Lyme disease …

John J Halperin MD

Neuroimmunology

Updated 04.03.2025
Released 05.08.1995
Expires For CME 04.03.2028

Lyme disease

Author: John J Halperin MD

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Editor: John E Greenlee MD

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Lyme disease

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Introduction

Overview

Historically, Lyme disease, infection with the tick-borne spirochete Borrelia burgdorferi sensu lato (Bb), has been reported to involve the nervous system in 10% to 15% of infected individuals–both in Europe and the U.S.–although data suggest this proportion may be decreasing with earlier diagnosis and treatment. Controlled studies indicate that neuroborreliosis is generally curable with oral antibiotics, particularly doxycycline, often with relatively rapid resolution of neurologic deficits. Although much is said about what some have termed “neurologic symptoms,” such as fatigue, “brain fog,” and concentration difficulty, occurring after microbiological cure of this infection, studies indicate that months after treatment these symptoms are not only unrelated to nervous system infection but occur with essentially the same frequency in treated patients and in healthy controls. Lyme disease diagnosis generally relies on 2-tier serologic testing, with positive or equivocal first-tier tests (ELISAs or equivalent) validated by either a Western blot or by a second independent ELISA. Demonstrated synthesis of anti-Bb antibody in the CSF (intrathecal antibody production; ITAb) is considered necessary to make a diagnosis of definite CNS Lyme neuroborreliosis, a diagnosis that may be further supported by demonstrated marked elevation of CSF CXCL13 concentration.

Key points

	• Lyme disease, infection with tick-borne spirochetes of the B burgdorferi sensu lato group, historically has been reported as affecting the central or peripheral nervous system in up to 10% to 15% of patients–a number that may be declining with earlier diagnosis and treatment.
	• Clinical phenomena associated with Lyme neuroborreliosis (LNB) classically include one or more of the following: cranial neuropathy (most often the facial nerve), painful radiculoneuropathy, and lymphocytic/monocytic meningitis.
	• Diagnosis of definite CNS Lyme neuroborreliosis requires demonstration of a CSF pleocytosis and intrathecal production of anti-Bb antibody. If either is absent, cases are considered possible/probable, not definite.
	• Serodiagnosis after the first month of infection has high sensitivity and specificity.
	• Treatment with 2- to 4-week courses of oral antibiotics is curative in most cases of Lyme neuroborreliosis; parenteral treatment is recommended if there is evidence of parenchymal brain or spinal cord involvement or if objectively demonstrable active disease persists after appropriate oral treatment.
	• Persisting difficulties after treatment, often referred to as “post-treatment Lyme disease syndrome,” may occur but are not associated with nervous system infection and, in most controlled studies, are no more common than in controls.
	• Misinterpretation of testing and clinical observations results in many patients being treated unnecessarily for what is incorrectly thought to be Lyme disease, with considerable potential for side effects and patient expense.

Historical note and terminology

The term "Lyme arthritis" was first broadly introduced in 1977 and was subsequently expanded to "Lyme disease" when it was recognized that the disorder commonly involves multiple organ systems in addition to joints (77). However, many aspects of this disease were described much earlier in the 20th century. In 1910, Afzelius first reported the typical cutaneous lesion, erythema migrans (formerly erythema chronicum migrans). In 1922, Garin and Bujadoux described tick bite-associated meningoradiculitis, the most typical neurologic presentation in this disorder. Following a more detailed description of this syndrome by Bannwarth, the notion that bites of Ixodes ticks could lead to a syndrome of lymphocytic/monocytic meningitis with painful radiculoneuritis became widely accepted by European clinicians. The first reports of Lyme arthritis described cases of what had been thought to be juvenile rheumatoid arthritis among children in the region of Lyme, Connecticut (77). Detailed epidemiologic studies led to the association of this disorder with bites of Ixodes ticks. In 1979, Reik and colleagues described a neurologic syndrome in American patients with Lyme disease virtually identical to that described by Garin and Bujadoux (67). In 1983, the responsible spirochete, Borrelia burgdorferi, was identified as the causative agent in American patients with Lyme disease. Shortly thereafter, closely related microorganisms were identified in European patients. Subsequent work has both broadened the scope of the neurologic disorders recognized as associated with this infection (known collectively as "Lyme neuroborreliosis") and refined the microbiological understanding of the responsible organisms. Advances in genomics have led to a proposed change in taxonomy, differentiating the organisms responsible for Lyme disease and related disorders, with the recommended name Borreliella, from the relapsing fever Borrelia (07)--a proposal that has yet to gain widespread acceptance. The broad group formerly termed B burgdorferi sensu lato would be termed Borreliella burgdorferi, with corresponding changes in the names for B afzelii and B garinii.

Clinical manifestations

Presentation and course

	• Lyme disease is a multisystem infectious disease. Skin involvement (erythema migrans) occurs in most; joint (Lyme arthritis) and nervous system (Lyme neuroborreliosis) involvement occur in a significant minority.
	• Nervous system involvement typically involves all or part of a triad of lymphocytic/monocytic meningitis, cranial neuritis, and radiculoneuropathy–the latter typically a painful radicular disorder virtually indistinguishable from a mechanical or zoster radiculopathy.
	• Historically, Lyme arthritis has been considered the most frequent extracutaneous manifestation in North America, and Lyme neuroborreliosis has been the most frequent in Europe. Recent data suggest these numbers have evolved, with both occurring less frequently than previously and the nervous system now the second most common site in both regions.
	• In North America, facial nerve palsy is the most common neurologic manifestation, occurring in more than half of Lyme neuroborreliosis patients. Radiculoneuritis is the most common in European patients and occurs less frequently in North America and rarely in children.
	• The diagnosis of definite CNS Lyme neuroborreliosis requires an appropriate clinical picture, CSF pleocytosis, and demonstration of intrathecal antibody production. If any one element is absent, the diagnosis is considered possible/probable Lyme neuroborreliosis. These criteria are often not applicable in Lyme neuroborreliosis limited to peripheral nerve.

Lyme disease, or Lyme borreliosis, is a multisystem infectious disease. The most commonly affected organ systems are skin, joints, nervous system, and heart. The most frequent manifestation is a characteristic erythematous, macular, usually painless rash at the site of an Ixodes tick bite, typically evolving over days to weeks to become many centimeters in diameter, known as erythema migrans. United States Centers for Disease and Prevention data indicate erythema migrans occurs in 70% to 75% of patients overall (73). Notably, it is described in as many as 90% of infected children (21). Whether this reflects a biological difference between children and adults, or more complete surveillance of small children by their parents, remains to be determined.

Erythema migrans

Erythema migrans, the characteristic skin lesion of Lyme disease, starts as a red macule or papule, which expands to form a large red ring with central clearing (Contributed by Dr. John Halperin.)

This erythroderma is virtually unique, although Southern Tick Associated Rash Illness (STARI) can closely mimic the cutaneous findings of Lyme disease. STARI occurs primarily in the Central Midwest United States, quite rarely in Lyme endemic areas, and causes a self-limited erythroderma that is identical in appearance but is not caused by borrelia and is not responsive to antibiotics. Following erythema migrans, which is an acute and usually localized cutaneous infection, patients may develop subacute problems secondary to bacterial dissemination. This dissemination may be accompanied by what is often referred to as a flu-like syndrome with fever, malaise, and diffuse aches and pains. In some, bacterial dissemination will result in a multicentric erythema migrans. Historic epidemiologic data indicate that in the United States arthritis occurs in 25% to 30%, with objective neurologic manifestations in about 12%--the latter similar to the usually quoted 15% Lyme neuroborreliosis incidence in European patients. Fewer than 2% of patients will develop cardiac conduction abnormalities (73). Others may develop a mild hepatitis or myositis.

