Neurologic Complications of Lyme Disease

Karen L. Roos, MD, FAAN Neuroinfectious Diseases p. 1040-1050 August 2021, Vol.27, No.4 doi: 10.1212/CON.0000000000001015
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KEY POINTS

In North America, only one spirochete in the genus Borrelia causes Lyme disease, Borrelia burgdorferi.

The most common neurologic complications of Lyme disease are cranial neuritis (most often cranial nerve VII), meningitis, and radiculoneuritis.

An Ixodes tick typically must remain attached for 24 to 48 hours to transmit Borrelia to the host.

The initial sign of infection with Borrelia burgdorferi is a nonpruritic targetoid skin lesion called erythema migrans that develops at the site of the tick bite.

The Centers for Disease Control and Prevention recommends a two-step serologic testing procedure for Lyme disease. First, an enzyme-linked immunosorbent assay (ELISA) for antibodies to B. burgdorferi should be obtained. If the ELISA is negative, the patient does not have Lyme disease. If the ELISA is positive or borderline, a Western blot for both IgM and IgG antibodies is performed.

The CSF to serum antibody index is used to determine if intrathecal production of antibodies to Borrelia has occurred.

Doxycycline is not recommended in pregnant women, women who are breast-feeding, and children younger than 8 years of age, although a short course of doxycycline is not likely to stain teeth.

No rationale exists for managing posttreatment Lyme disease syndrome with long-term antibiotic therapy; convincing biological and clinical evidence is lacking for the existence of chronic B. burgdorferi infection after the recommended treatment regimens for Lyme disease are completed.

Lyme disease IgM Western blots have a high false-positive rate and must be followed by IgG testing.

PURPOSE OF REVIEW This article reviews the symptomatology, diagnosis, and treatment of neuroborreliosis.

RECENT FINDINGS The most recent guidelines for the diagnosis and treatment of Lyme disease were published in 2020 by the Infectious Diseases Society of America, the American Academy of Neurology, and the American College of Rheumatology.

SUMMARY The most common neurologic complications of Lyme disease are cranial neuritis (most often a unilateral or bilateral facial nerve palsy), meningitis, and radiculoneuritis/mononeuropathy multiplex. Testing for Lyme disease begins with an enzyme-linked immunosorbent assay (ELISA). If the ELISA is positive or borderline, Western blots should be performed for both IgM and IgG antibodies. As a general rule, in infectious diseases, an IgM antibody response is followed by an IgG antibody response. A central nervous system infection has either a CSF pleocytosis or pathogen-specific intrathecal antibody production. Lyme meningitis, cranial neuropathy, radiculoneuropathy, or other peripheral nervous system manifestations are treated with oral doxycycline or IV ceftriaxone, cefotaxime, or penicillin G. No additional antibiotic therapy is indicated for patients with posttreatment Lyme disease syndrome or patients with concern for chronic Lyme disease with no evidence of previous or current Lyme infection.

Address correspondence to Dr Karen Roos, IU Health Neuroscience Center, 355 W 16th St, Indianapolis, IN 46202, [email protected].

RELATIONSHIP DISCLOSURE: Dr Roos has received publishing royalties from Elsevier and has given expert medical testimony during a trial.

UNLABELED USE OF PRODUCTS/INVESTIGATIONAL USE DISCLOSURE: Dr Roos reports no disclosure.

INTRODUCTION

Lyme disease, named for Lyme, Connecticut, where the disease was first definitively identified, is caused by infection with spirochetes of the genus Borrelia acquired from a bite of an infected Ixodes tick. In North America, only one spirochete in the genus Borrelia causes Lyme disease, Borrelia burgdorferi. In addition to B. burgdorferi, other Borrelia species causing Lyme Disease in Europe include Borrelia afzelii and Borrelia garinii (and the much rarer Borrelia spielmanii and Borrelia bavariensis).

The most recent map of the incidence of Lyme disease in the United States is presented in figure 10-1. The states with the highest incidence are Connecticut, Vermont, Maine, Delaware, Massachusetts, New Hampshire, Rhode Island, New Jersey, Maryland, Pennsylvania, New York, Virginia, West Virginia, Minnesota, and Wisconsin.

