MS specialist in the Department of Neurology at Cedars-Sinai, whose own mother was diagnosed with MS when Kaisey was a teenager. “A neurologic diagnosis is not something anyone expects to happen at that age, and MS is not curable.”
But it doesn’t have to derail patients’ lives. Instead, MS becomes something patients can manage, like diabetes. “Some patients diagnosed today can still have the career and family they planned,” Kaisey adds.
MS: A Bucket Diagnosis
With advanced imaging technology and revised diagnostic criteria to define MS more broadly, fewer patients are falling through the cracks. The problem is, more people are being misdiagnosed with MS.
In a study led by Cedars-Sinai neurologist Marwa Kaisey, MD, 1 out of every 5 or 6 patients who received a firm diagnosis of MS turned out to be suffering from something else. And up to 72% of them had been taking disease-modifying therapies they didn’t need, sometimes for decades.
These statistics reflect the challenge of correctly spotting MS. Symptoms like intermittent numbness, tingling and fatigue are common in conditions ranging from menopause to diabetes. To complicate matters, brain MRIs for disorders like migraines produce an image that’s eerily similar to a brain MRI of an MS patient.
In Kaisey’s study, migraine was the most common misdiagnosis among patients with MS—with good reason. Both conditions disproportionately affect young women and both present with similar symptoms, such as numbness and tingling. Other misdiagnoses include cerebral palsy, neuropathy and even anxiety.
“We have to find that sweet spot where we’re identifying people at the onset of disease, but we’re not misdiagnosing people,” says Nancy Sicotte, MD.
Scientists used to believe pregnancy made MS worse because many women experience a relapse during the postpartum period. But when examined over an entire year, relapse activity is about the same, whether patients become pregnant or not—and relapses tend to decrease during the third trimester. So, instead of telling women they can’t have children, doctors find that an MS diagnosis frequently precipitates family-planning discussions.
That was certainly the case for Fire, whose diagnosis nudged her and her husband to start the family they’d been avoiding talking about for more than a decade. “I was terrified of the medication and admitting my MS was real. Starting a family seemed like a way to put all of that on the back burner since none of the medications for MS are approved for use during pregnancy,” she says.
After Fenris was born, Fire continued working toward her degree. She was determined not to let MS get in the way of her dreams. And since she was nursing Fenris, she stayed off medication postpartum. Her life seemed to be on course. But eight months after Fenris was born, MS threw Fire off her axis again when she woke up with blurry vision.
She went to the optometrist who determined she was suffering from optic neuritis, a condition linked to MS in which damage to the myelin surrounding the optic nerve interferes with the transmission of visual information from eye to brain.
“By the time I left the optometrist’s office, I could see clearly only out of one eye. The other eye could only sense light,” Fire says. “It completely freaked me out.”
She received a standard treatment for patients suffering a relapse: high-dose steroid infusions for three days. “It knocked the relapse down quickly, returning my vision to normal within days, while waiting it out could have taken months,” she says.
Unfortunately, steroids also come with serious long-term drawbacks, putting patients at risk for cataracts and osteoporosis—while doing nothing to halt the progression of MS.
Plus, steroids can make life pretty miserable. “I remember not being able to sleep, and my husband remembers me being angry and stressed out,” Fire says.
Add it all together, and the experience nudged her toward another change: disease-modifying therapy.
The medical response to an MS diagnosis today is radically different from what physicians could offer a few decades ago.
“If a neurologist thought a patient had MS—a condition with no effective treatment—there wasn’t any urgency to make the diagnosis,” Sicotte says. “In particular, we didn’t want to tell somebody, ‘I think you have MS but I’m not sure,’ which would cause significant stress and might not be accurate.”
By the time Kaisey’s mom was diagnosed in the late 1990s, only three medications were available. Now there are more than 15, including therapeutics that could dramatically alter the course of the disease. All of this means that the way doctors care for people with MS has shifted significantly, and the development of disease-modifying therapies has been lightning fast. “There’s a lot of hope in what we do,” Kaisey says.
But deciding which therapy to pursue first can be a life-changing gamble. Until recently, doctors focused exclusively on treatments that target immune T cells, the “effecter” cells that infiltrate the brain and spinal cord and strip the nerves of myelin. Some of these therapies make T cells less inflammatory. Others block them from getting into the brain and spinal cord. The newest medicines in this class sequester T cells, locking them up inside the lymph nodes.
The rub: As these therapies become more adept at obliterating T cells, patients become more vulnerable to infection. “There’s an increased risk of unintended consequences, including a life-threatening brain infection called progressive multifocal leukoencephalopathy, or PML, which is caused by a virus that about half of us carry,” Sicotte says, noting that the virus is harmless in people with normal immune systems.
Recently, scientists uncovered another key player in the attack on patients’ immune systems: B cells. “We think what’s happening is that B cells are presenting bits and pieces of myelin to the T cells and saying, ‘Here, go find this and get rid of it; it’s a foreign invader,’” Sicotte says. The T cells go in search of myelin and, when they find it, they launch their attack.