Multifocal erythema migrans (1)

Each lesion represents a separate nidus of infection that has disseminated from the initial site of inoculation. (Contributed by Dr. John Halperin.)
Multifocal erythema migrans (2)

Each lesion represents a separate nidus of infection that has disseminated from the initial site of inoculation (Contributed by Dr. John Halperin.)
Multifocal erythema migrans (3)

Each lesion represents a separate nidus of infection that has disseminated from the initial site of inoculation. (Contributed by Dr. John Halperin.)
Multifocal erythema migrans (4)

Each lesion represents a separate nidus of infection that has disseminated from the initial site of inoculation. (Contributed by Dr. John Halperin.)

In both Europe and North America, nervous system involvement typically consists of all or part of the triad of lymphocytic/monocytic meningitis (occurring in isolation in about 2% of CDC-confirmed Lyme disease cases), cranial neuritis, (primarily facial nerve palsy, occurring in about 8% of Lyme disease patients), and radiculoneuropathy (in about 4% of confirmed U.S. cases) (73). Data suggest these numbers may either have been overestimated or have changed over time. One systematic study from Ontario found that most patients reported as having “arthritis” actually had arthralgias, with frank arthritis occurring in just 2.8% of patients with Lyme disease (31), a number identical to the estimate of 2.8% from analysis of a large German database (12). Similarly, the Ontario data found just 3.7% of patients with Lyme disease had facial nerve palsy. In the German data just 3.8% of patients with Lyme disease had Lyme neuroborreliosis (not stratified by site of involvement) in contrast to the usually quoted 10% to 15% of European patients–the latter based primarily on older Scandinavian studies. Given the recent observation that the duration of erythema migrans is two to three times longer in patients who develop Lyme neuroborreliosis than in those without disseminated disease, this may reflect earlier recognition and treatment of this infection (57). Alternatively, the possible role of referral and anchoring biases, imprecisely applied diagnoses, or other issues cannot be underestimated.

Studies do suggest neurologic symptomatology differs in children and adults, which may factor into differences among studies, many of which have been skewed towards one or the other. Among Czech patients with Lyme neuroborreliosis-related motor weakness (76), weakness affected a limb in 20% of adults (radiculoneuropathy) and the face in 75%; in children these numbers were 3% and 97%, respectively, a disparity corroborated in a Dutch study (89) (not limited to patients with motor weakness, as in the Czech study) in which polyradiculitis occurred in 51% of adults with any form of Lyme neuroborreliosis, but just 3% of children.

Virtually any cranial nerve may be involved, although the seventh is the most common, with facial nerve palsies occurring in greater than 50% of all patients with Lyme neuroborreliosis. Lyme disease is one of the small number of disorders (along with sarcoidosis and Guillain-Barre syndrome) commonly associated with bilateral facial palsies, occurring in up to 30% of adults with Lyme-associated facial nerve palsies but less than 6% of children. Painful radiculitis, historically considered the most common presentation in European adults with Lyme neuroborreliosis, may precisely mimic a mechanical or zoster monoradiculopathy or may be more disseminated, causing an apparent plexitis or even a diffuse disorder that may clinically resemble Guillain-Barre syndrome (89). Although it is often stated that painful radiculopathy is much less common in the United States than in Europe, a study of U.S. patients with Lyme facial nerve palsy found that a third had concomitant radicular symptoms (48). Rare patients (up to 3% in one European series) may develop a focal encephalitis with prominent white matter involvement, or a myelopathic picture, the latter reported to occur in 7% of European patients with radiculitis (74; 36; 30). No systematic data are available in U.S. patients (33). Studies of experimental infection in primates have demonstrated meningeal and radicular involvement, but not CNS parenchymal infection (24).

Some patients will come to medical attention only when the disease has been present for a longer period of time. Lyme arthritis is generally considered a subacute or late manifestation. This is typically an asymmetric, large joint (eg, knee, elbow, hip) recurring oligoarthritis (77). The other common late manifestations are neurologic. At one extreme (fortunately rare), this may include a chronic encephalomyelitis, with focal abnormalities on neurologic examination and brain MRI scans (24). At the other neuroanatomic extreme, neurologic manifestations may entail a mild peripheral neuropathy that may resemble a symmetric distal polyneuropathy, a more focal mononeuropathy multiplex, or even a polyradiculopathy (24). One European report suggests that peripheral nerve involvement may be more common than is commonly assumed (78). A large proportion of experimentally infected primates develop a vasculopathic neuropathy, a mononeuropathy multiplex analogous to that seen clinically. Demyelinating neuropathies have been reported rarely in patients with this disorder, an association that may well be coincidental (72). Some patients with longstanding untreated B burgdorferi infection will develop mild difficulty with memory and complex intellectual tasks in the context of symptomatic multisystem involvement (24). This may, in rare patients, be due to a mild encephalomyelitis but almost always is due to the remote effects of systemic infection and inflammation (ie, a metabolic encephalopathy).

Table 1. Neurologic Disorders in Lyme Disease and their Pathophysiology Grouped by Pathophysiologic Mechanism

Peripheral nerve
	• Mononeuropathy multiplex
		- Cranial neuropathy - Radiculopathy - Brachial plexopathy - Lumbosacral plexopathy - Confluent mononeuropathy multiplex - Motor neuropathy - “Guillain Barre-like” (rarely, if ever, demyelinating)
Central nervous system
	• Infection in subarachnoid space
		- Radiculitis - Cranial neuropathy - Meningitis - Pseudotumor-like, particularly in children, usually with meningeal inflammation
	• Parenchymal infection
		- Encephalitis (“MS-like”) - Myelitis
Not nervous system infection
	• Toxic/metabolic encephalopathy

Diagnosis requires combining clinical observations with laboratory data. Clinical diagnostic criteria (case definition) used by the Centers for Disease Control are useful but deliberately restrictive, being designed for surveillance purposes and, therefore, rigor and consistency rather than sensitivity. These require either a physician-diagnosed erythema migrans, measuring at least 5 cm in diameter, or laboratory evidence of infection with B burgdorferi (culture, significant change in antibody level, a single positive 2-tier serology (blood), or disproportionate antibody elevation in CSF) in combination with either (a) acute onset of otherwise unexplained heart block; (b) a relapsing large joint oligoarthritis; or (c) mononuclear cell meningitis, cranial neuritis, radiculoneuritis, or encephalomyelitis. The last in particular should be confirmed by demonstration of production of anti-B burgdorferi antibody in the CSF. Notably, the CDC revised the case definition for high incidence regions in 2022, basing diagnosis in those regions on laboratory evidence alone (38). Not surprisingly, this resulted in a 1.7-fold increase in the number of cases meeting the case definition – a jump that immediately elicited panicked articles in the press!

In general clinical practice, acceptance of the diagnosis is reasonable if a patient has an epidemiologically plausible exposure, has a clinical disorder within the realm of those reported to occur in this infection (40), and has had either an erythema migrans (early disease) or a positive serology. IgG antibodies should be demonstrable by 2-tiered testing in all patients with disease of more than 4 to 6 weeks’ duration. IgM responses are useful in the first 4 weeks or so after initial infection but are almost certainly irrelevant after this and should be disregarded. The common causes of false-positive serology (eg, syphilis, polyclonal B cell expansion) should be excluded. In patients with positive serologies and atypical disorders, or with negative serologies and typical syndromes, the diagnosis is possible but must be entertained with caution.

Prognosis and complications

• Appropriate antimicrobial treatment is highly effective in effecting microbiologic cure and symptom resolution, although as in any neuropathologic process residual damage to nerve or CNS may not reverse entirely.

• Post Lyme disease treatment symptoms, such as fatigue, “brain fog,” concentration difficulty, mood disorders, and others, occur rarely in patients who have had CNS Lyme neuroborreliosis and overall occur with about the same frequency in Lyme disease patients as in the general population. The extent to which these may be examples of a more common postinfectious syndrome remains to be determined, but they clearly do not relate to brain infection–either persistent after treatment or during the acute infection itself.