The neurologic manifestations of Lyme disease are collectively referred to as neuroborreliosis. The focus of this article is on the most common neurologic complications of Lyme disease, which are cranial neuritis (most often cranial nerve VII), meningitis, and radiculoneuritis; rarer neurologic manifestations and posttreatment Lyme disease syndrome are also mentioned. Serologic diagnosis and its importance in understanding the contentious topic of “chronic Lyme disease” are also reviewed.

LIFE CYCLE OF IXODES TICKS AND TRANSMISSION OF BORRELIA

An Ixodes tick typically must remain attached for 24 to 48 hours to transmit Borrelia to the host. Most humans are infected through the bites of nymphs, which are smaller than 2 mm in length. Although adult ticks can also transmit infection, they are much larger and thus more readily seen and removed before they are able to transmit infection. As the tick ingests the host’s blood, the spirochetes can multiply in the tick’s gut and migrate to the tick’s salivary glands where they are subsequently injected into the host as the tick continues to feed on the host.

The life cycle of Ixodes scapularis ticks lasts approximately 2 years. During this time, they go through four life stages: eggs, six-legged larva, eight-legged nymph, and adult. After the eggs hatch, the ticks must have a blood meal at every stage from a new host (mammals, birds, reptiles, and amphibians) to survive (figure 10-2). Rodents and deer are the most common intermediate hosts before human exposure.

SYSTEMIC MANIFESTATIONS OF LYME DISEASE

The initial sign of infection is a nonpruritic targetoid skin lesion called erythema migrans that develops at the site of the tick bite (figure 10-3). This is a slowly enlarging erythematous lesion that classically appears as a target as the erythema in the center of the lesion clears. Central clearing does not always occur, in which case the rash appears as an enlarging erythematous lesion. The skin lesion is a site of active spirochete proliferation from which hematogenous dissemination of the spirochetes leads to systemic involvement. In approximately one-fourth of patients, more than one skin lesion is present, believed to result from hematogenous dissemination of spirochetes from the site of the initial tick bite. Because the rash is nonpruritic, it is possible that it is missed when it occurs on areas of the body that are difficult to see, such as the back. Erythema migrans is reported to occur in 90% of infected children because they are typically closely examined by their parents.

In addition to the cutaneous manifestations of Lyme disease, a monarthritis or oligoarthritis may occur; the knee is the most frequently involved joint. Cardiac complications may also be present, of which atrioventricular conduction defects are most commonly reported.

NEUROLOGIC COMPLICATIONS OF LYME DISEASE

The most common neurologic complications of Lyme disease are cranial neuritis (most often a unilateral or bilateral facial nerve palsy), meningitis, and radiculoneuritis. These may occur independently or concurrently.

Cranial Neuritis

Unilateral or bilateral cranial nerve VII palsy is one of the most common neurologic manifestations of Lyme disease. Patients develop lower motor neuron facial weakness. In a series of 559 patients presenting with a facial nerve palsy in a Lyme disease–endemic area, Lyme disease was the etiology in 4.7% of patients. The majority of patients with facial nerve palsy due to Lyme disease presented in the months of July to September, and most had headache.

Less commonly, cranial nerves III, IV, VI, and VIII may be involved. The mechanism of cranial neuritis in Lyme disease is thought to be due to mild meningitis based on the finding of CSF lymphocytic pleocytosis in spinal fluid from patients presenting with a cranial neuritis. However, CSF analysis is generally unnecessary for diagnosis in patients who develop facial nerve palsy in a Lyme disease–endemic region and have positive serum serology (see figure 10-1 for the endemic regions).

Meningitis

The most common symptom in Lyme meningitis is headache (case 10-1). Patients may have photo- and phonosensitivity, but fever and meningismus may be mild or absent. Analysis of the CSF demonstrates a lymphocytic pleocytosis, a mildly increased protein concentration, and a normal glucose concentration. Papilledema due to intracranial hypertension has been reported in children with Lyme meningitis and may rarely occur in adults.

