Nervous system Lyme disease

INTRODUCTION — Lyme disease is a tick-borne illness caused primarily by three pathogenic species of the spirochete Borrelia (B. burgdorferi, B. afzelii, and B. garinii). B. burgdorferi is the principal cause of the disease in the United States. All three pathogenic species occur in Europe, and two (B. afzelii and B. garinii) have been identified in Asia. Lyme disease has a broad spectrum of clinical manifestations and severity, probably due in part to differences in the infecting species and in part to referral and ascertainment biases.

Lyme disease is a multisystem infectious disease. The nervous system is the third most commonly involved organ system after skin and joints and is involved in 10 to 15 percent of infected individuals in both Europe and the United States [1].

Nervous system involvement begins during early disseminated Lyme disease, when spread of the spirochetes can result in meningeal seeding [2]. Lymphocytic/monocytic meningitis, facial nerve palsy, and radiculoneuritis constitute the classic triad of acute, early neurologic Lyme disease. These manifestations may occur alone or in combination; in the United States radiculoneuritis is diagnosed less commonly than meningitis or facial palsy.

The diagnosis of nervous system Lyme disease rests on three elements:

●Since the disease is transmitted exclusively by bites of Ixodes ticks, there must be the possibility of exposure

●The clinical disorder should include objective evidence of both nervous system disease and Lyme disease

●Laboratory testing (positive two-tier Lyme serologies with or without positive cerebrospinal fluid [CSF] Lyme antibodies) should support the diagnosis

Untreated infection probably subsides in some patients but persists in others. Appropriate antimicrobial treatment results in microbiologic cure in the overwhelming majority of patients, regardless of the duration of the infection.

The neurologic manifestations of Lyme disease will be reviewed here. Other aspects of Lyme disease are discussed separately:

●(See "Clinical manifestations of Lyme disease in adults".)

●(See "Lyme disease: Clinical manifestations in children".)

●(See "Diagnosis of Lyme disease".)

●(See "Treatment of Lyme disease".)

MENINGITIS — Lymphocytic/monocytic meningitis, alone or in combination with cranial nerve or spinal nerve root involvement, represents the most common form of nervous system involvement. Meningitis usually occurs several weeks to a few months after the tick bite and may be the first manifestation of Lyme disease. It is unusual for meningitis to begin many months or years after the initial infection.

Clinical manifestations — Symptomatic lymphocytic/monocytic meningitis of Lyme disease is largely indistinguishable from viral meningitis, with headache, fever, photosensitivity, and neck stiffness. Studies in children suggest that it has a slightly more indolent onset than viral meningitis, with a few more days elapsing between the first symptom and clinical presentation. (See "Aseptic meningitis in adults" and "Viral meningitis in children: Clinical features and diagnosis", section on 'Clinical features'.)

Among Lyme disease cases verified by the United States Centers for Disease Control and Prevention (CDC), approximately 2 percent have meningitis in isolation [3].

Headache and mild neck stiffness are not reliable predictors of meningitis in a patient with Lyme. In a European study of 161 adults with erythema migrans and suspected central nervous system (CNS) involvement, a cerebrospinal fluid (CSF) pleocytosis was present in only 31 (19 percent) [4]. CSF pleocytosis was more likely in patients who also had radicular pain, meningeal signs, and larger or multiple erythema migrans skin lesions. By contrast, headache, neck pain, fatigue, and memory or concentration problems did not predict a CSF pleocytosis or other abnormalities.

Evaluation — CSF and serum testing are essential in the evaluation of any patient with suspected acute meningitis. (See "Clinical features and diagnosis of acute bacterial meningitis in adults", section on 'Cerebrospinal fluid analysis'.)

Neuroimaging is needed if there is a clinical suspicion of raised intracranial pressure (particularly papilledema) or parenchymal brain involvement with focal neurologic signs or changes in mental status. (See "Clinical features and diagnosis of acute bacterial meningitis in adults", section on 'Indications for CT scan before LP'.)

Serologic testing — Patients with suspected Lyme disease should undergo serologic testing for antibodies to B. burgdorferi [5-7]. Except for unusual patients who present with neurologic manifestations within four to six weeks of infection, serologic testing is highly sensitive and specific for the diagnosis of Lyme disease, particularly when using the two-tier approach. (See "Diagnosis of Lyme disease".)

The two-tier strategy, which is recommended by the CDC, typically uses a sensitive enzyme-linked immunosorbent assay (ELISA) followed by a Western blot or a second ELISA with different targets.

●If the ELISA is positive or equivocal, then the same serum sample should be tested by Western blot. A second, orthogonal ELISA may be substituted as the second-tier assay and is as valid as a Western blot, easier to perform on large numbers of samples, and easier to standardize [8].

