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Felicia Chow, MD: Hello. I'm Dr Felicia Chow. Welcome to Medscape's InDiscussion series on meningitis. Today we'll discuss Lyme meningitis and other emerging neuroborrelioses with Dr Karen Roos. Dr Roos is the John and Nancy Nelson professor emeritus of neurology at the Indiana University School of Medicine. Welcome to InDiscussion.
Karen Roos, MD: I'm thrilled to be here.
Chow: It's so great to have you, Karen. I have heard you talk about Lyme disease in different forums, including in grand rounds presentations. I've also read what you've written about Lyme disease and neurologic involvement of Lyme. I'm excited to have you on the podcast today. As a neuro infectious disease provider here in San Francisco, seeing patients mostly from the Bay Area and other parts of the state, I consider us out here to be junior varsity compared to other parts of the country in terms of our ability to care for people with Lyme and to make the diagnosis based on the number of patients we see compared to other parts of the country. I really consider it to be an emerging pathogen on the West Coast. I think there are some data to suggest that maybe the geographic range of the tick vector and animal reservoir are pushing westward into other parts of the country where the infection has not been seen as much up to now. Maybe you could start by telling us about the epidemiology of Lyme disease where you practice and how it compares with the epidemiology in other parts of the country.
Roos: Lyme disease is certainly beginning to show up in northern California, Washington, and Oregon. Right now, the areas that have the highest incidence of Lyme disease continue to be the northeastern states. As we all know, Lyme disease was named for Lyme, Connecticut, where the disease was first described. It's now moved as far south as Virginia, West Virginia and Pennsylvania. It is also endemic in Wisconsin and Minnesota. We see a fair number of patients with Lyme disease because a lot of our patients vacation in Door County, Wisconsin, and in northern Minnesota. It's like anything: The more you see it, the more comfortable you become with it. And patients are knowledgeable themselves. I do think eventually this will continue to move west. The species of the Ixodes tick that transmits Lyme disease is different on the East Coast than in Northern California, in Oregon and Washington, but the disease is exactly the same.
Chow: What about the seasonal distribution of infections?
Roos: It's interesting because we look at late May, June, and July as Lyme disease season, and then July is when we start looking at arthropod-borne central nervous system (CNS) infections. It's interesting that it's noticed epidemiologically that when there have been periods of time during winter months that have been warmer, there's been Lyme disease outside of that window. But typically, that's when it occurs.
Chow: That's interesting to hear. Here in California, because some of the winter months are not as cold as on the East Coast, and we have more temperate climate, it has been interesting to see patients who seem to be infected during those winter months and see those differences between a more temperate climate and other parts of the country.
Roos: I think you're going to increasingly see that because it definitely is a warmer-weather infection, and people typically get Lyme disease from the nymph stage of the tick because the nymphs are really tiny. They're only 2 mm, so you don't see them. They aren't as easy to take off your body as an adult tick is. It takes 2 years to become an adult tick. But the nymphs, they're really tiny. They only take a year to become a nymph after they've hatched. They more often transmit Borrelia burgdorferi (Lyme disease).
Chow: What are some of the most common neurologic manifestations of Lyme disease here in the United States that clinicians should be familiar with?
Roos: I like to think of them in three categories. The first is cranial neuritis. We are well aware that Lyme disease most often causes either unilateral or bilateral facial nerve palsy. That's the most common cranial neuritis. It may also affect III, IV, VI, and VIII. Children may even present with papilledema. Interestingly, the cranial neuritis is often associated with a cerebrospinal fluid (CSF) lymphocytic pleocytosis. I think that there's an intersection between the cranial neuritis and the meningitis, which is my second category of neurological Lyme disease. So, if you tap patients with a cranial neuritis, you often will find a lymphocytic pleocytosis. I look at cranial neuritis, then meningitis. The meningitis of Lyme disease is a mild form of meningitis. Patients typically have headache and photophobia. They have very mild meningismus and may have a very mild fever. So, it's not really striking. The third category that I find is the one that's most difficult to associate with Lyme disease is the radiculoneuritis, the mononeuropathy multiplex. That's the third category that I think of as the three categories of neurologic Lyme disease — by far the most common being the cranial neuritis with the associated CSF lymphocytic pleocytosis.