With appropriate antimicrobial therapy of early Lyme disease (erythema migrans), approximately 90% to 95% of patients will be cured. Improvement of neurologic symptoms is typically rapid. In children with facial nerve palsy or radiculoneuritis, 79% recovered fully in 3 weeks and 97% at 3 months. Among 147 adults, 68% recovered fully by 3 months, and five had residual symptoms at 1 year—one with bilateral facial weakness and four with residual lower extremity weakness (76). The exact proportion of patients cured after more long-standing involvement is unclear but is probably in the range of 80% to 85% (61). Some patients will develop late sequelae despite early treatment, although prospective studies indicate that this is rare with adequate initial treatment (40). Late manifestations may consist of chronic large joint oligoarthritis, which may be HLA-linked, or, potentially more problematic but fortunately rarely seen, encephalomyelitis. Many patients with significant neurologic impairment improve substantially if treated with appropriate antimicrobial therapy.

Controlled studies indicate that prognosis after treatment, even of later disease, is excellent (44; 75; 90; 40; 04). Although many have focused on persistent nonspecific or neurobehavioral symptoms following treatment of Lyme disease, labeling this “post-treatment Lyme disease syndrome,” the existence of such an entity is questionable. One study found a slight excess of such symptoms (prevalence 27.2%, or 3.9% greater than in the general population) (86). Similarly, a large Danish population-based study found that there was an increase in mental disorders in patients after Lyme when compared to the general population, but specifically not after Lyme neuroborreliosis, with an increase comparable to that found earlier in the same database following other serious infections (46; 18). Notably, a separate study using the same database but limited to patients with a CSF-based diagnosis of definite Lyme neuroborreliosis found no increase in these symptoms (85). Virtually all other studies have found no excess compared to healthy controls (13; 82; 98; 93; 03; 02). Even chronic fatigue, commonly thought of as a key element of post Lyme disease syndromes, does not appear to be a particularly common after-effect (96; 92; 93; 03). Perhaps informative is a French study in which more patients than controls described fatigue and memory difficulty at long-term follow-up, but scores were comparable on both Fatigue Severity Scale and the physical and mental components of the SF12, ie, patients were concerned about these commonly linked symptoms, but their concerns were not supported by objective measures (20). Interestingly, the best predictors of which patients will have persistent symptoms include (a) at initial presentation having either paresthesias or elevation in the sum of the Beck Depression Inventory score plus number of pain sites (95); (b) pretreatment expectations that treatment would be effective and the patient’s presumption that they were receiving active, not placebo therapy (88); or (c) a history of multiple – including psychiatric - comorbidities (20). One plausible conclusion might be that receiving the diagnosis of Lyme disease heightens awareness of these subjective symptoms but does not cause them, a form of anchoring bias. Importantly, multiple studies indicate these chronic symptoms are not associated with nervous system infection (15; 23; 56; 03). Most importantly, it is clear that additional antimicrobial therapy provides such patients no meaningful benefit (29; 34; 37; 19; 17; 08; 09).

Clinical vignette

A 38-year-old woman was seen in early October for new onset of facial palsy. She had been in excellent health until early August of that year when, while summering in a Lyme endemic area, she noted an expanding erythematous rash on her abdomen, ultimately about 8 inches in diameter and lasting about 3 weeks. This improved following treatment with an oral first-generation cephalosporin, but she then developed 6 weeks of diffuse arthralgias and headaches. She next developed acute right facial paralysis, evolving over 24 hours, with retroauricular pain, hyperacusis, and decreased sense of taste. Past medical history was otherwise unremarkable; examination was notable only for a complete peripheral right seventh nerve palsy.

She was treated with oral penicillin 2 g daily for 2 weeks. Although she improved, she had significant residual symptoms and underwent lumbar puncture. Fluid was completely normal. Serum Lyme ELISA was strongly positive, with the patient's value being 12.7 times the negative cut-off; the spinal fluid value, after appropriate correction, was identical to that in the serum. She then received 2 weeks of intravenous ceftriaxone and over the next month recovered completely.

Biological basis

Etiology and pathogenesis

	• Lyme disease/Lyme borreliosis is caused by infection with B burgdorferi sensu lato spirochetes, which are transmitted to humans exclusively by bites of infected Ixodes ticks—a transmission that requires at least 24 hours attachment with U.S. B burgdorferi strains.
	• Pathogenesis of nervous system infection is unclear. Presence of viable spirochetes is essential as antimicrobial therapy is usually curative. The immune response clearly amplifies the impact of the infection–both as demonstrated by the high concentrations of some cytokines in CSF of infected patients and the clinical deficits elicited when only a very small spirochete load appears to be present.
	• Some data suggest a possible role for spirochete-glial interactions.

Lyme disease is caused by spirochetes of the B burgdorferi sensu lato complex, transmitted by the bite of Ixodes ticks. Six members of this family (B burgdorferi sensu stricto, B mayonii, B garinii, B afzelii, B spielmanii, and B bavariensis) are pathogenic for humans, causing the predominant clinical forms of Lyme borreliosis (47). All but B mayonii cause disease in Europe, where most cases with nervous system involvement appear to be caused by B garinii or the closely related strain B bavariensis (47). B burgdorferi sensu stricto is the agent of almost all North American Lyme disease, with rare cases caused by B mayonii (63).

Lyme disease is a zoonosis, in which humans are an inadvertent host. The sole vectors are hard-shelled Ixodes ticks (Ixodes scapularis in most of the United States, Ixodes pacificus in California, and Ixodes ricinus in Europe). These ticks go through a 3-phase, 2-year (in temperate climates) life cycle, partaking of one blood meal in each phase. In the first phase, the larva, which is the size of a print period and hatches uninfected, will typically feed on a small mammal, most often a white-footed mouse. If this host is already infected with B burgdorferi, the tick can become infected. The tick will then mature into a nymph and subsequently have its second meal. If previously infected, the tick can now transmit spirochetes; if not previously infected, the tick again can acquire infection if it feeds on an infected host. Transmission of the infection from tick to host takes time – typically, the tick must feed for at least 24 to 48 hours (for B burgdorferi SS; shorter attachments may allow transmission with the common European vectors and borrelia) before the probability becomes high that the new host on which it is feeding will become infected with the Lyme agent. During this interval, ingested blood triggers proliferation of spirochetes in the tick gut. They then disseminate in the tick, reach its salivary glands and can then be injected into the host. Even in areas where a high proportion of ticks carry Borrelia, only about 5% of humans with identified Ixodes tick bites will become infected, only half of whom will be symptomatic (91).

The mature adult tick will subsequently take its third meal, preferring to attach to a large mammal such as a bear or deer, giving rise to the common names attached to these ticks—the "deer tick" in the northeast United States and the "bear tick" in the Midwest. Although other arthropod hosts have been shown to carry B burgdorferi (horseflies, mosquitoes), the unique nature of the tick's feeding cycle is probably essential for transmission to other species, making it highly unlikely that vectors other than Ixodes ticks would transmit Lyme disease in all but the most extraordinary circumstances.

The pathophysiology of peripheral nerve and brain involvement remains unclear (68; 65; 24). The few available pathologic studies demonstrate multifocal perivascular inflammation in nerves (50; 24). MRI imaging suggests a similar multifocal inflammatory process in brain and spinal cord. With the exception of one report identifying B garinii in a biopsied sural nerve of an affected patient, it has generally been impossible to demonstrate intact spirochetes in nerves or the brain (70). However, active infection is clearly an essential element, as elimination of organisms with antimicrobial treatment prevents further neurologic damage and typically leads to significant improvement (25). Notably, cytokines released in response to outer surface protein A (OspA) from B burgdorferi, and even from nonviable spirochetes, can induce both astrocyte proliferation and apoptosis in vitro potentially providing a mechanism by which infection with a small number of organisms could cause a disproportionate effect (60; 65). Studies suggest glia play an important role in this cytokine production (54; 64). Interestingly, the in vitro production of cytokines induced in cultured astrocytes by Borrelia OspA is inhibited by the clinically effective antibiotics doxycycline and minocycline (10). Whether such mechanisms play a role in human disease and its response to treatment remains to be determined.