CASE 10-1

A 39-year-old man and his 18-year old daughter presented for neurologic consultation after vacationing at their Cape Cod, Massachusetts, home in early June. They were aware they were in a Lyme disease–endemic area and used tick repellant, wore long sleeve shirts and long pants when hiking, and examined themselves frequently for ticks. During their trip, they were visited by a family member and his golden retriever. Shortly after returning home, the father developed headache with photosensitivity, and his daughter accompanied him to the visit because she woke up with mild right facial weakness.

On examination, the father had mild meningismus but was afebrile. His daughter was unable to smile on the right side and had weakness of eye closure with Bell’s phenomenon. She recalled a nonpruritic targetoid skin lesion, but he did not. Lumbar puncture and CSF analysis was obtained on the father because he had symptoms and signs of meningitis, and it revealed a lymphocytic pleocytosis of 100 cells/mm3, protein of 70 mg/dL, glucose of 45 mg/dL, and oligoclonal bands. Lumbar puncture was not performed on his daughter.

They were both treated with doxycycline 100 mg orally 2 times a day for 28 days. Serum enzyme-linked immunosorbent assay (ELISA) for Borrelia burgdorferi antibody returned positive 48 hours later for both the father and daughter; confirmatory testing with Western blot IgM was positive on initial testing, and IgG was positive on subsequent testing 4 weeks later. Ixodes ticks were identified on the dog during the time the family was together in the Cape Cod home.

COMMENT

The patients were in a Lyme disease–endemic area, and both had signs and symptoms of neurologic complications of Lyme disease. Cranial nerve VII palsy is treated with doxycycline. Either oral doxycycline or IV ceftriaxone is considered acceptable treatment for Lyme meningitis, and the decision about which is used for treatment should be based on the severity of the meningitis.

Radiculoneuritis

Nervous system Lyme disease may present with pain and weakness in one or more limbs. This was initially attributed to a radiculitis or a plexitis, but in electrophysiologic studies and in the experimentally infected rhesus macaque monkey, this has been demonstrated to be a mononeuropathy multiplex.

Lyme Neuroborreliosis in Europe

In the United States, it is rare for patients with Lyme disease to develop brain parenchymal or spinal cord involvement. In Europe, infection of the central nervous system (CNS) occurs in 2% to 4% of patients with Lyme neuroborreliosis, manifesting as encephalitis or a myelitis with a spastic gait and bladder dysfunction. Much more commonly, the spinal nerve roots or cranial nerves are involved. If the meninges are involved as well (ie, meningoradiculoneuritis), that is called Garin-Bujadoux-Bannwarth syndrome, or Bannwarth syndrome for short. Stroke as a result of vasculitis has also been described in the European literature in case reports and small case series.

DIAGNOSIS

The Centers for Disease Control and Prevention (CDC) recommends a two-step serologic testing procedure for Lyme disease. First, an enzyme-linked immunosorbent assay (ELISA) for antibodies to B. burgdorferi should be obtained. If the ELISA is negative, the patient does not have Lyme disease. If the ELISA is positive or borderline, a Western blot for both IgM and IgG antibodies is performed. IgM antibodies are useful only in patients whose illness is shorter than 3 to 6 weeks in duration. Beyond this time period, isolated IgM antibodies are more likely to represent nonspecific cross-reactivity and cannot be interpreted as evidence of B. burgdorferi infection. IgG antibodies are positive in all patients with Lyme disease, except in the earliest period of infection, in which case spinal fluid analysis may be necessary to make the diagnosis of neuroborreliosis (case 10-2). figure 10-4 provides an algorithm for treatment decisions based on the presence or absence of erythema migrans, duration of symptoms, and results of IgM and IgG if ELISA is positive or borderline.

CASE 10-2

A 26-year-old man presented with a 4-month history of pain in the lateral area of his left thigh. He worked as a lineman repairing electrical power lines and wore a heavy tool belt. He did not live in nor had he traveled to an area endemic for Lyme disease. He had not had a lesion that resembled erythema migrans. He asked to be tested for Lyme disease.

The enzyme-linked immunosorbent assay (ELISA) was borderline, Western blot IgM was positive, and Western Blot IgG was negative. The patient was counseled that his symptoms were not due to Lyme disease based on these results and that he most likely had meralgia paresthetica from his toolbelt.