●If the initial ELISA is negative, the sample needs no further testing.

A more detailed discussion of serologic testing is discussed in a separate topic review. (See "Diagnosis of Lyme disease".)

Cerebrospinal fluid analysis

●Indications – In a patient with a clinical presentation suggesting acute meningitis, CSF examination is mandatory to exclude potentially dangerous pathogens and determine the causative agent, if possible. (See "Clinical features and diagnosis of acute bacterial meningitis in adults", section on 'Laboratory Evaluation' and "Aseptic meningitis in adults".)

●Routine studies – CSF studies should include cell count and differential, protein and glucose concentrations, and Gram stain and bacterial cultures. Syphilis testing should be obtained as well. Viral studies and cultures should be obtained, with testing for herpes simplex virus, West Nile virus, enteroviruses, and/or other organisms as suggested by individual circumstances. Additional CSF studies might include CSF cytology and/or other studies as dictated by the specific circumstances. (See "Aseptic meningitis in adults".)

Patients presenting with Lyme meningitis typically have a modest CSF pleocytosis of up to several hundred lymphocytes and/or monocytes per microL; the median count in acute neuroborreliosis is approximately 160 cells/microL (160 X 10⁶ cells/L) [9,10]. The CSF protein concentration is usually moderately elevated and is typically no greater than approximately 200 to 300 mg/dL (2 to 3 g/L). The CSF glucose concentration is relatively normal.

●CSF antibodies – Testing the CSF for intrathecal production of antibodies to B. burgdorferi is useful for establishing the diagnosis of Lyme meningitis; this requires simultaneous measurement of specific antibodies in CSF and serum, demonstrating a higher proportion of Lyme-specific antibodies in the CSF. However, both the sensitivity and specificity are unclear. A negative test for Lyme antibodies in the CSF does not conclusively exclude CNS Lyme disease [5-7].

An important limitation is that antibodies may persist in CSF (or blood) for years, even after successful treatment [11]. Thus, testing the CSF for antibodies is not useful for monitoring response to treatment. A decline in CSF pleocytosis, or possibly the B cell-attracting chemokine CXCL13, may be more helpful as both typically decline with successful treatment; however, follow-up CSF analysis is not typically needed to determine treatment success.

•Specificity concerns – False-positive CSF anti-B. burgdorferi antibody results can occur; however, these can often be mitigated.

Syphilis, the only organism that causes both cross-reactive antibodies and meningitis, can be differentiated from Lyme by measuring CSF reaginic antibodies such as the Venereal Disease Research Laboratory (VDRL), which are present in syphilis but not in Lyme.

Additionally, a false-positive CSF anti-B. burgdorferi antibody result can occur because antibodies can diffuse into the CSF from the peripheral blood. In the setting of active CNS Lyme infection, local B cell production of anti-B. burgdorferi antibodies outpaces that which diffuses in from peripheral blood. Measurement of antibodies in both serum and CSF can determine whether the amount of antibody in the CSF is proportionately greater than would be expected from passive entry of antibodies from the blood. Determining this CSF:serum Lyme antibody index requires adjusting for total immunoglobulin concentration in the two fluids. Laboratories use several different techniques to perform this adjustment [12-14]. All result in an index reflecting the relative proportion of specific antibody in the two compartments. If the CSF proportion exceeds that in blood (conceptually, index >1, although the precise threshold varies depending on the technique used by the laboratory), this represents evidence of CNS infection.

Indexing addresses another limitation of measuring CSF Lyme antibodies in isolation. A blood-brain barrier disruption for any reason results in an overall increase in CSF immunoglobulin concentration, causing increased background nonspecific binding in any serologic assay. Without adjusting for this overall increase in antibodies, this increased background will routinely result in false positives for many serologic tests.

As mentioned above, specificity is also lost in the setting of a prior CNS Lyme infection, as antibodies may persist long after successful treatment. In this circumstance, active CNS infection is inferred from the presence of a CSF pleocytosis or protein elevation.

•Sensitivity concerns – Understanding test sensitivity is challenging, primarily because the studies that have attempted to address this issue have used different patient populations [15,16]. European studies suggested sensitivity of approximately 90 percent [17,18], although given the European Federation of Neurological Sciences definition, which requires demonstration of intrathecal antibody production to diagnose definite CNS neuroborreliosis, this may be subject to ascertainment bias [19,20]. Similarly, in studies from the United States, estimates of sensitivity have ranged from approximately 90 percent in a small cohort with Lyme meningitis to approximately 50 percent in a more heterogeneous patient group [12].