Prevention

	• Because infection is spread solely by hard shelled Ixodes ticks, and these ticks’ preferred hosts are field mice and other small animals, avoidance of tick habitats (rural, suburban) is effective.
	• If exposure to tick habitats is likely, wearing light colored clothing makes ticks more visible; spraying clothing with acaricides or tick repellants is effective.
	• In North America, where 24 hours of tick attachment is necessary for infection, a tick check at the end of the day, with removal of any that are found, is usually effective.
	• In the event of a tick bite, a single dose of doxycycline at the time substantially decreases the risk of infection.

The best method to avoid becoming infected with B burgdorferi is to avoid Ixodes tick bites. Standard recommendations include the wearing of light-colored, long-sleeved shirts and long pants tucked into socks when in tick-infested areas. As any parent knows, achieving this goal in young children in summer is problematic, at best. Extensive spraying of skin with tick repellants or acaricides may be ill-advised, as these are partially absorbed and may be neurotoxic, particularly in small children. Spraying clothes with these agents, however, can be helpful. Because ticks must be attached for many hours before transmission is likely, a simple and thorough tick check at the end of the day will often suffice. Prophylactic antibiotics, specifically a single 200-mg dose of doxycycline (in adults) (40), can lessen the risk of infection following tick bites if in highly endemic areas. However, the risk of adverse drug reactions must be weighed against the need to treat 50 patients to prevent one case of Lyme disease.

Outer surface protein A vaccines can provide some protection against infection and were approved by the U.S. Food and Drug Administration. However, limited demand, combined with litigation about possible immune-mediated complications, led to their withdrawal from the market. That notwithstanding, newer vaccines are under development.

Differential diagnosis

Associated or underlying disorders

	• In patients with plausible exposure, either a recent erythema migrans or current positive 2-tier serology with +IgG, and symptoms within the usual Lyme neuroborreliosis spectrum of more than 4 to 6 weeks’ duration, Lyme neuroborreliosis can be the presumptive diagnosis and treatment initiated.
	• In patients with other CNS disorders and plausible exposure to infected Ixodes ticks, 2-tier testing should be performed. If uncertainty remains, CSF should be examined. Presence of a CSF pleocytosis with increased intrathecal production of specific antibody confirms a diagnosis of CNS Lyme neuroborreliosis.

The differential diagnosis in patients with Lyme disease ranges from the remarkably simple to the quite complex. In patients with erythema migrans or a positive serology and part of the classic neurologic triad (meningitis, cranial neuritis, or painful radiculoneuritis), diagnostic confusion is unlikely. In patients with subacute disseminated peripheral nerve involvement, confusion with Guillain-Barre syndrome can be problematic, particularly with a facial diplegia. However, patients with severe Lyme-associated disseminated neuropathy frequently have a significant CSF pleocytosis. Some patients may develop a primarily motor polyradiculitis that can resemble a motor neuronopathy, particularly if subacute. Generally, evaluation of the CSF will differentiate among these entities.

One of the most difficult clinical dilemmas involves patients with encephalomyelitis (30). This very rare disorder can resemble clinically, and on MRI scan, a first episode of multiple sclerosis. Moreover, as in neurosyphilis and other chronic CNS infections, patients with nervous system Lyme disease may have oligoclonal bands in the CSF as well as increased overall intrathecal immunoglobulin synthesis. However, patients with this as a manifestation of Lyme disease usually have more cells in the CSF than typically seen in multiple sclerosis and almost always have demonstrable intrathecal production of specific anti-B burgdorferi antibodies. Large, atypical appearing lymphocytes have occasionally been reported in the CSF as well. The most difficult situation occurs when a patient previously treated for suspected Lyme encephalomyelitis has a second attack. Differentiating between inadequately treated Lyme disease and a new attack of multiple sclerosis may not be possible using generally available laboratory techniques.

Importantly, large population-based studies have now shown that there is no association between Lyme neuroborreliosis and dementia, Alzheimer disease, Parkinson disease, motor neuron disease, epilepsy, or Guillain-Barre syndrome (22) nor children with attention deficit disorder, learning or intellectual developmental disorders, or receipt of psychostimulants for attention deficit disorder (84). Similarly, although on rare occasion Lyme neuroborreliosis can cause encephalitis or myelitis with areas of increased T2 signal in the brain, the originally suggested association of Lyme neuroborreliosis with small T2 hyperintensities has been clearly shown not to be the case (59; 42). Current guidelines recommend against including Lyme disease in the differential diagnosis of this MRI finding (40).

Diagnostic workup

	• Because direct microbiologic diagnosis (culture, nucleic acid testing) has very low technical sensitivity, diagnosis rests on demonstration of synthesis of specific anti-B burgdorferi antibody within the CSF, which requires simultaneous measurement of immunoreactivity in CSF and serum, normalizing for the total amount of immunoglobulin in each (intrathecal antibody production; ITAb).
	• Patients with demonstrated ITAb may have increased total CSF IgG synthesis and oligoclonal bands.
	• Because of potential serologic cross reactivity, neurosyphilis should be excluded.
	• Apparent ITAb often persists long after curative therapy. In the absence of evidence of active CNS inflammation, this result must be interpreted with caution.
	• The European literature has emphasized that in clinically appropriate patients, there may be active CNS infection—and apparent ITAb—in a seronegative patient. In such patients, the first-tier test has usually been positive or borderline but the confirmatory test negative– not an unusual finding early in infection. Therefore, in such second-tier negative patients CSF may well be informative.

Laboratory diagnosis of Lyme disease is generally indirect. Although B burgdorferi can be grown in vitro and can often be cultured from the typical cutaneous lesion (erythema migrans) or from large volume blood cultures in research labs, clinical sensitivity of CSF culture is typically no better than 10% to 15% and in some series is as low as 1% (58). The needed culture medium is not routinely available in most clinical microbiological laboratories, so this is usually impractical. Even inoculating CSF directly into culture medium at the time of the lumbar puncture, incubating for 2 to 6 weeks, then testing using polymerase chain reaction (PCR) to detect bacterial nucleic acid, does not meaningfully increase the diagnostic sensitivity (41). Consequently, CSF PCR or culture is not recommended for clinical diagnosis (40). In the absence of the typical cutaneous lesion, serologic testing for immunologic evidence of exposure to B burgdorferi is generally used, typically using ELISAs that measure overall immunoreactivity to either the entire spirochete or one or several recombinant peptides. This approach is subject to all the usual limitations of serologic diagnosis. Generally, several weeks are required following exposure before enough antibodies are present in peripheral blood for the response to be detectable. Particularly if infection was present for an extended period of time, patients may continue to produce antibody for years following successful treatment. This makes it difficult to use antibody measurements either to differentiate between current infection and past exposure or to assess treatment response. As with other serologic tests, cross-reactions to other bacteria occur. Spirochetal disorders such as syphilis, relapsing fevers, and even periodontal disease due to Treponema denticola are particularly prone to cause false positives. However, other causes of polyclonal B cell stimulation, such as subacute bacterial endocarditis, have also been shown to produce cross-reactive false positives in ELISAs but not Western blots.

Increased specificity is provided by sequentially performing two tests with differing individual specificities—samples with borderline or positive results on a first ELISA then undergo a second, different test. Although useful in clarifying results in samples with borderline or low positive results on the first ELISA, samples negative on the first test should not be subjected to a second one; this does not increase sensitivity and typically decreases specificity. Recent work has focused on assays measuring reactivity to single spirochete antigens such as the VlsE lipoprotein of B burgdorferi. VlsE testing appears to be more reliable than 2-tier testing in European patients where substantially greater borrelia strain variability makes Western blot-based diagnosis more challenging (11).