COMMENT

Western blot IgMs are useful only in patients whose illness is shorter than 3 weeks or at most 6 weeks in duration. In a patient with symptoms longer than this period and due to Lyme disease, an IgG antibody response should be observed. Patients regularly ask to be tested for Lyme disease. This is entirely reasonable if they live in or have traveled to an area endemic for Lyme disease and have symptoms consistent with neuroborreliosis such as headache, facial nerve palsy, or radiculoneuritis/mononeuropathy multiplex.

Patients with active neuroborreliosis have a CSF pleocytosis. Because Borrelia antibodies can be passively transferred from serum to CSF, CSF antibodies do not necessarily indicate CNS infection. Therefore, the CSF to serum antibody index is used to determine if intrathecal production of antibodies to Borrelia has occurred. The antibody index is defined in the following equation:

antiBorreliaIgGinCSF/antiBorreliaIgGin serumtotalIgGinCSF/totalIgGin serum

The antibody index is considered positive when the result is greater than 1.3 to 1.5.

Spinal fluid analysis is especially helpful in patients who develop neuroborreliosis symptoms in an endemic area for Lyme disease in whom serology is negative. The absence of CSF lymphocytic pleocytosis is evidence against CNS Lyme infection (case 10-3).

CASE 10-3

A 32-year-old woman presented in October with a 3-day history of a facial nerve palsy on the right side. She had been hiking in a Lyme disease–endemic area and every evening examined her skin closely for ticks. She had not found a tick attached to her skin or had a lesion of erythema migrans. On review of systems, she acknowledged she had a headache but stated she often had headaches. She had no fever or weight loss.

Lyme disease enzyme-linked immunosorbent assay (ELISA) was negative. Because it may have been too early for her to have a measurable antibody response, spinal fluid analysis was performed. No evidence of a CSF pleocytosis or intrathecal antibody production was found. The patient was reassured that she did not have Lyme disease and was treated with steroids for Bell’s palsy.

COMMENT

Spinal fluid analysis may be considered in patients with facial nerve palsy and negative Lyme disease serology in a Lyme disease–endemic area when they have headache and present during tick season, even if they have no history of a recent tick bite or the appearance of a lesion of erythema migrans. Alternative approaches to obtaining CSF analysis would be to treat with corticosteroids and repeat serology several weeks later or treat with corticosteroids and doxycycline (see the section titled “Treatment”) while awaiting repeat Lyme disease serology.

TREATMENT

The most recent guidelines for the diagnosis and treatment of Lyme disease were published in 2020 by the Infectious Diseases Society of America, the American Academy of Neurology (AAN), and the American College of Rheumatology.

These guidelines recommend prophylactic therapy for a high-risk tick bite with doxycycline given as a single oral dose of 200 mg for adults and 4.4 mg/kg (up to a maximum dose of 200 mg) for children. A high-risk tick bite is defined as a bite from an Ixodes species tick that was attached for 36 hours or longer in an area highly endemic for Lyme disease.

The 2020 guidelines recommend that patients with Lyme meningitis, cranial neuropathy, or radiculoneuropathy be treated with IV ceftriaxone, IV cefotaxime, IV penicillin G, or oral doxycycline. Numerous European studies have shown that oral doxycycline is as effective as IV antibiotics for neuroborreliosis, and it has excellent CNS penetration. Doxycycline is not recommended in pregnant women, women who are breast-feeding, and children younger than 8 years of age, although a short course of doxycycline is not likely to stain teeth. Doxycycline is dosed 100 mg orally, 2 times a day, for 2 to 4 weeks. IV antibiotics are recommended in patients with severe neurologic manifestations such as the extremely rare Lyme encephalitis, myelitis, or encephalomyelitis. Ceftriaxone is dosed 2 g once a day for 14 to 28 days for adults and children, cefotaxime 2 g every 8 hours for 14 to 28 days, and penicillin G 20 million units daily in divided doses every 4 hours for 2 to 4 weeks.

