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What Is the ‘Crap Gap’ Between MS Infusions?

Posted on October 31, 2022
Medically reviewed by
Evelyn O. Berman, M.D.
Article written by
Emily Wagner, M.S.

If you’re living with multiple sclerosis (MS), you may be taking a disease-modifying therapy (DMT) to help treat it. Although these medications are extremely effective at limiting relapses and the formation of MS lesions, they can come with some side effects. One of these is the “crap gap,” or a period of time in between drug infusions when your MS symptoms may return.

Many people with MS have reported these symptoms to their neurologists, prompting researchers to start studying crap gap and how it occurs in people with MS. Questions still remain, including how to prevent the crap gap from occurring.

What Is the Crap Gap?

The crap gap, also known as the wearing-off effect, occurs between infusions of MS medications. This may be the time before your next infusion when the drug is wearing off, or it may occur right after your most recent infusion before the drug begins to work.

During this time, MS symptoms tend to worsen and you may feel generally “off.” Side effects of the crap gap that you may experience include:

  • Fatigue
  • “Cog fog” or cognitive side effects
  • Problems with motor function and balance
  • Burning, tingling, or pins-and-needles sensations

The crap gap is typically seen with DMTs that are infused at specific time intervals, such as ocrelizumab (Ocrevus) and natalizumab (Tysabri). Both of these medications are monoclonal antibody drugs, which are human-made antibodies that target different parts of the immune system. Ocrelizumab works by binding to B cells, preventing them from attacking the nerves in MS. Natalizumab works by binding to a type of white blood cell known as lymphocytes, which prevents them from crossing the blood-brain barrier. Because the lymphocytes can’t pass into the central nervous system, they can’t attack the nerves and brain to cause MS symptoms.

One study found that between 50 percent and 70 percent of people who use natalizumab reported experiencing crap gap symptoms. Another recent study on ocrelizumab also found that 61 percent of participants reported experiencing symptoms.

What Causes the Crap Gap?

Once a person is infused with an MS drug, their body begins to break it down. The time it takes the body to break down half of a drug dose is known as its half-life. The half-life of ocrelizumab is 28 days, and the half-life of natalizumab is around 11 days. Ocrelizumab is infused every six months, and natalizumab is infused every month. This means when it’s the time of the next infusion, a minimal amount of the drug left in the body. Crap gap symptoms typically start to appear a few weeks to a month before the next MS drug infusion.

Researchers aren’t quite sure what causes crap gap symptoms, but they have a few theories. One is that having a higher body mass index (BMI) makes it more likely you’ll experience the crap gap. A study from the journal Multiple Sclerosis and Related Disorders looked at participants who take ocrelizumab and found that those with a higher body weight had lower blood concentrations of the drug and had more B cells.

People who take natalizumab may experience crap gap symptoms because not enough of the drug is bound to their immune cells. This is known as receptor occupancy (RO), or the amount of natalizumab that is attached to lymphocytes. A study cited the journal Neurology: Neuroimmunology & Neuroinflammation found that among people with relapsing-remitting MS, those with low RO regularly had crap gap symptoms. Similarly to the ocrelizumab study, people with a higher BMI often had symptoms as well, which may be caused by a low RO.

Because the effects of DMTs appear to wear off over time for some people, researchers have investigated whether changing the time between doses has any effect on crap gap symptoms. During the COVID-19 pandemic, some people had to wait to receive their drug infusions. Many couldn’t travel to their infusion centers, and hospitals extended appointments to prevent people from being exposed to the virus.

A study from the journal Multiple Sclerosis and Related Disorders looked at extended-interval dosing of ocrelizumab for infusions. The normal dosing schedule for ocrelizumab is every six months. In the study, the average time between infusions was 30 to 38 weeks. The researchers found that more time between infusions didn’t predict who experienced crap gap symptoms.

MyMSTeam Members and the Crap Gap

MyMSTeam members have shared their concerns about experiencing crap gap symptoms between treatments. Although reports of the crap gap mainly focus on ocrelizumab and natalizumab, some members have experienced it with other medications as well.

One member posted a question: “Does anyone that takes rituximab notice anything different when it’s time for another infusion? I am due for my second infusion in four weeks. The first was six months ago. Feeling extremely drained and like I’m getting a cold. My left leg felt unsteady when I walked on my break at work. Maybe it’s just happening on its own, or it’s infusion time?”

Another member replied, “Hello, I take a Tysabri infusion every 30 days. And typically the week before, my symptoms start coming down a bit heavier than normal. Especially my balance, fatigue, and speech.”

“On the Ocrevus boards on Facebook, people talk about what has been termed the crap gap — the period of a month or so before the next infusion where they feel worse. Since Ocrevrus is given every six months, people talk about feeling good for five-plus months and then for the final three to four weeks feel horrible, as if the time between infusions should be less,” shared another member.

Can the Crap Gap Be Prevented?

Although moving infusions earlier in the dosing schedule may seem like a good idea, doing so can cause some complications. For example, one serious side effect of natalizumab is progressive multifocal leukoencephalopathy. This condition occurs when a person takes a medication that reduces immune system function (such as natalizumab) and becomes infected with the John Cunningham virus (also called human polyomavirus 2 or JC virus), which that attacks myelin (the outer coating of nerve cells). Doctors hope that limiting infusions as much as possible can help prevent PML from occurring.

Doctors and researchers are still learning more about the crap gap and how it causes symptoms. As such, there currently aren’t any recommended treatments for crap gap symptoms. If you begin to experience MS symptoms between infusions, talk to your doctor about medications that may help. There are several prescription medications used to help treat pain, brain fog, and muscle symptoms.

Talk With Others Who Understand

On MyMSTeam, the social network for people with multiple sclerosis and their loved ones, more than 193,000 members come together to ask questions, give advice, and share their stories with others who understand life with multiple sclerosis.

Have you had the crap gap while on certain medications? Share your experience in the comments below, or start a conversation by posting on your Activities page.

All updates must be accompanied by text or a picture.
Evelyn O. Berman, M.D. is a neurology and pediatric specialist and treats disorders of the brain in children. Review provided by VeriMed Healthcare Network. Learn more about her here.
Emily Wagner, M.S. holds a Master of Science in biomedical sciences with a focus in pharmacology. She is passionate about immunology, cancer biology, and molecular biology. Learn more about her here.

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