Depressed with MS
A multiple sclerosis (MS) diagnosis can be depressing, and not just because of the psychological and emotional fallout of the diagnosis. Unlike other chronic diseases, such as cancer, diabetes or lupus, with MS, a biological basis explains why patients feel depressed.
“Depression is part of the disease process,” Nancy Sicotte, MD, explains. “Changes in the brain that are associated with MS disease activity impact structures in the brain that are important for mood.”
That assault on the brain means even optimistic patients can get hit with the sense that their world is falling apart and may not be worth patching back together. In fact, at least 50% of people with MS will experience depression at some point during the course of their disease.
But there is some good news: Preliminary research suggests those brain changes may be reversible with appropriate treatment.
“We usually recommend a combination of medication and therapy,” Cedars-Sinai neurologist Marwa Kaisey, MD, says. Cedars-Sinai is one of three sites in the United States recruiting patients to participate in a study testing whether online cognitive behavioral therapy can improve symptoms of depression among MS patients.
“An online platform is a nice idea because people with MS sometimes have mobility issues or they’re working, raising a family or just busy living life, and it’s hard for them to keep a weekly appointment,” Kaisey says.
The course has already been validated among people with depression who do not have MS.
Enter B-cell depleters. These drugs are not associated with PML because they don’t affect the number of T cells. Instead, they eliminate only the B cells that activate T cells to go after myelin.
In the past, doctors typically started patients on the safest, most time-tested treatments—the oldest T cell-targeting therapies—and, if those treatments didn’t control the disease, they would gradually work up to more effective but riskier options. The latter class of drugs interferes with the immune system’s standard operating procedure and can generate side effects like repeated infections, and kidney or heart problems.
“Despite the increased risk of side effects, we have seen a complete 180-degree shift where we sometimes start patients on the most effective treatments from the very beginning, including B-cell depleters,” Kaisey says.
Both Sicotte and Kaisey are part of a team of investigators exploring which form of therapy is best for newly diagnosed patients through a national, multicenter clinical trial called TREAT-MS. The goal of the trial: to determine whether patients would benefit more from early, aggressive therapy, or from ramping up from less intense medications to more aggressive ones if those initial drugs fail.
“We are not just trying to stall disease progression, we’re also trying to predict what their disease process will look like 10, 20, even 40 years down the line,” Kaisey says.
Historically, about half of relapsing-remitting MS patients would develop secondary progressive MS within 10 years. Emerging research suggests that disease-modifying treatments allay progression—and the effect seems to be even better with the newer generation of therapies.
I’m not sure having MS makes a difference in our daily existence. My life is pretty great and I’m grateful that modern medicine has come as far as it has with regard to this disease.” —Amy Fire
Homing in on a treatment strategy is as personal as it is complex. Physicians determine a patient’s risk profile and then examine lifestyle factors like travel habits and fear of needles, and medical issues like the presence of other chronic conditions.
Deciding between the options was easy for Fire. She has a low threshold for big risks and wanted to play it safe. She started with Copaxone but, when it turned out she was allergic to the drug, she and Sicotte selected a similar injectable, Rebif.
“The medication does nothing to minimize my symptoms,” Fire says. “I just want the peace of mind of knowing I’m doing everything possible to stall the progression of the disease.”
The Big Unknown
Despite her anxiety, Fire shows no signs of slowing down. She and her husband live in Berkeley with their two children. Every six months, she travels to Los Angeles to check in with Sicotte. “It’s like going to see an old friend,” Fire says. “I really feel like she cares about me and she cares about my kids.”
In addition to taking medication to keep the disease from progressing, Fire plans family menus around local, seasonal vegetables, tries to manage her stress levels by getting help at home and exercises regularly. “Exercise is a wonder drug for any neurological condition, not just MS,” Sicotte says. “You’re going to do better if you’re in good shape.”
But Fire can occasionally dwell in worry despite her treatment and healthy habits. Her relapse in 2014, after Fenris was born, scared her. “I had to face questions like ‘Am I going to be able to chase my kids around the playground? Or is that not for me with this disease?’”
Fire manages the impact of her condition day by day, often finding it tough to distinguish which symptoms are related to disease progression and which are just part of “midlife mommying.” “I sometimes feel especially tired at the end of a day. Is that because of MS or is it because many moms feel depleted when their kids are finally in bed?” Fire muses. “There’s no definitive answer.”
At the same time, she and her husband savor their work together, both in their careers and in raising their family. She even ran a 5K in 2017. “We sometimes struggle to get through the day, just like any other American couple trying to raise kids,” she says. “So I’m not sure having MS makes a difference in our daily existence. My life is pretty great and I’m grateful that modern medicine has come as far as it has with regard to this disease.”
Meanwhile, scientists keep knocking down preconceived notions about what it means to have MS. With the introduction of new and better therapies, MS has transformed from a diagnosis of despair into a manageable condition.
“Now when I diagnose someone, I’m able to say, ‘You likely will be able to live the life you planned. MS is going to be part of your life, but it’s not going to be your whole life,’” Kaisey says. “That’s a win!”