POSTTREATMENT LYME DISEASE SYNDROME AND CHRONIC LYME DISEASE

Posttreatment Lyme disease syndrome is not synonymous with chronic Lyme disease. Posttreatment Lyme disease syndrome requires a history of symptomatology of Lyme disease, laboratory proof that the patient had Lyme disease, and treatment with one of the earlier-mentioned recommended antimicrobial therapies. The CDC lists pain, fatigue, and difficulty thinking as symptoms in posttreatment Lyme disease syndrome that can persist for months to years. The CDC states that prolonged antibiotic therapy provides no benefit to patients who have these symptoms. The Infectious Diseases Society of America and the European Federation of Neurological Associations “assert that while some patients report postinfection sequelae, there is no rationale for the use of long-term antibiotic therapy for [posttreatment Lyme disease syndrome] given the consistent lack of convincing biologic or clinical evidence for the existence of chronic B. burgdorferi infection after completion of recommended treatment regimens for Lyme disease.”

A recent review of posttreatment Lyme disease included the following symptoms: fatigue, chronic pain, cognitive concerns, paresthesia, and poor sleep. The authors suggest that the symptoms of posttreatment Lyme disease may be caused by a dysregulated host immune response or nonspecific immune activation.

“Chronic Lyme disease” is a controversial entity in which fatigue, depression, pain, and cognitive concerns are attributed to Lyme disease without a history of characteristic symptoms or a legitimate laboratory diagnosis of Lyme disease. See case 10-4 for discussion of the approach to this scenario.

CASE 10-4

A 46-year-old woman was referred by her primary care physician for “chronic Lyme disease.” She had been treated for 8 months with IV ceftriaxone for fatigue, pain, and “brain fog.” She had not been to a Lyme disease–endemic area and never had a nonpruritic targetoid skin lesion, joint pain, a seventh cranial nerve palsy, meningitis, or radiculitis. She brought her medical records with her, including a laboratory record that stated, “Lyme Western blot IgM positive.”

A Western blot IgG was sent and returned negative. The patient was counseled at her subsequent visit that she did not have Lyme disease, that she did not need to continue antibiotic treatment, and that antibiotics may be harmful to her. She was reassured that, although the cause of her symptoms was unclear, she did not have a chronic infection in her brain. She was offered to undergo a lumbar puncture with the explanation that, if infection and inflammation were present in the brain, the spinal fluid would be abnormal. She was told to expect that the results would be normal, but if it would give her peace of mind, she could go ahead with a lumbar puncture. She was not anxious to undergo the procedure but was comforted by knowing about a possible way to determine if she had a chronic infection in her brain.

COMMENT

Chronic Lyme disease is a controversial entity that is not considered to have a scientific basis. Lyme disease IgM Western blots have a high false-positive rate and must be followed by IgG testing. Chronic antibiotic therapy is not indicated for chronic fatigue, pain, and brain fog, and it can be harmful.

CHEMOKINES AND CYTOKINES

Even before severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), cytokines and chemokines were frequently written about by those of us who are interested in dexamethasone in the prevention of the neurologic complications of bacterial meningitis. The SARS-CoV-2 pandemic has again focused research and therapeutic trials on cytokines and chemokines.

In meningitis complicating Lyme disease, infection of the CNS with B. burgdorferi is followed by a rapid increase in CSF CXCL13 (a B cell–attracting chemokine) and intrathecal B. burgdorferi antibody production. Elevated levels of CXCL13 are also present in the CSF of patients with neurosyphilis, human immunodeficiency virus (HIV), aseptic meningitis, and CNS lymphoma. The significance of this observation is unclear at this time, but the concentration of this chemokine falls rapidly after initiation of antibiotic therapy.

Chemokines and cytokines may have a role in patients who develop cognitive symptoms during an acute infectious disease that persist after the disease despite eradication of the pathogen. However, what is not understood is how chronic cognitive symptoms could be caused by chemokines and cytokines when an encephalopathy or stroke did not develop during the acute illness.