Thus, in a patient with a clinical picture suggesting Lyme meningitis, a positive study from a reputable laboratory should be viewed as significant evidence in favor of the diagnosis [13]. However, negative CSF studies should not eliminate neurologic Lyme disease from consideration if clinical circumstances support the diagnosis.

●Polymerase chain reaction – The polymerase chain reaction (PCR) for B. burgdorferi is not recommended for routine evaluation of patients with suspected CNS Lyme disease [5-7]. It has low diagnostic sensitivity, probably reflecting the very low number of organisms typically present in spinal fluid [21]. In addition, some laboratories have difficulty avoiding false positives; thus, the positive and negative predictive values both tend to be low. (See "Diagnosis of Lyme disease", section on 'Polymerase chain reaction'.)

●CXCL13 – The concentration of the B cell-attracting chemokine CXCL13 is elevated in many inflammatory disorders of the CNS, including infections such as neurosyphilis [22], but appears to be disproportionately elevated in individuals with active nervous system Lyme disease. However, further study to standardize interpretation criteria is required before this test can be recommended as routine [5-7]. This test is not generally available in the United States except in research settings.

CXCL13 may be elevated before intrathecal antibodies are detectable and seems to decrease rapidly with successful treatment, making it a potentially useful adjunct in identifying both active infection and treatment response [23,24]. Among 17 patients with CNS Lyme disease, concentrations of CXCL13 were proportionately greater in CSF than in serum and were highly elevated in all CSF samples compared with the CSF of 178 controls without nervous system Lyme disease (mean 15,149 versus 247 pg/mL) [25]. Five patients who had received at least two weeks of treatment for Lyme disease did not have substantially elevated CXCL13 concentrations (mean 202 pg/mL), whereas five patients who had been treated for less than two weeks had slightly elevated CXCL13 concentrations (mean 1412 pg/mL). Among the 178 controls, seven had an elevated CXCL13 concentration, five with CNS lymphoma and two with bacterial meningitis. Relapsing-remitting multiple sclerosis has also been reported to cause elevated levels of CXCL13 in the CSF [26].

Diagnosis and differential diagnosis — The diagnosis of Lyme meningitis is made in a patient with a compatible CSF profile and positive serologic test and/or CSF antibody index.

Viral meningitis is the most common cause of aseptic meningitis; other infectious pathogens can also produce a similar clinical picture and CSF profile. Proposed algorithms to separate Lyme meningitis from viral meningitis rely on the somewhat less abrupt onset of Lyme meningitis coupled with the presence of other findings suggestive of Lyme disease, such as the percentage of mononuclear cells in the CSF and the presence of cranial neuropathy [27]. Other causes of aseptic meningitis and the appropriate evaluation of such patients are discussed separately. (See "Aseptic meningitis in adults" and "Viral meningitis in children: Clinical features and diagnosis", section on 'Evaluation'.)

Treatment and prognosis — In patients presenting with meningitis due to an as yet unidentified pathogen, empiric antibiotic therapy is typically initiated immediately, before definitive test results are available. Once Lyme is diagnosed, the treatment can be modified. Antibiotic regimens for the treatment of Lyme meningitis are summarized in the following table (table 1) and discussed in detail separately. (See "Treatment of Lyme disease", section on 'Acute neurologic manifestations'.)

Most patients respond to treatment. Lyme meningitis is generally self-limited, even without treatment. A repeat lumbar puncture is generally not needed. While antibodies generally only decline slowly following effective treatment, if there are concerns about treatment efficacy, documenting a decline in the CSF pleocytosis can be helpful.

FACIAL NERVE PALSY — Seventh (facial) nerve palsy occurred in 9 percent of United States Centers for Disease Control and Prevention (CDC) confirmed cases of Lyme disease [3]. It tends to occur early in infection (eg, weeks to several months after the tick bite). It is unusual for acute facial nerve palsy to occur many months or years after the initial infection.

Lyme facial palsy and Lyme meningitis are often seen together, occurring in 63 percent of patients with Lyme meningitis in a European series and 50 percent of patients in an American series [10,28].

Clinical presentation — Facial palsy due to Lyme disease appears similar to that of idiopathic Bell's palsy, with sudden onset (evolving over hours to a day or two) of unilateral facial paralysis; some patients have bilateral involvement, either simultaneously or in rapid succession. (See "Bell's palsy: Pathogenesis, clinical features, and diagnosis in adults", section on 'Clinical features'.)

Evaluation and diagnosis — Lyme disease should be suspected and evaluated in patients with facial nerve palsy if there is the possibility of Lyme exposure. In one study in an endemic region, one-quarter of cases of facial nerve palsy in the summer were likely due to Lyme disease, based upon serologies [29]. (See "Bell's palsy: Pathogenesis, clinical features, and diagnosis in adults".)