The CDC recommends the universal use of 2-tiered testing. Since 1994, the recommended second test has been the Western blot, which identifies the specific antigens to which the patient's antibodies react. Results are interpreted by standard, well-validated (for North American patients) criteria (See Table 2), that optimize positive and negative predictive values. If five of the 10 specified IgG bands, or two of the three IgM bands are present in patients with long- or short-standing symptomatology respectively, the blot is considered positive.

In United States patients, replacing the Western blot as the second-tier test with ELISAs measuring reactivity to an antigen different from the one(s) used in the initial test, such as VlsE, provides sensitivity and specificity comparable to using Western blots and is now considered an acceptable alternative (11; 52). Importantly, regardless of the methodology used, patients with symptoms of more than 1 to 2 months duration should have a demonstrable IgG response. Purely IgM reactivity in any such patient is far more likely to be spurious than informative (40).

Table 2. Western Blot Criteria

IgG (5 of 10)	IgM (2 of 3)
18 kD 23 kD 28 kD 31 kD 39 kD 41 kD 45 kD 58 kD 66 kD 93 kD	23 kD 39 kD 41 kD

In general, serologic testing should only be performed when there is a reasonable pretest likelihood of Lyme disease (ie, when an epidemiologically plausible exposure occurs and the clinical symptoms are within the spectrum of those known to be caused by this infection) (40). Indiscriminate serologic testing in other circumstances will result in more false than true positive results, with consequent unnecessary diagnostic confusion, patient apprehension, unneeded therapy, and treatment complications. Early concerns about patients remaining seronegative beyond the first or second month of infection, particularly if given subcurative doses of antibiotics, have not been supported by subsequent studies.

When attempting to confirm central nervous system infection, the most useful and readily available technique is to examine cerebrospinal fluid, both for nonspecific markers of inflammation and for evidence of production of anti-B burgdorferi antibodies within the central nervous system (79; 40; 24). Current European guidelines require that patients have either a CSF pleocytosis or intrathecal antibody production to make the diagnosis of possible neuroborreliosis, with both being required to diagnose definite neuroborreliosis (55). Demonstrating intrathecal antibody production requires comparing specific CSF and serum antibody concentrations, adjusting for blood-brain barrier function, and correcting for the amount of antibody present in peripheral blood. Technically, this can be accomplished with a capture assay, mathematically (66), or by measuring CSF and serum immunoglobulin concentration, diluting both fluids so that the final immunoglobulin concentration is identical, and then performing the Lyme-specific ELISA on both. Regardless of the technique used, it is essential that both CSF and serum antibody be measured and the two compared. Estimates of the technique’s sensitivity vary between 50% in patients with more chronic syndromes (45) and 90% in acute CNS disease (27). The specificity is likely over 95% (after excluding neurosyphilis), but sensitivity may be lower very early in disease and, not surprisingly, in patients in whom the peripheral but not central nervous system is involved (43).

One important question has been whether there are circumstances in which intrathecal antibody production may be present in a seronegative patient. European studies have long suggested this occurs occasionally–a finding that would suggest a need for CSF testing in clinically relevant settings even in a seronegative individual. A study that may help address this reviewed findings in 30 seronegative Dutch patients with ITAb (99). In 28 of these patients, the ELISA or chemoluminescent assay (CLIA) was positive or borderline but the Western blot was negative. In two patients, no confirmatory test was performed. Although this was correctly interpreted as seronegativity, in fact it likely reflects the fact that it takes time for the immune response to fully develop. Lyme neuroborreliosis often occurs quite early in infection. In these patients, tests were presumably obtained before the full range of antibody specificities had developed. Presumably, the reason CSF antibody is more apparent is the much lower background of other antibodies in CSF constituting background signal. However, the implication is that in a clinically appropriate setting, in patients with a positive or borderline ELISA/CLIA but negative confirmatory test, CSF exam may well be informative and worth considering–if it will impact treatment decisions. At the other end of the disease continuum, a different shortcoming of this method is that, even after successful treatment, this measure of intrathecal antibody production may remain elevated for years; however, nonspecific markers of CNS inflammation, including CSF pleocytosis, typically normalize.

The B cell attracting chemokine, CXCL13, may be demonstrable in CSF very early in infection, potentially supporting the diagnosis, and seems to decline rapidly with successful treatment (69; 71), an observation confirmed in adults and children in both Europe and North America (32). Similar, though often less marked, elevations occur in other CNS inflammatory disorders, including neurosyphilis and HIV (49; 62; 16). Although CXCL13 concentration may provide a useful marker of disease activity, its limited specificity requires it be used in conjunction with other indicators such as measures of intrathecal antibody production (62; 16). Another marker that has been investigated, plasma neurofilament light, which has been found to be elevated in other CNS insults, has been found to be elevated in Lyme neuroborreliosis, decreasing rapidly with successful treatment (53; 28). Importantly, NFl is not elevated in patients with posttreatment symptoms.

Many groups have applied the polymerase chain reaction to detect bacterial DNA. Diagnostic sensitivity in CSF is unfortunately extremely low; a review by the Mayo Clinic lab, in which pretest probability was unknown, found PCR to be positive in just 0.06% of submitted CSF samples (63). Limitations of specificity largely relate to eliminating the risk of contamination. Urine Lyme antigen assays are no longer commercially available and appear to be unreliable (35). ELISA spot assays (analogous to TB spot tests), purporting to demonstrate cell mediated immunity to the spirochete, have not been found to be reliable, and lymphocyte transformation assays have been shown to have very limited utility (87; 83).

Management

	• Antibiotic treatment of Lyme neuroborreliosis is microbiologically and clinically curative in the overwhelming majority of cases.
	• Treatment with oral doxycycline or amoxicillin, parenteral ceftriaxone, cefotaxime or high dose penicillin is largely equivalent.
	• Courses longer than 3 to 4 weeks of any agent add significant risk with no demonstrable benefit.

Although some still debate what constitutes the optimal treatment of nervous system Lyme disease, the evidence supports several conclusions (40). In patients with early cutaneous disease, amoxicillin 1.5 g daily or doxycycline 200 mg daily for 2 to 4 weeks is generally effective. Erythromycin, although effective in vitro, is less efficacious in vivo. Some macrolides such as azithromycin or clarithromycin have some role, although they may be somewhat less effective than amoxicillin or doxycycline. In patients with meningitis or other CNS infections, most centers in the United States have used either meningeal doses of penicillin or parenteral third-generation cephalosporins with good CNS penetration, such as ceftriaxone (2 g daily) or cefotaxime (6 g daily) (40). Several studies have suggested that ceftriaxone and cefotaxime are about equally efficacious; most authorities in the United States consider them to be superior to penicillin. A meta-analysis of European studies comparing oral doxycycline to parenteral regimens in patients with Lyme meningitis or cranial neuritis suggests they are equally effective in this population (26), an approach considered acceptable in current European and U.S. guidelines (55; 40). Interestingly, a meta-analysis of 31 randomized controlled treatment trials concluded all currently recommended regimens–oral and parenteral–are equally effective (97), a conclusion supported by a European study in a pediatric population as well (04). The question is being studied in patients in the United States, but no data are available. Although there are strain differences between European and U.S. Borrelia, antimicrobial sensitivities are generally comparable. Until this question is rigorously tested in the United States, it is probably reasonable to use oral doxycycline in mildly affected patients and ceftriaxone or cefotaxime in those with more severe CNS Lyme disease, pending further studies.

Glucocorticoids, used in some patients concurrently with antibiotics to control radicular pain, or facial palsy, can be used, but with caution. No controlled clinical studies have been carried out, but animal studies suggest they may potentially play a helpful role (65). Retrospective studies in facial nerve palsy have provided conflicting conclusions but in aggregate suggest that use of corticosteroids does not worsen outcomes (94; 05; 48).