CONCLUSION

In North America, Lyme disease is caused by infection with the spirochete, B. burgdorferi, which occurs from the bite of an infected Ixodes tick that has been attached for 24 to 48 hours. The most common neurologic complications of Lyme disease are cranial neuritis (most often a unilateral or bilateral facial nerve palsy), meningitis, and radiculoneuritis/mononeuropathy multiplex. Testing for Lyme disease begins with an ELISA. If the ELISA is positive or borderline, Western blots should be performed for both IgM and IgG antibodies. IgM antibodies are useful only in patients whose illness is shorter than 3 weeks or at most 6 weeks in duration. Beyond this time period, IgM antibodies are more likely to represent nonspecific cross-reactivity and cannot be interpreted as evidence of acute infection. As a general rule, in infectious diseases, an IgM antibody response is followed by an IgG antibody response. A CNS infection has either a CSF pleocytosis or pathogen-specific intrathecal antibody production. Lyme meningitis, cranial neuropathy, radiculoneuropathy, or other peripheral nervous system manifestations are treated with oral doxycycline or IV ceftriaxone, cefotaxime, or penicillin G. No additional antibiotic therapy is indicated for patients with posttreatment Lyme disease syndrome or patients with concern for chronic Lyme disease with no evidence of previous or current Lyme infection.

KEY POINTS

  • In North America, only one spirochete in the genus Borrelia causes Lyme disease, Borrelia burgdorferi.
  • The most common neurologic complications of Lyme disease are cranial neuritis (most often cranial nerve VII), meningitis, and radiculoneuritis.
  • An Ixodes tick typically must remain attached for 24 to 48 hours to transmit Borrelia to the host.
  • The initial sign of infection with Borrelia burgdorferi is a nonpruritic targetoid skin lesion called erythema migrans that develops at the site of the tick bite.
  • The Centers for Disease Control and Prevention recommends a two-step serologic testing procedure for Lyme disease. First, an enzyme-linked immunosorbent assay (ELISA) for antibodies to B. burgdorferi should be obtained. If the ELISA is negative, the patient does not have Lyme disease. If the ELISA is positive or borderline, a Western blot for both IgM and IgG antibodies is performed.
  • The CSF to serum antibody index is used to determine if intrathecal production of antibodies to Borrelia has occurred.
  • Doxycycline is not recommended in pregnant women, women who are breast-feeding, and children younger than 8 years of age, although a short course of doxycycline is not likely to stain teeth.
  • No rationale exists for managing posttreatment Lyme disease syndrome with long-term antibiotic therapy; convincing biological and clinical evidence is lacking for the existence of chronic B. burgdorferi infection after the recommended treatment regimens for Lyme disease are completed.
  • Lyme disease IgM Western blots have a high false-positive rate and must be followed by IgG testing.