In particular, we suggest serologic testing for:

●A young child who has been in an endemic area. Facial nerve palsy is rare in small children, other than those with Lyme disease.

●An adult in an endemic area, during spring through fall.

Appropriate serologic testing is described above. (See 'Serologic testing' above.)

Most patients have quite elevated concentrations of anti-B. burgdorferi antibody in their peripheral blood, often with a prominent immunoglobulin M (IgM) component, either alone or in combination with an elevated IgG response. Occasionally the cranial neuropathy occurs before the patient has become seropositive; in such patients, a follow-up titer in several weeks is typically diagnostic. (See "Diagnosis of Lyme disease", section on 'Early disseminated and late Lyme disease'.)

Whether or not to assess cerebrospinal fluid (CSF) in patients with facial nerve palsy and suspected Lyme disease is a subject of debate [30]. Associated meningitis is common, but its presence does not usually alter treatment.

●In patients with a typical (isolated) facial nerve palsy and a positive serology indicating Lyme infection, CSF analysis may not be required if the patient can take doxycycline.

●Patients with isolated facial palsy and negative serology are typically diagnosed with idiopathic Bell's palsy.

●If the patient also has symptoms of meningitis, then CSF analysis is appropriate to evaluate causes as discussed above. (See 'Cerebrospinal fluid analysis' above.)

The differential diagnosis of bilateral facial nerve palsies is limited and includes Guillain-Barré syndrome, sarcoidosis, HIV infection, and other basilar meningitides. (See "Bell's palsy: Pathogenesis, clinical features, and diagnosis in adults", section on 'Differential diagnosis'.)

Treatment and prognosis — The appropriate antimicrobial treatment of facial nerve palsy due to Lyme disease is summarized in the table (table 1) and discussed in detail separately. (See "Treatment of Lyme disease", section on 'Acute neurologic manifestations'.)

Antimicrobial treatment of isolated facial nerve palsy is primarily recommended to prevent additional complications of disseminated Lyme disease since antibiotic therapy may not have a major impact on the outcome of the facial palsy itself. Most patients with Lyme facial palsy recover spontaneously; in one study, the median time to recovery was 26 days (range 1 to 270 days) [31]. The prognosis may be worse for patients with bilateral disease.

Glucocorticoids have demonstrated benefit in adult patients with idiopathic Bell's palsy, if administered within the first 72 hours. There have been no high-quality studies establishing their possible benefit or harm in individuals with facial nerve palsy related to Lyme disease [5]. Because they are only effective if given early, they should not be withheld if there is uncertainty about the Lyme disease diagnosis. In patients with a clear diagnosis of Lyme disease, their role remains to be established, with plausible arguments for and against their continuation [5-7]. Systematic studies of this question are needed. (See "Bell's palsy: Treatment and prognosis in adults".)

RADICULONEURITIS (BANNWARTH SYNDROME) — Lyme radiculoneuritis is reported in 3 percent of United States Centers for Disease Control and Prevention (CDC)-verified cases of Lyme disease [3]. Although this typically presents fairly early (within weeks to a few months) in infection, there may be a several month delay.

In Europe, a painful radiculoneuritis appears to be a more common manifestation of nervous system Lyme [32], although this may reflect differences in recognition of the syndrome rather than a true difference in frequency. The term "Garin-Bujadoux-Bannwarth syndrome" (or "Bannwarth syndrome") has been applied to the constellation of painful radiculoneuritis (the hallmark of the syndrome) with variable motor weakness, sometimes accompanied by facial nerve palsy and a cerebrospinal fluid (CSF) pleocytosis [33-35].

Clinical manifestations — Patients typically present with radicular pain in one or several dermatomes, accompanied by corresponding sensory deficits, motor weakness, and/or reflex changes. This syndrome is described in detail separately. (See "Polyradiculopathy: Spinal stenosis, infectious, carcinomatous, and inflammatory nerve root syndromes", section on 'Clinical presentation'.)

Older European literature had suggested that involvement occurred in dermatomes related to the site of the tick bite [36,37], although a thorough subsequent study called this into doubt [19,33]; the issue has not been addressed systematically in the United States.

Evaluation and diagnosis — The diagnostic evaluation begins with neurologic localization. Nerve conduction studies and electromyography are not required but are helpful to confirm the presence of a polyradiculopathy in patients in whom the clinical examination is ambiguous. (See "Polyradiculopathy: Spinal stenosis, infectious, carcinomatous, and inflammatory nerve root syndromes", section on 'Electrodiagnostic studies'.)