Chow: It's interesting to hear you talk about that last category, in which you put together the radiculoneuritis patients and that mononeuritis multiplex category as well. That's a referral that I've been receiving more often, a patient who has a neuropathy. Usually, it will be more of what looks like signs and symptoms of length-dependent, usually sensory-predominant neuropathy. Lyme testing will have been done as part of the general workup. Then that may be positive from serum. And then they get referred to us with the question of is their neuropathy related to their positive Lyme serologies? What are your thoughts about that type of patient and the likelihood of Lyme as the cause of their neuropathy?
Roos: That's a common question and part of the problem is untangling the laboratory diagnosis piece. We have to look at how the diagnosis was made. For me, that's really critical because so many patients get referred with Lyme disease and other symptoms, and we have to carefully look at their lab results. Initially, we do the enzyme-linked immunosorbent assay (ELISA), and then we have one of two choices. There's now three enzyme immunoassays available, and you can either make the diagnosis by going with a positive or borderline ELISA, then you send a Western blot. That's been historically how we've made the diagnosis, and we can talk about that at length. As of recently, you can send two of the three US Food & Drug Administration (FDA)-approved enzyme immunoassays, which is very nice. The enzyme immunoassays are easier for the lab to do, and they're also easier, quite frankly, for the clinician to interpret. Again, just to remind everyone, there are now three FDA-approved enzyme immunoassays, so you can use two of them to confirm the diagnosis.
Chow: In a patient who has a neuropathy and has Lyme testing that is consistent with Lyme disease or Lyme infection, it sounds like that is also potentially a category of patient who also could have their symptoms attributed to Lyme infection.
Roos: Absolutely. And it's readily treated with doxycycline, so it's well worth it to give them a course of doxycycline so they don't need intravenous (IV) ceftriaxone. The doxycycline works fine, and that's a good way to go.
Chow: We will talk more about diagnostics and treatment in a moment, but sticking with how patients with nervous system involvement of Lyme infection present, how frequently do you see brain parenchymal involvement of Lyme infection and a myelopathy or myelitis that can be attributed to Lyme infection? It seems uncommon here in the United States, but is that your experience?
Roos: That's my experience as well. It's frequently written about in Europe. There's a different species of Borrelia called Borrelia afzelii that causes the meningoencephalitis. It's more frequently written about in Europe, but I don't think it's that frequent there either. In the United States, only about 2% of patients with Lyme disease will have a meningoencephalitis. The expectation is that it's not Borrelia burgdorferi, which is by far and away the most common spirochetal cause of Lyme disease in the United States, but perhaps they acquired another species traveling to Europe or to Asia.
Chow: Do you think that any of the differences or the likelihood of seeing, for example, brain parenchymal involvement or spinal cord involvement in Lyme infection has to do with seeing patients early in their course as opposed to late in their course? In the same way that we think about syphilis infection, where someone with late neurosyphilis would be more likely to have an encephalitis or tabes dorsalis with spinal cord involvement. Do you think part of the reason why we see or don't see those types of presentations with Lyme is because we're mostly seeing early infection?
Roos: Well, the feeling is it's more likely related to the species of Borrelia than it is to the time, because the neurological manifestations occur during early disseminated disease. Late disseminated diseases are when more of the arthritis-type complications occur that people are familiar with, especially in the New England area. But I think it's really the species of Borrelia that affects what type of clinical presentation you have.
Chow: Great. One last question about different manifestations of neuroborreliosis or of Lyme neuroborreliosis. What about strokes and vascular involvement with neuroborreliosis? I feel like that's something that will come up from time to time, and I certainly have seen case reports of ischemic strokes in the setting of neuro Lyme in Europe. But again, it isn't really something that I've ever seen or is on my radar. What is your experience in terms of that?