Media

References

01: ACOG Committee. Lyme disease during pregnancy. ACOG committee opinion: committee on obstetrics: maternal and fetal medicine. Number 99–November 1991. Int J Gynaecol Obstet 1992;39:59-60. PMID 1358705
02: Andreassen S , Lindland EMS, Beyer MK, et al. Assessment of cognitive function, structural brain changes and fatigue 6 months after treatment of neuroborreliosis. J Neurol 2023;270(3):1430-8.** PMID 36380166
03: Andreassen S, Solheim AM, Ljostad U, et al. Cognitive function in patients with neuroborreliosis: A prospective cohort study from the acute phase to 12 months post treatment. Brain Behav 2022;12(6):e2608. PMID 35593485
04: Arnason S, Skogman BH. Effectiveness of antibiotic treatment in children with Lyme neuroborreliosis - a retrospective study. BMC Pediatr 2022;22(1):332. PMID 35676665
05: Avellan S, Bremell D. Adjunctive corticosteroids for Lyme neuroborreliosis peripheral facial palsy—a prospective study with historical controls. Clin Inf Dis 2021;73(7):1211-5. PMID 33905494
06: Avner BS. Descriptive data on trends among patients hospitalized with Lyme disease in Southwest Michigan, 2017-2021. Open Forum Infect Dis 2023;10(1):ofac658. PMID 36726545
07: Barbour AG, Adeolu M, Gupta RS. Division of the genus Borrelia into two genera (corresponding to Lyme disease and relapsing fever groups) reflects their genetic and phenotypic distinctiveness and will lead to a better understanding of these two groups of microbes (Margos et al 2016). There is inadequate evidence to support the division of the genus Borrelia. Int J Syst Evol Microbiol 2017;67(6):2058-67. PMID 28141502
08: Berende A, ter Hofstede HJ, Vos FJ, et al. Randomized trial of longer-term therapy for symptoms attributed to Lyme disease. N Engl J Med 2016;374(13):1209-20. PMID 27028911
09: Berende A, Ter Hofstede HJM, Vos FJ, et al. Effect of prolonged antibiotic treatment on cognition in patients with Lyme borreliosis. Neurology 2019;92(13):e1447-55.** PMID 30796143
10: Bernardino AL, Kaushal D, Philipp MT. The antibiotics doxycycline and minocycline inhibit the inflammatory responses to the Lyme disease spirochete Borrelia burgdorferi. J Infect Dis 2009;199(9):1379-88. PMID 19301981
11: Branda JA, Body BA, Boyle J. Advances in serodiagnostic testing for Lyme disease are at hand. Clin Infect Dis 2018;66(7):1133-9.** PMID 29228208
12: Brestrich G, Hagemann C, Diesing J, et al. Incidence of Lyme Borreliosis in Germany: A retrospective observational healthcare claims study. Ticks Tick Borne Dis 2024;15:102326. PMID 38417196
13: Cerar D, Cerar T, Ruzić-Sabljić E, Wormser GP, Strle F. Subjective symptoms after treatment of early Lyme disease. Am J Med 2010;123(1):79-86. PMID 20102996
14: Cross R, Ling C, Day NPJ, McGready R, Paris DH. Revisiting doxycycline in pregnancy and early childhood--time to rebuild its reputation? Expert Opin Drug Saf 2016;15(3):367-82. PMID 26680308
15: Dersch R, Sommer H, Rauer S, Meerpohl JJ. Prevalence and spectrum of residual symptoms in Lyme neuroborreliosis after pharmacological treatment: a systematic review. J Neurol 2016;263(1):17-24.** PMID 26459093
16: Eckman EA, Clausen DM, Herdt AR, Pacheco-Quinto J, Halperin JJ. Specificity and diagnostic utility of CSF CXCL13 in Lyme neuroborreliosis. Clin Inf Dis 2021;72(10):1719-26. PMID 32221538
17: Fallon BA, Keilp JG, Corbera KM, et al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology 2008;70(13):992-1003. PMID 17928580
18: Fallon BA, Madsen T, Erlangsen A, Benros ME. Lyme borreliosis and associations with mental disorders and suicidal behavior: a nationwide Danish cohort study. Am J Psychiatry 2021;178(10):921-31. PMID 34315282
19: Feder HM Jr, Johnson BJ, O'Connell S, et al. A critical appraisal of "chronic Lyme disease". N Engl J Med 2007;357(14):1422-30. PMID 17914043
20: Foret J, Paren AJ, Zayet S, et al. Residual symptoms and quality of life after treated Lyme neuroborreliosis: case-control study (QoLYME). Open Forum Infect Dis 2025;12(2):ofaf042.** PMID 39981069
21: Gerber MA, Shapiro ED, Burke GS, Parcells VJ, Bell GL. Lyme disease in children in southeastern Connecticut. N Engl J Med 1996;335:1270-4. PMID 8857006
22: Haahr R, Tetens MM, Dessau RB, et al. Risk of neurological disorders in patients with European Lyme neuroborreliosis: a nationwide, population-based cohort study. Clin Infect Dis 2020;71(6):1511-6.** PMID 31598647
23: Halperin JJ. Editorial commentary: neuroborreliosis: what is it, what isn't it? Clin Infect Dis 2016;63(3):354-5. PMID 27161776
24: Halperin JJ, Eikeland R, Branda JA, Dersch R. Lyme neuroborreliosis: known knowns, known unknowns. Brain 2022;145(8):2635-47.** PMID 35848861
25: Halperin JJ, Logigian EL. Borrelia burgdorferi, the brain and biologic plausibility. Neurology 2005;64(4):585.
26: Halperin JJ, Shapiro ED, Logigian E, 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. PMID 17522387
27: Halperin JJ, Volkman DJ, Wu P. Central nervous system abnormalities in Lyme neuroborreliosis. Neurology 1991;41:1571-82. PMID 1922798
28: Hirzel C, Grütter A, Grandgirard D, Hoepner R, Suter-Riniker F, Leib SL. Evaluating neurofilament light chain serum levels as a diagnostic marker for Lyme neuroborreliosis. Ther Adv Neurol Disord 2025;18:17562864251314011. PMID 39845576
29: Hu LT, Klempner MS. Update on the prevention, diagnosis, and treatment of Lyme disease. Adv Intern Med 2001;46:247-75. PMID 11270961
30: Hudasch D, Konen FF, Möhn N, et al. Neuroborreliosis with encephalitis: a broad spectrum of clinical manifestations. BMC Infect Dis 2025;25(1):182. PMID 39920572
31: Johnson KO, Nelder MP, Russell C, et al. Clinical manifestations of reported Lyme disease cases in Ontario, Canada: 2005-2014. PLoS One 2018;13:e0198509. PMID 5983483
32: Jung L, Lâm TT, Streng A, Fingerle V, Liese J. Elevated cerebrospinal fluid CXCL13 is a helpful marker for the early diagnosis of neuroborreliosis in children. Pediatr Infect Dis J 2025;44(6):577-81. PMID 39898650
33: Kaiser EA, George DK, Rubenstein MN, Berger JR. Lyme myelopathy: case report and literature review of a rare but treatable disorder. Mult Scler Relat Disord 2019;29:1-6. PMID 30654245
34: Klempner MS, Hu LT, Evans J, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 2001a;345(2):85-92. PMID 11450676
35: Klempner MS, Schmid CH, Hu L, et al. Intralaboratory reliability of serologic and urine testing for Lyme disease. Am J Med 2001b;110(3):217-9. PMID 11182109
36: Knudtzen FC, Eikeland R, Bremell D, et al. Lyme neuroborreliosis with encephalitis; a systematic literature review and a Scandinavian cohort study. Clin Microbiol Infect 2022;28(5):649-56.** PMID 34768019
37: Krupp LB, Hyman LG, Grimson R, et al. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology 2003;60(12):1923-30. PMID 12821734
38: Kugeler KJ, Earley A, Mead PS, Hinckley AF. Surveillance for Lyme disease after implementation of a revised case definition — United States, 2022. MMWR Morb Mortal Wkly Rep 2024;73:118-23.** PMID 38358952
39: Lakos A, Solymosi N. Maternal Lyme borreliosis and pregnancy outcome. Int J Infect Dis 2010;14(6):e494-8. PMID 19926325
40: 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):262-73.** PMID 33257476
41: Leth TA, Nymark A, Knudtzen FC, et al. Detection of Borrelia burgdorferi sensu lato DNA in cerebrospinal fluid samples following pre-enrichment culture. Ticks Tick Borne Dis 2023;14(3):102138. PMID 36746091
42: Lindland ES, Røvang MS, Solheim AM, et al. Are white matter hyperintensities associated with neuroborreliosis? The answer is twofold. Neuroradiology 2025;67(1):37-48.** PMID 39422730
43: Ljostad U, Mygland A. Relevance of the antibody index to diagnose Lyme neuroborreliosis among seropositive patients. Neurology 2008;71(2):151; author reply 151-2. PMID 18606973
44: Ljostad U, Mygland A. The phenomenon of 'chronic Lyme'; an observational study. Eur J Neurol 2012;19(8);1128-35. PMID 22416947
45: Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestations of Lyme disease. N Engl J Med 1990;323(21):1438-44. PMID 2172819
46: Lund-Sorensen H, Benros ME, Madsen T, et al. A nationwide cohort study of the association between hospitalization with infection and risk of death by suicide. JAMA Psychiatry 2016;73(9):912-9. PMID 27532502
47: Margos G, Wilske B, Sing A, et al. Borrelia bavariensis sp. nov. is widely distributed in Europe and Asia. Int J Syst Evol Microbiol 2013;63(Pt 11):4284-8. PMID 23838444
48: Marques A, Okpali G, Liepshutz K, Villa AMO. Characteristics and outcome of facial nerve palsy from Lyme neuroborreliosis in the United States. Ann Clin Transl Neurol 2022;9(1):41-9. PMID 35064770
49: Marra CM, Tantalo LC, Sahi SK, Maxwell CL, Lukehart SA. CXCL13 as a cerebrospinal fluid marker for neurosyphilis in HIV-infected patients with syphilis. Sex Transm Dis 2010;37(5):283-7. PMID 20393380
50: Mathis S, Soulages A, Le Masson G, Vallat JM. Epidemics and outbreaks of peripheral nervous system disorders: I. infectious and immune-mediated causes. J Neurol 2021;268(3):879-90. PMID 32914207
51: Mead P, Hinckley A, Kugeler K. Lyme disease surveillance and epidemiology in the United States: a historical perspective. J Infect Dis 2024;230(Supplement_1):S11-7.** PMID 39140721
52: Mead P, Petersen J, Hinckley A. Updated CDC recommendation for serologic diagnosis of Lyme disease. MMWR Morb Mortal Wkly Rep 2019;68(32):703. PMID 31415492