In a patient with polyradicular signs and symptoms, Lyme should be suspected in endemic areas when the patient presents in the late spring through autumn months and does not have an apparent mechanical precipitant to their symptoms. Such patients should undergo serologic testing for Lyme, which is highly sensitive and specific for Lyme disease and establishes the diagnosis. (See 'Serologic testing' above.)

Further testing is appropriate in some patients to exclude other entities in the differential diagnosis:

●Neuroimaging – Magnetic resonance imaging (MRI) with gadolinium contrast of the involved nerve root level is appropriate when structural or mechanical entities are suspected. (See "Polyradiculopathy: Spinal stenosis, infectious, carcinomatous, and inflammatory nerve root syndromes", section on 'Magnetic resonance imaging'.)

In some European (and a few United States) patients with Bannwarth syndrome, segmental spinal cord involvement at the same level as the affected nerve root has been documented [38,39].

●Lumbar puncture – Whether or not to obtain CSF is a subject of debate, but it is probably unnecessary in patients with positive Lyme serology as long as an alternative etiology is not suspected [30]. Many patients with polyradiculitis will have inflammatory CSF, but its presence does not alter treatment.

Rare patients have been described in whom Lyme antibodies were demonstrable in CSF but not blood, primarily in Europe [17]. This is most likely to occur in patients in whom neurologic symptoms develop in the first six weeks after exposure. Among 77 patients with a high a priori likelihood of Bannwarth syndrome, negative serology with positive CSF for antibodies to B. burgdorferi was observed in only one patient [33]. If CSF is obtained, studies should be obtained to exclude other possible diagnoses as described separately. (See "Polyradiculopathy: Spinal stenosis, infectious, carcinomatous, and inflammatory nerve root syndromes", section on 'Lumbar puncture'.)

Treatment and prognosis — Antibiotic regimens for the treatment of B. burgdorferi infection are summarized in the table (table 1) and discussed in detail separately. (See "Treatment of Lyme disease", section on 'Acute neurologic manifestations'.)

In observational studies, most patients improve with antibiotic therapy within the first four weeks [32,33]. If untreated, painful radiculoneuritis also resolves but has a more protracted course [32,40,41].

LESS COMMON MANIFESTATIONS

Other cranial neuropathies — Although facial nerve involvement represents approximately 80 percent of all Lyme disease-associated cranial neuropathies, other cranial nerves can be affected.

●Clinical features – Just as facial nerve palsies can be bilateral, multiple cranial neuropathies can co-occur, either simultaneously or sequentially. Involvement of the nerves innervating the extraocular muscles, the vestibulocochlear nerve, occasionally the trigeminal nerve, and infrequently the lower cranial nerves has been reported, producing symptoms of diplopia, vertigo, facial numbness, and others [42].

Retrospective data suggest that optic neuritis (inflammation of the second cranial nerve) occurs rarely, if ever [43,44]. Some patients with meningitis develop intracranial hypertension and associated papilledema and optic nerve symptoms. (See 'Intracranial hypertension' below.)

●Evaluation and treatment – The evaluation of a cranial neuropathy typically includes contrast-enhanced magnetic resonance imaging (MRI) to exclude vascular, structural, or inflammatory abnormalities (see individual topic reviews that discuss individual cranial nerve palsies). Serologic testing for Lyme disease requires a high index of suspicion but should be sought when a patient presents with an unexplained cranial neuropathy, particularly if they reside in an endemic area and present in the spring through the fall months.

As with facial nerve palsy, a positive serologic test in such patients sufficiently supports the diagnosis, and patients are treated with antibiotics. (See 'Facial nerve palsy' above.)

Cerebrospinal fluid (CSF) analysis is generally not required if serology is compelling and only one cranial nerve is involved. In the setting of multiple cranial neuropathies, CSF may need to be examined to exclude other forms of basilar meningitis. (See 'Cerebrospinal fluid analysis' above.)

Lyme encephalomyelitis — Rare patients in both Europe and the United States have been reported to have an inflammatory encephalomyelitis associated with Lyme disease [13,45,46]. Years ago, this disorder was estimated to occur in one person per million at risk per year and is probably even lower now. It has been reported as both an early and a late manifestation of disease.

Lyme encephalomyelitis represents a true infection of the neuraxis that can superficially resemble multiple sclerosis, with inflammatory-appearing parenchymal abnormalities on brain or spinal cord MRI and inflammatory changes in the CSF, including increased total immunoglobulin synthesis and oligoclonal bands.

●Clinical manifestations – Patients with encephalomyelitis present with acute or subacute onset of multifocal central nervous system (CNS) signs and symptoms [46,47].

●Neuroimaging features – MRI of the brain and spine with gadolinium contrast administration is required for evaluation of patients with this presentation.

