Living with multiple sclerosis (MS) comes with unique challenges, especially if you’re taking a disease-modifying therapy (DMT) that’s infused intravenously (through a vein). Although DMTs are good at limiting relapses and preventing new brain lesions in MS, they can have side effects. Some also are linked with what’s called the “crap gap.”

What is the crap gap? It’s the time between infusions when MS symptoms might temporarily get worse. Many people living with MS share their concerns about this situation with their neurologists. Scientists are still working to understand why the crap gap happens and how to address it, but so far, it does not seem related to disease activity.

What Are the Symptoms of the Crap Gap?

The crap gap, sometimes called the wearing-off effect, can happen between intravenous infusions of MS medications. It might occur in the days or weeks before your next infusion, as the medication starts to wear off. Some people may also notice symptoms right after an infusion, before the medication has had time to fully work.

Symptoms of the crap gap include fatigue, brain fog, balance issues, and tingling sensations, which often surface as the medication wears off before the next infusion.

During this time, you may notice a worsening of MS-related symptoms and feel generally unwell, or “off.” Symptoms of the crap gap include:

• Fatigue
• Cognitive symptoms affecting thinking and memory, known as “brain fog” or “cog fog”
• Problems with motor function and balance
• Burning, tingling, or pins-and-needles sensations

Which Drugs Have a Crap Gap?

Crap gap symptoms typically occur with DMTs that are infused at specific intervals, such as ocrelizumab (Ocrevus) and natalizumab (Tysabri, Tyruko).

What Happens When Ocrevus Wears Off?

Many people who take ocrelizumab report that MS symptoms get worse before the next scheduled dose. The most commonly reported symptoms include tiredness, brain fog, and sensory symptoms such as numbness, tingling, and pins and needles.

A 2021 study of people using ocrelizumab found that 61 percent of participants reported this “wearing-off phenomenon.” In a 2024 study, researchers found that many people with MS who had at least two doses of ocrelizumab experienced the crap gap. About 39 percent of participants said the phenomenon happened sometimes, about 14 percent said it always occurred, and over half noticed symptoms starting more than four weeks before their next dose. The symptoms often disappeared as soon as or right after the next treatment was given.

How Do Infused Disease-Modifying Therapies Work?

Infused DMTs are monoclonal antibody medications. These drugs are laboratory-made versions of proteins that are naturally produced by the immune system. Ocrelizumab binds to lymphocytes (a type of white blood cell) called B cells, preventing them from attacking the nerves in MS. Natalizumab attaches to specific proteins on inflammatory immune cells, which prevents the cells from crossing the blood-brain barrier — a network of blood vessels and tissue that protects the brain from harmful substances.

Since inflammatory immune cells can’t pass into the central nervous system, they can’t attack the nerves, helping to reduce MS symptoms and prevent further damage. Monoclonal antibodies can’t withstand digestion, so they must be injected or infused.

Which DMTs Are Less Likely To Have a Crap Gap?

DMTs are given in different ways. DMTs taken orally (by mouth, as pills or capsules) or through subcutaneous (under the skin) self-injection at home aren’t typically linked with a crap gap, possibly because most are taken daily or more often than infused DMTs. In 2024, the FDA approved a subcutaneous form of Ocrevus called Ocrevus Zunovo, which contains ocrelizumab and hyaluronidase-ocsq.

DMTs that aren’t infused include oral medications like dimethyl fumarate (Tecfidera) and fingolimod (Gilenya, Tascenso ODT). Self-injected drugs include interferons (Avonex and Betaseron, among other brands), glatiramer acetate (Copaxone, Glatopa), and ofatumumab (Kesimpta).

If you have severe crap gap symptoms that are difficult to tolerate, keep in mind that they may not be related to MS activity. However, you might still consider talking to your doctor about switching to a DMT taken in a different way. Never stop taking a DMT without first consulting your neurologist. If you decide to change treatments, they can advise you about how best to switch and whether you’ll need a washout period before starting a new drug.