53: Mens H, Fjordside L, Gynthersen R, et al. Plasma neurofilament light significantly decreases following treatment in Lyme neuroborreliosis and is not associated with persistent symptoms. Eur J Neurol 2023;30(5):1371-7. PMID 36692938
54: Myers TA, Kaushal D, Philipp MT. Microglia are mediators of Borrelia burgdorferi-induced apoptosis in SH-SY5Y neuronal cells. PLoS Pathog 2009;5(11):e1000659. PMID 19911057
55: Mygland A, Ljostad U, Fingerle V, Rupprecht T, Schmutzhard E, Steiner I. EFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis. Eur J Neurol 2010;17(1):8-16, e1-4. PMID 19930447
56: Nilsson K, Skoog E, Jones V, et al. A comprehensive clinical and laboratory evaluation of 224 patients with persistent symptoms attributed to presumed tick-bite exposure. PLoS One 2021;16(3):e0247384. PMID 33735220
57: Ogrinc K, Bogovic P, Maraspin V, et al. Why is the duration of erythema migrans at diagnosis longer in patients with lyme neuroborreliosis than in those without neurologic involvement? Pathogens 2024;13. PMID 10893153
58: Ogrinc K, Bogovič P, Rojko T, et al. Proportion of confirmed Lyme neuroborreliosis cases among adult patients with suspected early European Lyme neuroborreliosis. Infection 2025. [Epub ahead of print] PMID 39747734
59: Orbaek M, Bodilsen J, Gynthersen RMM, et al. CT and MR neuroimaging findings in patients with Lyme neuroborreliosis: a national prospective cohort study. J Neurol Sci 2020;419:117176. PMID 33130434
60: Parthasarathy G, Fevrier HB, Phillipp MT. Non-viable Borrelia burgdorferi induce inflammatory mediators and apoptosis in human oligodendrocytes. Neurosci Lett 2013;556:200-3. PMID 24157855
61: Pfister HW, Preac-Mursic V, Wilske B, et al. Randomized comparison of ceftriaxone and cefotaxime in Lyme neuroborreliosis. J Infect Dis 1991;163:311-8. PMID 1988514
62: Pilz G, Steger R, Wipfler P, et al. Beyond LNB: Real life data on occurrence and extent of CSF CXCL13 in neuroinflammatory diseases. J Neuroimmunol 2020;338:577087. PMID 31715459
63: Pritt BS, Mead PS, Johnson DK, et al. Identification of a novel pathogenic Borrelia species causing Lyme borreliosis with unusually high spirochaetaemia: a descriptive study. Lancet Infect Dis 2016;16(5):556-64. PMID 26856777
64: Ramesh G, Borda JT, Gill A, et al. Possible role of glial cells in the onset and progression of Lyme neuroborreliosis. J Neuroinflammation 2009;6:23. PMID 19706181
65: Ramesh G, Didier PJ, England JD, et al. Inflammation in the pathogenesis of lyme neuroborreliosis. Am J Pathol 2015;185(5):1344-60. PMID 25892509
66: Reiber H, Peter JB. Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs. J Neurol Sci 2001;184(2):101-22. PMID 11239944
67: Reik L, Steere AC, Bartenhagen NH, Shope RE, Malawista SE. Neurologic abnormalities of Lyme disease. Medicine 1979;58:281-94. PMID 449663
68: Rupprecht TA, Koedel U, Fingerle V, Pfister HW. The pathogenesis of Lyme neuroborreliosis: from infection to inflammation. Mol Med 2008;14(3-4):205-12. PMID 18097481
69: Rupprecht TA, Manz KM, Fingerle V, et al. Diagnostic value of cerebrospinal fluid CXCL13 for acute Lyme neuroborreliosis. A systemic review and meta-analysis. Clin Microbiol Infect 2018;24(12):1234-40. PMID 29674128
70: Schneider TR, Frank S, Beuttler A, et al. Detection of intact Borrelia garinii in a sural nerve biopsy. Muscle Nerve 2021;63(6):E52-5. PMID 33651403
71: Strle F, Henningson AJ, Strle K. Diagnostic utility of CXCL13 in Lyme neuroborreliosis. Clin Infect Dis 2021;72(10):1727-9. PMID 32221531
72: Schrestha K, Kadkhoda K. Early Lyme disease-associated Guillain Barre syndrome: a case report. IDCases 2022;27:e01432. PMID 35169541
73: Schwartz AM, Hinckley AF, Mead PS, Hook SA, Kugeler KJ. Surveillance for Lyme Disease - United States, 2008-2015. MMWR Surveill Summ 2017;66(22):1-12. PMID 29120995
74: Schwenkenbecher P, Pul R, Wurster U, et al. Common and uncommon neurological manifestations of neuroborreliosis leading to hospitalization. BMC Infect Dis 2017;17(1):90. PMID 28109263
75: Skogman BH, Glimaker K, Nordwall M, Vrethem M, Odkvist L, Forsberg P. Long-term clinical outcome after Lyme neuroborreliosis in childhood. Pediatrics 2012;130(2):262-9. PMID 22802606
76: Smiskova D, Picha D, Slizek M, Dzupova O. Paretic complications of tick-borne encephalitis and Lyme neuroborreliosis in the Czech Republic: characteristics and clinical outcome. Ticks Tick Borne Dis 2024;15(2):102302. PMID 38101105
77: Steere AC, Malawista SE, Hardin JA, Ruddy S, Askenase W, Andiman WA. Erythema chronicum migrans and Lyme arthritis. The enlarging clinical spectrum. Ann Intern Med 1977;86:685-98. PMID 869348
78: Stenor CPM, El Mahdaoui S, Wolfram N. Ultrasonic evidence of mononeuritis multiplex caused by Lyme neuroborreliosis. Muscle Nerve 2022;65(1):E4-E6. PMID 34644405
79: Stiernstedt GT, Granstrom M, Hederstedt B, et al. Diagnosis of spirochetal meningitis by enzyme linked immunosorbent assay and indirect immunofluorescence assay in serum and cerebrospinal fluid. J Clin Microbiol 1985;21:819-25. PMID 3889049
80: Strobino BA, Abid S, Gewitz M. Maternal Lyme disease and congenital heart disease: a case-control study in an endemic area. Am J Obstet Gynecol 1999;180:711-6. PMID 10076152
81: Strobino BA, Williams CL, Abid S, Chalson R, Spierling P. Lyme disease and pregnancy outcome: a prospective study of two thousand prenatal patients. Am J Obstet Gynecol 1993;169:367-74. PMID 8362948
82: Stupica D, Veluscek M, Blagus R, et al. Oral doxycycline versus intravenous ceftriaxone for treatment of multiple erythema migrans: an open-label alternate-treatment observational trial. J Antimicrob Chemother 2018;73(5):1352-8. PMID 29385444
83: Summer G, Fingerle V, Spörl A, Rupprecht TA. LTT-validity in diagnosis and therapeutical decision making of neuroborreliosis: a prospective dual-centre study. Infection 2025;53(2):649-56. PMID 39541035
84: Tetens MM, Graham EE, Andersen NS, et al. No associations between neuroborreliosis in children and psychiatric neurodevelopmental disorders: a nationwide, population-based, matched cohort study. J Child Psychol Psychiatry 2025;66(5):716-24.** PMID 39618006
85: Tetens MM, Haahr R, Dessau RB, et al. Assessment of the risk of psychiatric disorders, use of psychiatric hospitals, and receipt of psychiatric medication among patients with Lyme neuroborreliosis in Denmark. JAMA Psychiatry 2021;78(2):177-86.** PMID 33026438
86: Ursinus J, Vrijmoeth HD, Harms MG, et al. Prevalence of persistent symptoms after treatment for Lyme borreliosis: A prospective observational cohort study. Lancet Reg Health Eur 2021;6:100142. PMID 454881
87: van Gorkom T, Voet W, Sankatsing SUC, et al. Prospective comparison of two enzyme-linked immunosorbent spot assays for the diagnosis of Lyme neuroborreliosis. Clin Exp Immunol 2020;199(3):337-56. PMID 31665540
88: van Middendorp M, Berende A, Vos FJ, Hofstede HHMT, Kullberg BJ, Evers AWM. Expectancies as predictors of symptom improvement after antimicrobial therapy for persistent symptoms attributed to Lyme disease. Clin Rheumatol 2021;40(10):4295-308. PMID 8463383
89: van Samkar A, Bruinsma RA, Vermeeren YM, et al. Clinical characteristics of Lyme neuroborreliosis in Dutch children and adults. Eur J Pediatr 2023;182(3):1183-9. PMID 36607413
90: Weitzner E, McKenna D, Nowakowski J, et al. Long-term assessment of post-treatment symptoms in patients with culture-confirmed early Lyme disease. Clin Infect Dis 2015;61(12):1800-6. PMID 26385994
91: Wilhelmsson P, Fryland L, Lindblom P, et al. A prospective study on the incidence of Borrelia burgdorferi sensu lato infection after a tick bite in Sweden and on the Aland Islands, Finland (2008-2009). Ticks Tick Borne Dis 2016;7(1):71-9. PMID 26341726
92: Wills AB, Spaulding AB, Adjemian J, et al. Long-term follow-up of patients with Lyme disease: longitudinal analysis of clinical and quality of life measures. Clin Infect Dis 2016;62(12):1546-51. PMID 27025825
93: Wormser GP, McKenna D, Karmen CL, et al. Prospective evaluation of the frequency and severity of symptoms in Lyme disease patients with erythema migrans compared with matched controls at baseline, 6 months, and 12 months. Clinical Infect Dis 2020;71(12):3118-24. PMID 31996890
94: Wormser GP, McKenna D, Scavarda C, Karmen C. Outcome of facial palsy from Lyme disease in prospectively followed patients who had received corticosteroids. Diagn Microbiol Infect Dis 2018;91(4):336-8. PMID 29720355
95: Wormser GP, McKenna D, Shaffer KD, Silverman JH, Scavarda C, Visintainer P. Evaluation of selected variables to determine if any had predictive value for, or correlated with, residual symptoms at approximately 12 months after diagnosis and treatment of early Lyme disease. Diagn Microbiol Infect Dis 2021;100(3):115348. PMID 33774355
96: Wormser GP, Weitzner E, McKenna D, et al. Long-term assessment of health-related quality of life in patients with culture-confirmed early Lyme disease. Clin Infect Dis 2015b;61(2):244-7. PMID 25888674
97: Yang J, Wen S, Kong J, et al. Forty years of evidence on the efficacy and safety of oral and injectable antibiotics for treating Lyme disease of adults and children: a network meta-analysis. Microbiol Spectr 2021;9(3):e0076121. PMID 34756070
98: Zomer TP, Barendregt JNM, van Kooten B, et al. Non-specific symptoms in adult patients referred to a Lyme centre. Clin Microbiol Infect 2019;25(1): 67-70. PMID 30287411
99: Zomer TP, Bruinsma R, van Samkar A, et al. Lyme neuroborreliosis with antibodies in cerebrospinal fluid but not in serum. Eur J Neurol 2023;30(3):741-4. PMID 36607413

