When Nerve Pain and Numbness Are Linked to Long COVID

Our nerves help us sense, react to, and change our surroundings. Simply put, our nerves are our connection to the world. This connection is disrupted, however, when peripheral neuropathy strikes.

The peripheral nervous system starts when nerves leave the spinal cord and ends when the nerves reach our tissues. Peripheral neuropathy, defined as a disorder of the peripheral nervous system, interferes with this connection. This can manifest as tingling or numbness (often in the hands and feet) that spreads over time. The feeling can be akin to how a limb feels when it “goes to sleep.”

Research shows that around 2.4% of the population suffers from peripheral neuropathy, with that number rising to about 8% in older patients. Most recently, clinicians have also identified this condition in some patients who have had COVID-19. One study found that as many as 56% of COVID-19 patients reported symptoms of peripheral neuropathy post-infection.

What causes peripheral neuropathy?

Neuropathies can have a slew of causes. Trauma, inflammation, diabetes, infections (viral or bacterial), certain medications, inherited conditions, poor nutrition, and hormone imbalances can be responsible. All of these factors can lead to toxicity and inflammation of the nerve and its coating, which in turn contributes to the physical breakdown of the cell and its ability to function. But no clear cause is found in nearly a quarter of the patients with this type of neuropathy.

Clinicians use further sub-classifications to describe the extent of the disease and how it manifests. For example, mono-neuropathies involve just one nerve, while polyneuropathies include many nerves.

Additionally, it’s crucial to know exactly what is going wrong with the nerve:

• If the neuropathy is “demyelinating,” this means that the nerve has lost part of its myelin coating, a physiological “accelerator” of nerve signals that helps nerves talk very quickly to one another and to muscles.
• Damage to the cell body of the nerve can occur if it is compressed or cut off from metabolic necessities (including glucose, the molecule that our cells use for energy) due to impingement from, for example, an abnormal growth or tumor.
• Axonal damage, which affects the long stem of the nerve cell that lets it “talk” to other nerves, can happen due to similar metabolic toxicities or trauma. This is what scientists currently think happens, in large part, in other non-COVID viral models of peripheral neuropathy, such as HIV, hepatitis C, etc.

Why would COVID-19 cause peripheral neuropathy?

Lindsay McAlpine, MD, a neurologist and founder of the Yale NeuroCOVID Clinic, has conducted research on what is now known clinically as peripheral neuropathy after COVID-19. She notes that there are two main categories of neuropathy following COVID-19 infection. One is the “acute illness mediated type,” in which patients find themselves with sudden, severe neuropathy, generally around the same time as their active illness. The second is small fiber neuropathy, which results from damage to the thinnest, unmyelinated nerves in our body and often begins with burning pain in the feet. It typically arises somewhat later—around two to 12 weeks post-illness.

Peripheral neuropathy in COVID-19 patients has been reported in both axonal and demyelinating forms, according to the medical literature. Researchers suspect that COVID-19 associated neuropathy could be driven by several causes. One might be immune system dysfunction, in which the body attacks itself instead of, or in addition to, attacking viral particles. Or COVID-19 may have hemodynamic effects that interfere with how blood flows through the body’s blood vessels, damaging the nerves and leading to “ischemia” due to restricted blood/nutrient flow, known as critical illness neuropathy.

How do clinicians diagnose peripheral neuropathy?

To diagnose peripheral neuropathy, your clinician will ask you questions about your symptoms—when did they start, for example, and how would you describe the pain? The questions that Dr. McAlpine asks her patients include: “Is the pain intermittent? Is it localized to a certain part of your body? Is it patchy? Does it radiate? Are you numb, itchy, and/or hypersensitive?” Hallmarks of peripheral neuropathies include not only pain, but also weakness and numbness. Your answers to these questions can help clinicians pinpoint the cause of your symptoms.

As part of the diagnostic work-up, you’ll typically see a neurologist, who will perform a complete neurological exam with deep reflex checks—leveraging the same reflex hammer your primary care doctor may use on your knee at your yearly checkups. This helps clinicians tell if some of the nerve circuits that are not under your conscious control are functioning correctly. If something is abnormal here, it may point to another cause of your symptoms that is not related to small nerve fibers. For example, is it possible that Long COVID could be working in tandem with another cause to trigger symptoms?