Roos: I don't think that our listeners need to have it on their radar either. There are only a few case reports or some series of case reports, and they're all from Europe, where the species of Borrelia is different than that which we see in the United States.
Chow: Great. Now we'll shift gears and go back to the topic that you brought up earlier about diagnostics. You mentioned the two-tiered approach in terms of, first, the Lyme enzyme immunoassay, followed by a Western blot. You also mentioned the modified approach in which you can actually use two different enzyme immunoassays to make the diagnosis. Are there certain situations where either of those diagnostic approaches may be less sensitive in making the diagnosis of Lyme?
Roos: That's a good question. I think we have more experience with using the ELISA and the Western blot and knowing to send both the immunoglobulin M (IgM) and the immunoglobulin G (IgG) in the Western blot. Then, we have experience with using two enzyme immunoassays. So, I think that area is something that we still have a lot to learn about. But with the ELISA to the Western blot IgM, looking for two of the three bands, and then to the IgG looking for five of the 10 bands, we have so much experience. I think people feel more comfortable, especially in patients where the diagnosis is not clear. That tried-and-true method is probably still the better way to go. I think we could even do both and see what we're getting. I think with time, we will move to two enzyme immunoassays because it's easier for the lab to do. It's cleaner than doing the Western blot, which tends to have its own set of problems. I think that that's where we stand today.
Chow: Is there ever a situation where you may have a negative serologic test from blood for Lyme, but you might still consider neuroborreliosis in someone who's presenting with one of those syndromes that you mentioned earlier, such as a cranial neuritis or meningitis?
Roos: That's an excellent question. Typically, we know by 4 weeks that you will have positive serology, but you could develop a cranial neuritis or a meningitis prior to that 4-week period. That's where you're going to want to do a lumbar puncture and examine the CSF. With Lyme neuroborreliosis, we know that you will have a CSF lymphocytic pleocytosis, a slightly elevated protein concentration, and a normal glucose concentration. Now, what's really helpful and what the Europeans have taught us is how to do the antibody index. I think that the antibody index for any pathogen is remarkably helpful. I've always felt that way, especially with Lyme disease, when there's any kind of confusion to demonstrate the intrathecal production of antibodies. That's where we're going to use as our numerator the Borrelia IgG in CSF over the Borrelia IgG in serum. That denominator is the total IgG in CSF over the total IgG in serum. We're looking for a number greater than 1.3 to 1.5. Using the antibody index to demonstrate intrathecal production of antibodies to any pathogen you can substitute any pathogen for is very helpful in making a diagnosis of a CNS infection.
Chow: Yes, I agree with that thinking about that ratio as opposed to just looking at antibody testing from CSF. Fortunately, there are some commercially available tests to help us with that specific index for Lyme infection. That has helped in terms of diagnosis. What about in someone who has a predominantly peripheral presentation of Lyme? Is it still worth it to get CSF as part of your diagnostic workup for those patients?
Roos: Yes. There often is still an inflammatory reaction in spinal fluid, so you can see a lymphocytic pleocytosis, and you can again look for the intrathecal production of antibody. I do think it's worth it.
Chow: Great. In terms of treatment, tell us about your approach on oral treatment with doxycycline vs intravenous treatment with something like ceftriaxone. Earlier you mentioned that doxycycline works well and is a good treatment for neurologic involvement of Lyme infection. Is that the case for all patients with Lyme neuroborreliosis, or do you think about patients differently depending on the syndrome they're presenting with?
Roos: It is our sense that doxycycline works very well and completely eradicates infection — whether you have a cranial neuritis, a meningitis, a radiculoneuritis, or mononeuropathy multiplex. I don't use ceftriaxone anymore, and we've gotten patients away from those months of IV ceftriaxone therapy. Of course, if you have a different species of Borrelia, and you have a meningoencephalitis, you're going to probably want to use IV ceftriaxone. Otherwise, oral doxycycline has excellent CNS penetration, and I treat patients for a month. There's this debate about prescribing for 2 weeks, 3 weeks, or 4 weeks. I have found that patients have such peace of mind if we just use 4 weeks. Doxycycline tends to be very well tolerated. I use the 4 weeks of oral doxycycline and spare them needing an IV for Borrelia burgdorferi that's acquired in the United States.
