• Disease-modifying therapies (DMTs) taken by intravenous infusion are given once every few weeks or months.
• Some people with multiple sclerosis (MS) experience periods of worsening symptoms between infusions known as the “crap gap.”
• If you find the crap gap difficult to tolerate, you can talk to your doctor about switching to a DMT that’s taken orally or by an injection you give yourself at home.

Living with MS comes with its unique challenges, especially if you’re taking a DMT that’s infused intravenously (through a vein). Although DMTs are good at limiting relapses and preventing new brain lesions in MS, they do have some side effects. Ever heard of the crap gap? It’s the phase between infusions when MS symptoms might feel worse.

People living with MS commonly report these symptoms to their neurologists, and researchers are still learning about the crap gap, including why and how it happens.

Symptoms of the Crap Gap

The crap gap, also known as the wearing-off effect, happens between intravenous infusions of MS medications. This could be the time before your next infusion (when the drug is wearing off) or right after a trip to the infusion center (before the drug begins to work).

During this time, MS symptoms may feel worse, and you may feel generally “off.” Side effects of the crap gap include:

• Fatigue
• Cognitive symptoms 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). One study published in 2021 found that 61 percent of people who use ocrelizumab reported experiencing symptoms.

How Do Infused Disease-Modifying Therapies Work?

Infused DMTs are monoclonal antibody drugs, which are cell culture versions (grown in a laboratory) of proteins made 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 also sticks to lymphocytes, which prevents them from crossing the blood-brain barrier — a network of blood vessels and tissue that protects the brain from harmful substances.

Because the lymphocytes can’t pass into the central nervous system (CNS), they can’t attack the nerves and brain to cause MS symptoms. The proteins in monoclonal antibodies can’t withstand the harsh conditions of the digestive system, so they must be injected into the body.

DMTs Less Likely To Have a Crap Gap

There are many DMTs that are administered in different ways. Oral DMTs (taken by pill or capsule) and DMTs taken by subcutaneous (under the skin) self-injection at home aren’t typically associated with a crap gap, possibly because most of them are taken daily or more frequently than infused DMTs.

DMTs that aren’t infused include oral medications like dimethyl fumarate (Tecfidera) and fingolimod (Gilenya). Additionally, there are self-injected drugs such as interferons (Avonex and Betaseron, among other brands), glatiramer acetate (Copaxone), and ofatumumab (Kesimpta).

If you experience severe crap gap symptoms that are difficult to tolerate, you might consider talking to your doctor about switching to a DMT taken in a different way. Never stop taking a DMT without consulting your neurologist. If you decide to change treatment options, 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 crap gap symptoms between MS treatments. Although reports of the crap gap mainly focus on ocrelizumab and natalizumab, some members also have experienced it with other medications, such as rituximab (Rituxan), another infused monoclonal antibody.

One member posted a 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. 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 known as its half-life. The half-life of ocrelizumab is 28 days, and the half-life of natalizumab is around 11 days. Ocrevus infusions are scheduled every six months, and Tysabri 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.

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, 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.

Weight May Be a Risk Factor

Having a higher body mass index (BMI) seems to increase a person’s risk of experiencing the crap gap. A 2021 study on people taking ocrelizumab found that those with a higher BMI had lower blood concentrations of the drug and more B cells, factors associated with MS attacks on the myelin coating of the CNS. One study from 2020 also found that people with a higher BMI more often had crap gap symptoms.

Can the Crap Gap Be Prevented?

Moving infusions earlier in the dosing schedule might seem like a good idea, but it can cause some complications. For example, one serious side effect of natalizumab is progressive multifocal leukoencephalopathy (PML). This condition could 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. Doctors hope that limiting the frequency of infusions can help lower the risk of PML.

Doctors and researchers are still learning more about the crap gap and how it causes symptoms. Currently, there are no recommended treatments 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 207,000 members come together to ask questions, give advice, and share their stories with others who understand life with multiple sclerosis.

Have you experienced the 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.