Expert Shares Key Insights on Diagnosis, Treatment

Among patients diagnosed with Lyme disease, up to 15% will develop Lyme neuroborreliosis, an infectious disease that affects the central nervous system (CNS).1-3 Lyme neuroborreliosis, which is caused by Borrelia burgdorferi, a tick-borne bacterial spirochete, is transmitted into the bloodstream through a tick bite. 1 Unless patients present with typical symptoms, it can be challenging for clinicians to diagnose Lyme neuroborreliosis.

Patients with Lyme neuroborreliosis can present with a wide range of symptoms that often mimic other neurologic conditions, and the clinical course of the disease is variable. Atypical clinical presentations may result in misdiagnosis and delayed treatment, which, in some patients, may lead to serious debilitation and persistent neurologic symptoms — even after correct diagnosis and treatment.1

Lyme neuroborreliosis should be on the radar for practicing clinicians, especially neurologists, infectious disease specialists, rheumatologists, and primary care practitioners, who most often would come into contact with patients exhibiting neurologic signs and symptoms of this notoriously difficult-to-diagnose and potentially debilitating infectious disease.

To raise clinician awareness on Lyme neuroborreliosis, we spoke with Paul Auwaerter, MD, professor of medicine and clinical director of the division of infectious diseases at Johns Hopkins University School of Medicine. Dr Auwaerter has participated in the joint collaboration between the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR) to develop the 2020 clinical practice guidelines for the prevention, diagnosis, and treatment of Lyme disease.4

I think it is reasonable for clinicians to keep a heightened interest in tick exposure, depending on what people present with symptom-wise.

Why is it no longer reliable to use low-risk months for ruling out Lyme neuroborreliosis?

Dr Auwaerter :Typically, late spring and early summer are the peaks, and that has to do with tick behavior because the nymphs (or so-called teenager ticks) are very hungry, so they do a lot of biting. Almost always, at least in the Mid-Atlantic and New England regions, the peak incidence of Lyme disease is in June and July. It then tails off through the fall because adult ticks prefer deer and larger animals to humans, and they just don’t feed as much, although you can still see it during these months.

The most frequent manifestation of Lyme disease is the erythema migrans rash, which can occur 3 to 30 days after a bite. There is seasonality to erythema migrans, but disseminated early Lyme disease, which could include neuroborreliosis and cardiac disease, may occur 2-3 months after acquiring the bite. If someone is bitten in October or November, they might not have manifestations until January when people are thinking it can’t possibly happen.

For late Lyme arthritis, the classic swollen knee can take up to 6 to 12 months to manifest. Many times, people may not even realize they have had a tick bite or infection because they don’t have any symptoms, yet they are harboring the organism and develop the swollen knee in January or February when they acquired the organism in July or August from the prior summer.

I think it is reasonable for clinicians to keep a heightened interest in tick exposure, depending on what people present with symptom-wise. For example, if someone presents with an acute fever in January it doesn’t make sense to consider a tick-borne illness, but swollen knee has a year-round potential for a presentation of Lyme disease.

What are the key indicators of active Lyme neuroborreliosis?

Can it be differentiated from other neurologic conditions, if at all, particularly if people do not exhibit the erythema migrans rash?

Dr Auwaerter : I think there are occasionally atypical presentations of Lyme disease, but really the vast majority do present in ways that I think should make clinicians think if this could be Lyme disease.

The most common is facial palsy, where one or even both sides of the face become weak because of cranial nerve VII involvement. Much more rarely, other cranial nerves can become involved.

I have also seen cases where people develop radiculitis, which is a pain syndrome just like shingles, although there is no rash visible like shingles. It can mimic things like sciatica, gallbladder pain, or a heart attack because of the band-like pain caused by the nerve roots becoming inflamed.