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

John J Halperin MD

Dr. Halperin of Overlook Medical Center and Sidney Kimmel Medical College of Thomas Jefferson University has stock ownership in Johnson & Johnson and has received consultant honorariums from Pfizer.
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Editor

John E Greenlee MD

Dr. Greenlee of the University of Utah School of Medicine has no relevant financial relationships to disclose.
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Former Authors

James G Greene MD PhD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: Occupations involving extensive outdoor exposure

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Lyme disease

Associated Disorders

Confusional state
Peripheral neuropathy
Recurrent meningitis

Differential Diagnosis

Guillain-Barre syndrome
Motor neuronopathy
encephalomyelitis
multiple sclerosis

Also Relevant

Diagnosis of CNS infections
Lyme disease: controversial issues
Recurrent meningitis
Vasculitic neuropathies

Clinical Categories

Patient Handouts

Web References

Guidelines

AAN: Treatment of Nervous System Lyme Disease

	• Using the newly introduced and broader case definition, approximately 62,500 U.S. cases of Lyme disease were confirmed in 2022. The number of clinically diagnosed and treated individuals is generally estimated at about 500,000 annually.
	• Despite expansion of the range of infected ticks and animal vectors, the vast majority of U.S. cases continue to be along the upper eastern seaboard and the upper Midwest, with exposure most likely in suburban and rural areas.

Lyme disease

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Neurologic Disorders in Lyme Disease and their Pathophysiology Grouped by Pathophysiologic Mechanism

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Associated or underlying disorders

Diagnostic workup

Table 2. Western Blot Criteria

Management

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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