What Does the Crap Gap Feel Like?

MyMSTeam members have shared their concerns about experiencing crap gap symptoms between MS treatments. Although their comments mainly focus on ocrelizumab and natalizumab, some members also have experienced the crap gap with other medications, such as rituximab (Rituxan), another infused monoclonal antibody.

One member posted this question: “Does anyone who 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. I’m 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 MyMSTeam member replied, “I take a Tysabri infusion every 30 days. And typically the last week before, my symptoms start coming down a bit heavier than normal — especially my balance, fatigue, and speech.”

What Causes the Crap Gap?

Researchers aren’t quite sure why crap gap symptoms occur, but they have a few theories. After a DMT infusion, the body begins to break down the drug. The amount of time it takes to break down half of a dose is called its half-life. However, the biological effects of a drug last longer than its actual presence in the body.

The half-life of ocrelizumab is 26 days, and the half-life of natalizumab is around 11 days. Ocrelizumab infusions are scheduled every six months, and natalizumab is infused every month. This means that by the time a person is ready for their next infusion, they have a minimal amount of drug in their body. Crap gap symptoms could start to appear a few weeks before the next MS drug infusion.

Researchers are still working to understand the crap gap, but some studies suggest that factors like body weight and receptor occupancy may play a role.

People who take natalizumab may experience crap gap symptoms because not enough of the drug binds to their immune cells. This is known as receptor occupancy, or the amount of natalizumab that is attached to lymphocytes. In one study of people with relapsing-remitting MS (periods of worsening symptoms followed by periods of few or no symptoms), those with low receptor occupancy regularly had crap gap symptoms.

The normal dosing schedule for ocrelizumab is every six months. A study from the journal Multiple Sclerosis and Related Disorders showed that extending infusion intervals of ocrelizumab didn’t trigger the wearing-off phenomenon.

Is Weight a Risk Factor?

Researchers believe that having a higher body mass index (BMI) might raise the risk of experiencing the crap gap. BMI is a measure using a person’s height and weight and is unrelated to any specific body type or size. A 2021 study found that people with higher BMIs who were taking ocrelizumab were more likely to have symptoms close to reinfusion time. Another study in 2020 also suggested that the crap gap happened more often among people with a higher BMI.

Can the Crap Gap Be Prevented?

There’s no clear evidence that the crap gap is connected to MS getting worse, so changing your DMT or infusion schedule might not be necessary if your condition is well managed overall. However, talk with your doctor about how much these symptoms affect you. They may suggest a few options to help you feel better.

If you’re struggling with the crap gap, talk to your doctor about alternative treatment options, such as oral or self-injected DMTs that don’t come with the same wearing-off effect.

Moving infusion schedules earlier might seem helpful, but it can increase risks. For example, one serious side effect of natalizumab is progressive multifocal leukoencephalopathy (PML). This condition can occur when a person takes a medication that reduces immune system function (such as natalizumab) and develops an infection by the John Cunningham virus (also called human polyomavirus 2 or JC virus), which can be fatal. The longer someone uses natalizumab, the greater the risk of PML. Doctors hope that limiting the frequency of infusions can help lower PML risk. Also, a 2024 study in Austria found that although PML cases have fallen since 2016 due to better monitoring, people often experience lasting disability.

Doctors and researchers are still learning more about the crap gap and how it causes symptoms. Currently, there are no specific treatments recommended for these symptoms. If your MS symptoms begin to worsen between infusions, talk to your doctor about medications that may help. Several prescription medications can be used to help manage pain, brain fog, fatigue, and muscle spasticity.

Talk With Others Who Understand

On MyMSTeam, the social network for people with multiple sclerosis and their loved ones, more than 217,000 members come together to ask questions, give advice, and share their stories with others who understand life with multiple sclerosis.

Have you experienced the MS crap gap while on an infused MS medication? Has anything helped ease your symptoms until your next infusion? Share your experience in the comments below, or start a conversation by posting on your Activities page.