Lyme encephalomyelitis is evident on MRI of the brain and/or spinal cord as areas of increased signal on T2 and fluid-attenuated inversion recovery (FLAIR) sequences [47,48]. These typically enhance with contrast.

More advanced neuroimaging studies are uncommonly performed. In one study, single-photon emission computed tomography (SPECT) brain scans, performed in a selected group of patients with well-characterized nervous system Lyme disease, demonstrated patchy brain hypometabolism [49]. However qualitative brain SPECT, the technique used in clinical settings, is highly variable even in normal patients and has no positive or negative predictive value in nervous system Lyme disease.

●Evaluation and diagnosis – Lyme should be suspected in patients with clinical and neuroimaging evidence of encephalomyelitis, if they reside in endemic areas, and especially when there is a known recent exposure. In such patients, evaluation for Lyme disease with serologic testing and CSF analysis, as described above, is essential. (See 'Serologic testing' above and 'Cerebrospinal fluid analysis' above.)

We do not recommend testing for Lyme in patients with nonspecific MRI white matter abnormalities in the absence of clinical features of encephalomyelitis [5-7].

Patients with Lyme encephalomyelitis typically have an inflammatory CSF profile and elevated immunoglobulin. The CSF Lyme antibody index is particularly useful in such patients. (See 'Cerebrospinal fluid analysis' above.)

Assessment for oligoclonal bands and IgG synthesis can also be informative. When nervous system Lyme disease has been present long enough for the B cell response to mature, there are often increases not only in specific anti-B. burgdorferi antibodies but also in nonspecific immunoglobulin concentrations. Measures such as the IgG synthesis rate or IgG index can be elevated, and oligoclonal bands can be seen in the CSF [50,51]. The frequency with which these findings are found has varied widely among series; they appear particularly prevalent in European studies. Oligoclonal bands and increased IgG synthesis consequently do not help differentiate CNS Lyme disease from multiple sclerosis and other CNS infections. (See "Evaluation and diagnosis of multiple sclerosis in adults", section on 'CSF analysis and oligoclonal bands'.)

Other causes of encephalomyelitis should also be excluded; this evaluation is described separately. (See "Acute disseminated encephalomyelitis (ADEM) in adults", section on 'Evaluation and diagnosis' and "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis", section on 'Evaluation and diagnosis'.)

●Treatment and prognosis – Lyme encephalomyelitis is reported anecdotally to be responsive to appropriate antimicrobial therapy; recommendations regarding antimicrobial therapy in this patient group are described separately. (See "Treatment of Lyme disease", section on 'Late neurologic findings'.)

As with any process affecting the CNS, there may be residual neurologic impairments caused by injury that occurred prior to treatment [39,52].

Intracranial hypertension — A clinical syndrome similar to pseudotumor cerebri or idiopathic intracranial hypertension (IIH) is reported with Lyme disease, more often in children than adults [53-55]. Virtually all of the reported cases have had inflammatory CSF, suggesting that the increased intracranial pressure is a result of meningitis, in contrast to IIH, in which the CSF profile is normal. Regardless of the mechanism, the symptoms and potential consequences are identical, including compression of cranial nerves with a particular threat to the optic nerves and vision.

Patients present similarly to IIH with headache and papilledema (swelling of the optic nerve head due to transmitted raised intracranial pressure) [53,56-60]. MRI demonstrates findings associated with elevated intracranial pressure (widened optic nerve sheath, flattening of the posterior globe) as well as contrast enhancement of the tentorium and various cranial nerves [56]. Lumbar puncture demonstrates an increased opening pressure, and CSF analysis often demonstrates a lymphocytic pleocytosis. Antibody testing of serum and CSF establishes the diagnosis of Lyme.

Patients with this syndrome are typically treated for both Lyme meningitis and increased intracranial pressure [56]:

●Antimicrobial therapy for Lyme meningitis (table 1) (see "Treatment of Lyme disease", section on 'Acute neurologic manifestations')

●Acetazolamide and other treatments for increased intracranial pressure (see "Idiopathic intracranial hypertension (pseudotumor cerebri): Prognosis and treatment", section on 'Carbonic anhydrase inhibitors')

Many patients recover within days to weeks, but symptoms can be more protracted in others [56,59].

Peripheral neuropathy — Although less common than cranial neuropathy and radiculoneuritis, other types of peripheral nerve involvement may occur with Lyme disease and probably represent various forms of mononeuropathy multiplex. Although rare cases of demyelinating neuropathies have been reported in Lyme disease, these are so infrequent as to likely be coincidental [61,62].