The next step involves lab tests to rule out common causes of neuropathy, as well as conditions, such as vitamin B12 deficiency or an autoimmune disease, that could either lead to neuropathy on their own or co-occur with COVID-19 and worsen neuropathy symptoms.

Next, your clinician will likely order an electromyography test (EMG)/nerve conduction study, which can help determine whether your symptoms appear to be related to large nerve fiber demyelination, axonal damage, or radiculopathy (due to a damaged or pinched nerve, most often in the spine). This test measures the electrical output of nerves when stimulated and will be negative (“normal”) if your peripheral neuropathy is due to small fiber nerve damage.

If the diagnosis is still elusive, clinicians typically order additional tests, including punch biopsies (the removal of small pieces of skin that are sent to a specialized lab to be assessed for small fiber density) and/or a special bloodwork panel that can look for uncommon causes of sensory neuropathy, which results in a loss of sensation in various parts of the body.

How is peripheral neuropathy treated?

Clinicians often rely on a mixed-methods approach, including physical therapy and rehabilitation. Dr. McAlpine stresses the importance of “optimizing the environment for nerve healing”—that is, controlling other diseases such as diabetes that could be worsening symptoms, while also treating symptoms that can interfere with a patient’s function and sleep with medications, such as gabapentin (Neurontin®), pregabalin (Lyrica®), and duloxetine (Cymbalta®), that treat nerve pain.

B vitamins play a crucial role in neural function, so supplementation of vitamins B1 and B12 might help relieve symptoms and protect nerves from future damage if a deficiency is the underlying cause. Oversupplementation with B6 is known to cause nerve damage and neuropathy

If evidence of autoimmune damage of the large or small nerve fibers is discovered during testing, clinicians can start IVIg—intravenous immunoglobulin—to help calm inflammation of the nerves. However, treatment with this medication can be time-consuming and costly. Insurance may not cover the drug, depending on the coverage plan and stated indication.

Because patients must sometimes wait up to several months to see a neurologist, Dr. McAlpine notes that primary care physicians may be able to prescribe gabapentin or one of the other medications listed above for at-home use to help treat symptoms while patients wait for their neurology appointment.

If you’d like more details on Long COVID-related small fiber neuropathy, Dr. McAlpine (Twitter/X: https://twitter.com/lindsaymca) has recently published a series of small case studies on this topic.

Rhys Richmond is an MD candidate at Yale School of Medicine.

Takeaway from Lisa Sanders, MD:

When I was a child, my sisters and I often debated which sense we could live without most easily. As I recall, it usually came down to either the sense of smell or touch. In our lives at that age, bad odors and the bangs and bruises of a normal active childhood were the most vivid and unpleasant of our sensory experiences. Of course as an adult, and a physician, I think differently. I wouldn’t give up any of them.

But for those with peripheral neuropathy, this essential perception can become burdensome. The constant burning or numbness or pins-and-needle sensations some of the patients we see suffer through can often be torturous. Moreover, peripheral neuropathy can be dangerous. It is the tiny nerves that populate our skin that alert us to injury or infection. They tell us about the world around us. And when those nerves give us bad information, the world becomes a much more hazardous place. And a much harder place to live in.

At this point, it’s essential to try to find the underlying cause of the neuropathy and treat that. In the US and Europe, long-standing diabetes is the most common cause of peripheral neuropathy. When diabetes is well controlled, the risk of developing this complication can be reduced. In Long COVID, we still don’t fully understand the cause. All we can do is help with the pain. The medications mentioned above can relieve some of the pain. Capsaisin, the component that gives hot peppers their heat, can sometimes help as well, as can ice. Dr. McAlpine’s work using intravenous gamma globulin to treat neuropathies caused by an immune system gone bad is intriguing. And it may suggest a possible long-term treatment. At this point, it’s only an interesting idea; we can’t know for certain until more research is done.

Read other installments of Long COVID Dispatches here.

If you’d like to share your experience with Long COVID for possible use in this blog (under a pseudonym), write to us at: LongCovidDispatches@yale.edu. It may appear, space permitting, in a future post.

Information provided in Yale Medicine content is for general informational purposes only. It should never be used as a substitute for medical advice from your doctor or other qualified clinician. Always seek the individual advice of your health care provider for any questions you have regarding a medical condition.