REFERENCES

1. Bierman SM, van Kooten B, Vermeeren YM, et al. Incidence and characteristics of Lyme neuroborreliosis in adult patients with facial palsy in an endemic area in the Netherlands. Epidemiol Infect 2019;147:e160. doi:10.1017/S0950268819000438
2. Centers for Disease Control and Prevention. Lyme disease maps: most recent year. Accessed March 22, 2021. cdc.gov/lyme/datasurveillance/maps-recent.html
3. Piesman J, Dolan MC. Protection against Lyme disease spirochete transmission provided by prompt removal of nymphal Ixodes scapularis (Acari: Ixodidae). J Med Entomol 2002;39(3):509–512. doi:10.1603/0022-2585-39.3.509
4. Halperin JJ. Nervous system Lyme disease. In: Biller J, Ferro JM, eds. Handbook of clinical neurology. Neurologic aspects of systemic disease part III.  Elsevier, 2014;121:1473–1483.
5. Centers for Disease Control and Prevention. Lyme disease maps: most recent year. Accessed March 22, 2021. cdc.gov/ticks/life_cycle_and_hosts.html
6. Halperin JJ. Neuroborreliosis and neurosyphilis. Continuum (Minneap Minn) 2018;24(5, Neuroinfectious Disease):1439–1458. doi: 10.1212/CON.0000000000000645
7. Halperin JJ. Neuroborreliosis. Neurol Clin 2018;36(4):821–830. doi:10.1016/j.ncl.2018.06.006
8. Garcia-Monco JC, Benach JL. Lyme neuroborreliosis: clinical outcomes, controversy, pathogenesis, and polymicrobial infections. Ann Neurol 2019;85(1):21–31. doi:10.1002/ana.25389
9. Halperin JJ, Luft BJ, Volkman DJ, Dattwyler RJ. Lyme neuroborreliosis. Peripheral nervous system manifestations. Brain 1990;113(pt 4):1207–1221. doi:10.1093/brain/113.4.1207
10. England JD, Bohm RP Jr, Roberts ED, Philipp MT. Mononeuropathy multiplex in rhesus monkeys with chronic Lyme disease. Ann Neurol 1997;41(3):375–384. doi:10.1002/ana.410410313
11. Rauer S, Kastenbauer S, Fingerle V, et al. Lyme neuroborreliosis. Dtsch Arztebl Int 2018;115(45);751–756. doi:10.3238/arztebl.2018.0751
12. Zajkowska J, Garkowski A, Moniuszko A, et al. Vasculitis and stroke due to Lyme neuroborreliosis—a review. Infect Dis (Lond) 2015;47(1):1–6. doi:10.3109/00365548.2014.961544
13. Wittwer B, Pelletier S, Ducrocq X, et al. Cerebrovascular events in lyme neuroborreliosis. J Stroke Cerebrovasc Dis 2015;24(7):1671–1678. doi:10.1016/j.jstrokecerebrovasdis.2015.03.056
14. Halperin JJ. Lyme disease: a multisystem infection that affects the nervous system. Continuum (Minneap Minn) 2012;18(6, Infectious Disease):1338–1350.
15. Lantos PM, Rumbaugh J, Bockenstedt LK, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America, American Academy of Neurology, and American College of Rheumatology: 2020 guidelines for the prevention, diagnosis, and treatment of lyme disease. Neurology 2021;96(6):262–273. doi:10.1212/WNL.0000000000011151
16. Halperin JJ, Shapiro ED, Logigian EL, et al. Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2007;69(1):91–102. doi:10.1212/01.wnl.0000265517.66976.28
17. Kullberg BJ, Vrijmoeth HD, van de Schoor F, Hovius JW. Lyme borreliosis: diagnosis and management. BMJ 2020;369:m1041. doi:10.1136/bmj.m1041
18. Centers for Disease Control and Prevention. Post-treatment Lyme disease syndrome. Accessed March 22, 2012. cdc.gov/Lyme/postlds/
19. Goodlet KJ, Fairman KA. Adverse events associated with antibiotics and intravenous therapies for post-Lyme disease syndrome in a commercially insured sample. Clin Infect Dis 2018;67(10):1568–1574. doi:10.1093/cid/ciy329
20. Rebman AW, Aucott JN. Post-treatment Lyme disease as a model for persistent symptoms in Lyme disease. Front Med (Lausanne) 2020;7:57. doi:10.3389/fmed.2020.00057
21. Berende AB, ter Hofstede HJM, Vos FJ, et al. Randomized trial of longer-term therapy for symptoms attributed to Lyme disease. N Engl J Med 2016;374(13):1209–1220. doi:10.1056/NEJMoa1505425
22. Marzec NS, Nelson C, Waldron PR, et al. Serious bacterial infections acquired during treatment of patients given a diagnosis of chronic Lyme disease—United States. MMWR Morb Mortal Wkly Rep 2017;66(23):607–609. doi:10.15585/mmwr.mm6623a3
23. Lantos PM, Branda JA, Boggan JC, et al. Poor positive predictive value of Lyme disease serologic testing in an area of low disease incidence. Clin Infect Dis 2015;61(9):1374–1380. doi:10.1093/cid/civ584
24. Seriburi V, Ndukwe N, Chang Z, et al. High frequency of false positive IgM immunoblots for Borrelia burgdorferi in clinical practice. Clin Microbiol Infect 2012;18(12):1236–1240. doi:10.1111/j.1469-0691.2011.03749.x
25. Marra CM, Tantalo LC, Sahi SK, et al. CXCL13 as a cerebrospinal fluid marker for neurosyphilis in HIV-infected patients with syphilis. Sex Transm Dis 2010;37(5):283–287. doi:10.1097/OLQ.0b013e3181d877a1
26. Fujimori MC, Nakashima I, Kuroda H, et al. Cerebrospinal fluid CXCL13 is a prognostic marker for aseptic meningitis. J Neuroimmunol 2014;273(1-2):77–84. doi:10.1016/j.jneuroim.2014.05.008
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