Chow: That's great. You've heard it here that Dr Roos really only uses oral doxycycline to treat Lyme neuroborreliosis. That speaks to the fact that it works well for our patients who have neurologic Lyme. The last thing I wanted to ask you about is prevention of Lyme infection, which is perhaps the most effective way that we can help our patients. Can you tell us about preventing Lyme infection?
Roos: Absolutely. It's important to emphasize that ticks don't fly, and ticks don't jump. The way you get a tick attached to your body is literally when it has its hind legs on tall grasses, and it gets its front legs onto you. It has to be attached for 24-48 hours to transmit infection. You have time to get it off your body. The recommendation is to use tweezers, not to use a lighter and burn it off or any other ideas like that. You have to get the tick off in time. Patients worry about Lyme, and I think it's very reassuring to just treat them with doxycycline 200 mg. That's become the prophylactic dose if someone has a tick, and they're concerned and don't know how long it's been there. One day of 200 mg of doxycycline, and they're safe. That's a good thing to do. There are a lot of excellent tick repellents. People are supposed to wear long pants and long shirts, but when you're hiking, that makes you pretty hot and most people tend not to do that. Examine yourself carefully for ticks. Again, you're more often to get disease from a nymph, which is only 2 mm, than from an adult tick. You have to look really closely. If you're worrying about it, take 200 mg of doxycycline, and we can prevent it.
Chow: I want to get your input on another Borrelia infection, Borrelia miyamotoi, which is an emerging tick-borne pathogen transmitted by the same ticks as Borrelia burgdorferi. I know that it's a spirochete of the relapsing fever family and typically causes an acute febrile illness. There are reports of Borrelia miyamotoi also causing a meningoencephalitis. I was hoping you could tell our listeners about what we know about Borrelia miyamotoi and how it can cause neurologic infection, along with some of the differences between miyamotoi and burgdorferi in terms of neurologic manifestations.
Roos: Excellent question. One of the first things to look for is patients will typically have a leukopenia or a thrombocytopenia, so that's helpful. Often, elevated liver function tests can be helpful. They may develop a meningoencephalitis. Thus far, it's only occasionally reported in immunocompetent patients and most often in immunocompromised patients. The immunocompromised patients who are most commonly affected are those on B-cell depleting therapies. Rituximab is the big one. For those patients, there is a polymerase chain reaction (PCR) test that you can send on blood and on CSF. That's been a tremendous breakthrough in laboratory diagnosis because you can't otherwise see the spirochete. The PCR test is good, and those are the patients we treat with ceftriaxone. Again, you can use the same sort of therapy, but they're sicker and often immunocompromised. Interestingly, they have the same chemokine in CSF as patients who have Borrelia burgdorferi — that is a chemokine that attracts B cells. I think there's some association between the fact that they're at risk because they're on a B-cell depleting therapy and the reaction that we know happens in CSF with Borrelia infections.
Chow: Is PCR testing commercially available, or is this something that we need to do through research testing?
Roos: No, it's commercially available.
Chow: Wonderful. With that, we'll have to end for now. We've had Dr Roos discussing Lyme meningitis and other emerging neuroborrelioses. Thanks so much, Karen, for joining us. This is Dr Felicia Chow for InDiscussion.
Resources
Arboviral Central Nervous System Infections
Lyme Neuroborreliosis: Known Knowns, Known Unknowns
Cerebrospinal Fluid Pleocytosis Level as a Diagnostic Predictor? A Cross-sectional Study
Enzyme Linked Immunosorbent Assay
Lyme Central Nervous System Infection IgG With Antibody Index Reflex, Serum and Spinal Fluid
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Cite this: Is It Really Lyme? Lyme Meningitis and Emerging Neuroborreliosis - Medscape - May 09, 2023.
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