●Pathogenesis – Detailed studies in patients [63] and in experimentally infected rhesus macaque monkeys [64] indicate that peripheral nerve involvement in Lyme disease primarily consists of a multifocal axonal process. Although pathologic studies indicate a role for inflammation, and treatment responsiveness indicates an essential role for active infection, the pathophysiology is not well understood. Spirochetes cannot be demonstrated in peripheral nerve, although small numbers have been identified in dorsal root ganglia of experimentally infected monkeys [65]. A possible role of immunologic cross-reactivity has been suggested but seems inconsistent with the rapid response to antimicrobial therapy.

●Clinical features – Early in infection, patients may present with an acute mononeuropathy affecting a single nerve or nerve root [66,67].

Later, in untreated infection, patients may develop what is referred to as a confluent mononeuropathy multiplex. This disorder produces a clinical picture simulating a distal polyneuropathy with distal (stocking-glove) sensory loss and weakness and appears to reflect involvement of multiple small nerve branches [63,68].

●Evaluation and diagnosis – In patients with a peripheral neuropathy, electrophysiologic assessment (electromyography and nerve conduction studies) can be helpful. In such patients, these studies typically reveal findings consistent with a patchy axonal polyneuropathy (ie, a mononeuropathy multiplex) [68]. Some patients undergo nerve biopsy to evaluate alternative causes of mononeuropathy multiplex; in Lyme, nonspecific inflammation and axonal injury may be identified [66].

A high index of suspicion is required to diagnose Lyme disease in this setting; however, serologic studies remain sensitive and specific in this setting [66]. CSF analysis is not required and when obtained is often normal.

●Treatment and prognosis – Antimicrobial treatment is appropriate in this setting (table 1) and is discussed in detail separately. (See "Treatment of Lyme disease", section on 'Late neurologic findings'.)

The pace and completeness of recovery depend in part on the severity of involvement at the time treatment is initiated.

Encephalopathy — Early studies found that many patients with active Lyme disease described fatigue, cognitive slowing, and memory difficulty [69]. However, these symptoms are nonspecific and are frequent concomitants of many inflammatory and other systemic disorders. (See "Acute toxic-metabolic encephalopathy in adults", section on 'Specific etiologies' and "Acute toxic-metabolic encephalopathy in adults", section on 'Differential diagnosis'.)

The evaluation of patients with nonfocal cognitive difficulties and memory or psychiatric issues is described separately. (See "Acute toxic-metabolic encephalopathy in adults", section on 'Diagnosis'.)

Only in rare instances have these symptoms been associated with a CNS Lyme infection (ie, a mild encephalitis). In such cases, patients with objective neurologic deficits were evaluated extensively and the possibility of Lyme was raised by CSF abnormalities and/or brain MRI findings and supported by serology [13,46,50,70,71]. In the absence of such objective evidence of brain infection and positive serology, these symptoms should not be considered evidence of nervous system infection with B. burgdorferi.

The antimicrobial management of patients with Lyme-attributed encephalopathy is discussed separately. (See "Treatment of Lyme disease", section on 'Late neurologic findings'.)

Uncertain and unlikely associations — Many patients with Lyme disease develop nonspecific symptoms, including headache, fatigue, cognitive slowing, and memory difficulty. However, these symptoms are not indicative of CNS infection and, moreover, are common in many other infectious and inflammatory states [4,72-74]. At any point in time, indistinguishable cognitive symptoms occur in as much as 2 percent of otherwise healthy people [75] and can have a significant negative impact on the quality of life.

An important consideration is which patients to test for Lyme disease, as the positive and negative predictive values of that test are influenced by the a priori likelihood of the disorder being present. Many, largely anecdotal, reports have resulted in the consideration of possible Lyme neuroborreliosis in patients with a variety of neurologic or neuropsychiatric disorders. Several systematic studies have now demonstrated that this is unnecessary [5-7].

●Chronic Lyme disease – The term "chronic Lyme disease" means different things to different people and may include post-Lyme disease symptoms, as well as other illness and symptom complexes. These do not clearly represent active B. burgdorferi infection.

A constellation of symptoms, common in the broader population, has been labeled "posttreatment Lyme disease syndrome" or "posttreatment Lyme disease symptoms." While patients often describe difficulties with memory and cognitive function, this symptom complex is not associated with active or prior nervous system infection with B. burgdorferi [76-78].

These syndromes are described in detail separately. (See "Clinical manifestations of Lyme disease in adults", section on 'Post-treatment Lyme disease syndrome and chronic Lyme disease'.)

●Others – Lyme disease is not associated with increased risk of neurodegenerative disease; patients with these presentations should not be routinely tested for Lyme disease [5-7].