Then, there is meningoradiculitis or meningitis. It is more common in Europe than we see here mainly because the genospecies of Borrelia burgdorferi in Europe seem to cause more neurologic disease or infection than they do in North America, but in North America we can see an aseptic meningitis or radiculitis or meningoradiculitis.

Much less commonly, you can see problems with mononeuritis multiplex and other neuropathies. More careful inspection finds that it is probably very uncommon to develop polyneuropathy due to Lyme disease.

The less common manifestation is cardiac with just 1% of reported cases with conduction defects or carditis.

Lyme arthritis occurs in up to 30% of untreated cases. Historically, this was overreported at around 50% of untreated cases because the arthritis box gets checked when people present with muscle aches and pains even though it is not a true case of Lyme arthritis. The classic case of Lyme arthritis involves swelling of the knee and if you don’t have that, then you probably don’t have “real” Lyme arthritis.

Can you provide insight into what type of cerebrospinal fluid changes are typically observed in patients with neurologic complications of Lyme disease? 

Dr Auwaerter : If you don’t have a patient with a classic or clear presentation, you typically will want to get spinal fluid. We get a cerebrospinal fluid (CSF) Index, which seems to be the best way of understanding if you have an authentic Lyme infection. The reason for this is if you are seropositive for Lyme in the blood, even a small amount of antibodies will naturally cross the blood-brain barrier into the spinal fluid.

The idea with the index is on the same day you get both blood and CSF, and you send it to a lab that will take the sample and normalize total protein values. Once the protein values are normalized, if the amount of antibodies are higher in the spinal fluid, meaning there is more intrathecal antibody production than in the serum, it is very indicative that you have active CNS infection.

In a 2021 study5, researchers mention testing for Lyme disease using ELISA followed by Western blots.

Could you explain the significance of both IgM and IgG antibodies in the diagnosis of Lyme disease and the timing of their appearance in the course of the infection?

Dr Auwaerter : There are 2 types of ways that the US Food and Drug Administration (FDA) has espoused for Lyme disease testing — the standard two-tier testing (STTT) and a newer modified two-tier testing.

The standard approach is you do a screening test with an EIA or ELISA looking for total antibodies against Borrelia. Then, you do immunoglobulin G (IgG) and immunoglobulin M (IgM) immunoblots, but the IgM immunoblots have a very high rate of false positivity, which is why they should only be used when the person is presenting with symptoms within the first 30 days or so. The longer the disease symptoms, especially non-specific symptoms like fatigue, have lasted, immunoblots probably do not accurately reflect infection, especially if the IgG immunoblot is negative.

Typically, with acute disease, if you only have had symptoms for a week or 2, the IgM will be positive first. Of course, the immune system may take days to mount a response against the pathogen, so in the first week or 2 of illness these tests often are negative in 40% or more of acute cases, and then you see IgM and then, IgG positivity.

For Lyme neuroborreliosis, most people are IgG positive by 4 weeks into their symptoms. If there is a high index of suspicion, I will even recheck at 6 weeks to see if someone has mounted responses.

For facial palsies, best data is from an old study from Long Island, New York that stated around 25% of facial palsy cases were related to Borrelia burgdorferi infection, which still means that the majority of facial palsies are idiopathic or caused by viruses or things other than Lyme disease.6

It is important to differentiate what is causing the Bells palsy since antivirals will not work in cases caused by Borrelia burgdorferi.7 Antibiotic treatment does not speed resolution of the facial palsy, but it prevents other sequelae of the disease. It takes time for the nerve to heal.

Previous research published in BMC Infectious Diseases supports the use of antibiotic prophylaxis following a confirmed tick bite.8

Dr Auwaerter : The general thought for Lyme neuroborreliosis, except for that very late encephalitis-type presentation, is that 14 to 21 days of antibiotic treatment is sufficient, whether it be doxycycline or ceftriaxone, which is the most commonly employed intravenous antibiotic. There are some other choices out there — some forms of penicillin — that might be used, but these 2 are the 2 work horses to treat neuroborreliosis.