In an analysis of the database containing the lifetime medical records of the Danish population [79], 2067 individuals (of a population of 5.8 million) were identified meeting European criteria for definite Lyme neuroborreliosis. Among these, there was no increased long-term risk of Alzheimer disease, Parkinson disease, motor neuron diseases, or nursing home residence. Within the first year of diagnosis there was a slight increased risk of being diagnosed with seizures (risk difference [RD] 0.29 percent, 95% CI 0.02-0.56) or Guillain-Barré syndrome (RD 0.53 percent, 95% CI 0.22-0.85). In another study of 689 retired French farmers followed prospectively for six years, serologic evidence of prior infection with Borrelia was not associated with cognitive decline, depressive symptoms, or functional decline [80]. Finally, a similar Danish study of patients with psychiatric symptoms found no association with diagnosed Lyme disease [81].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Infectious encephalitis" and "Society guideline links: Tick-borne infections (Lyme disease, ehrlichiosis, anaplasmosis, babesiosis, and Rocky Mountain spotted fever)".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Lyme disease (The Basics)")

●Beyond the Basics topics (see "Patient education: Lyme disease symptoms and diagnosis (Beyond the Basics)" and "Patient education: Lyme disease prevention (Beyond the Basics)" and "Patient education: Lyme disease treatment (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Common neurologic syndromes – Acute disseminated Lyme disease has three common neurologic presentations, which can occur as combined or individual syndromes:

•Meningitis – Lymphocytic/monocytic meningitis is the most common syndrome; patients present with headache, fever, photosensitivity, and neck stiffness. (See 'Meningitis' above.)

•Facial nerve palsy – Similar to idiopathic Bell's palsy, patients with Lyme-associated facial palsy usually present with unilateral facial paralysis; some patients have bilateral involvement, either simultaneously or in rapid succession. (See 'Facial nerve palsy' above.)

•Radiculoneuritis – Patients with radiculoneuritis or Bannwarth syndrome present with radicular pain in one or more dermatomes, accompanied by corresponding sensory deficits, motor weakness, and/or reflex changes. Nerve conduction studies and electromyography help confirm the neurologic localization. (See 'Radiculoneuritis (Bannwarth syndrome)' above.)

●Diagnosis – Lyme disease should be suspected in patients who present with one of the common clinical syndromes if they live in an endemic area and present in the spring through fall months.

•Serologic testing – Serologic testing is highly sensitive and specific for Lyme disease when using the two-tier approach. (See 'Serologic testing' above.)

•Lumbar puncture – Cerebrospinal fluid (CSF) analysis is required for patients who present with acute meningitis to evaluate for other more dangerous causes. For certain other presentations, it may be reasonable to diagnose and treat based on serologic testing alone.

When CSF is obtained, other routine studies and evaluations for other pathogens should be obtained. The appropriate test for Lyme disease is Borrelia burgdorferi antibody index measurement, comparing CSF with serum antibody concentrations. Polymerase chain reaction (PCR) for B. burgdorferi is not a useful test in most patients. (See 'Cerebrospinal fluid analysis' above.)

●Treatment – The appropriate antimicrobial management for these common clinical manifestations is summarized in the table (table 1) and discussed in detail separately. (See "Treatment of Lyme disease", section on 'Acute neurologic manifestations'.)

Glucocorticoids are recommended for the treatment of idiopathic Bell's palsy and should not be withheld from patients undergoing evaluation for Lyme disease. In patients with facial nerve palsy and a clear diagnosis of Lyme disease, it remains uncertain whether such treatment should be continued or not; either practice is reasonable.

●Less common neurologic manifestations – Nervous system Lyme disease can also include:

•Other cranial neuropathies – Virtually any cranial nerve palsy has been associated with Lyme disease. (See 'Other cranial neuropathies' above.)

•Lyme encephalomyelitis – Rare patients have been described with inflammatory encephalomyelitis. (See 'Lyme encephalomyelitis' above.)

•Intracranial hypertension – Some patients with central nervous system (CNS) Lyme present with a clinical syndrome similar to pseudotumor with headache and papilledema. (See 'Intracranial hypertension' above.)

•Peripheral neuropathy – Lyme disease is associated with a mononeuropathy multiplex. (See 'Peripheral neuropathy' above.)

The appropriate antimicrobial treatment of such patients is summarized in the table (table 1) and discussed in detail separately. (See "Treatment of Lyme disease", section on 'Acute neurologic manifestations'.)

For patients with intracranial hypertension with headache and papilledema in the setting of Lyme disease, we suggest initiating acetazolamide in addition to antimicrobial therapy (Grade 2C). (See 'Intracranial hypertension' above.)

●Uncertain associations – Nonspecific symptoms, including headache, fatigue, cognitive slowing, and memory difficulty, do not provide an indication for routine testing for Lyme disease. (See 'Uncertain and unlikely associations' above.)