How effective is oral vs IV antibiotic treatment in resolving neurological manifestations of Lyme disease?

Careful studies from Scandinavia have compared intravenous (IV) to oral doxycycline therapy or even more extended oral therapy with amoxicillin.9-11 Typically, there’s no significant difference between the 2 routes of administration. Due to the fact that IV antibiotics do have complication rates with their catheters, we generally espouse that oral doxycycline therapy for patients who are not hospitalized is sufficient with perhaps the rare exception of Lyme encephalitis or myelitis. Now, this is not to say that giving ceftriaxone is wrong for neuroborreliosis. In fact, it was an option in earlier guidelines, but there does not seem to be any compelling difference between IV or oral antibiotics.

Some clinicians make the argument that these studies have not been replicated in North America. There are different genospecies in different countries, so it is conceivable that there might be differences [in treatment efficacy]; however, I have had good experience for over a decade using doxycycline for neuroborreliosis.

Can you elaborate on the circumstances when existing neurologic complications might persist despite appropriate treatment?

Dr Auwaerter :First you have what I call the persistent, subjective symptom complex. Around 10-20% of people after antibiotic treatment still feel fatigued, brain fog, poor sleep, new anxiety or depression, muscle aches and pains, and irritable bowel syndrome.

Then, there are people with objective findings, such as nerves that no longer function well or facial palsy that has not resolved. That may be 2-3% or sometimes up to 5% of people. Persistent facial palsy seems to be a little lower when caused by Lyme disease than idiopathic Bells palsy.

In longitudinal study published in Clinical Infectious Diseases, Wormser and colleagues followed a cohort of people who were culture positive for Borrelia burgdorferi for more than 10 years, conducting periodic follow-ups. In that group, only 4% of people had persistent symptoms over all of those years at every visit.12 Generally, people seemed to revert to the general population with normative complaints. I do think that often people do get better over time. There are some people that don’t, and we need to understand that better.

What we do know is that long-term antibiotic use doesn’t seem to help people with persistent symptoms get better. There have been at least 7 studies that have shown that additional administration of antibiotics does not seem to get much durable improvement in symptoms. What I tend to do in these cases is really individualize care and treat symptomatically, ranging from behavioral therapy to pharmacologic interventions.

What are some improvements needed to diagnose post-treatment Lyme disease syndrome?

Dr Auwaerter : I think we clearly need improvements. We need a way we can accurately diagnose post-treatment Lyme disease syndrome (PTLDS). We also need a clinical diagnosis. It would be lovely if we had a reliable biomarker for PTLDS.

We need a better understanding of the mechanism of why PTLDS afflicts certain people and an intervention. So far, there has really been no wholesale, highly predictable intervention, or else we would be doing it. Instead, we take a very tailored approach … a lot of it is trial and error to get people feeling better, but it would be better to have a mechanistic and evidence-based approach to help people.

What would you like to share with other clinicians that you believe might be helpful in diagnosing and treating Lyme neuroborreliosis?

Dr Auwaerter : I want to emphasize that we have seen many people referred to our clinic with diagnoses and treatments for Lyme disease that often have other diagnoses that are better suited to them.

Up to three-quarters of the people that come to our clinic at Johns Hopkins for long-term symptoms do not exhibit active Lyme disease and are diagnosed with other medical conditions that account for their chronic symptoms.13,14 New or pre-existing conditions, including anxiety/depression, fibromyalgia, chronic fatigue syndrome, migraine disorder, osteoarthritis, and sleep disorder/apnea, often better explained persistent symptoms in many of our patients. Less common medical diagnoses that also accounted for these symptoms included multiple sclerosis, malignancy, Parkinson disease, sarcoidosis, or amyotrophic lateral sclerosis.13

If you take time to listen to people’s stories, examine them thoroughly, and do appropriate testing, you might come to different conclusions.

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