Review Article

Lyme Neuroborreliosis
Address correspondence to
Dr Adriana R. Marques,
BG 10/12C118, 10 Center
Drive, Bethesda, MD 20892,
Adriana R. Marques, MD amarques@niaid.nih.gov.
Relationship Disclosure:
Dr Marques receives research
and grant support as an
ABSTRACT intramural employee from the
Purpose of Review: Lyme disease, caused by the spirochete Borrelia burgdorferi, is National Institute of Allergy
and Infectious Diseases
the most common tick-borne illness in the United States and Europe. Lyme disease and the National Institutes
usually begins with the characteristic skin lesion, erythema migrans, at the site of the of Health.
tick bite. Following hematogenous dissemination, neurologic, cardiac, and/or rheu- Unlabeled Use of
Products/Investigational
matologic involvement may occur. Neurologic involvement occurs in up to 15% of Use Disclosure:
untreated B. burgdorferi infection and neurologists should be familiar with its Dr Marques discusses the
diagnosis and management. unlabeled/investigational use of
antibiotic regimens, including
Recent Findings: The most common early neurologic manifestations of Lyme disease amoxicillin, azithromycin,
are cranial neuropathy (particularly facial palsy), lymphocytic meningitis, and radic- cefotaxime, ceftriaxone,
uloneuritis, which often occur in combination. Late neuroborreliosis occurs much less clarithromycin, doxycycline,
erythromycin, and penicillin,
frequently than early disease. A combination of clinical and laboratory findings is which are recommended by
recommended for the diagnosis of Lyme neuroborreliosis. Treatment with recom- the American Academy of
mended antibiotic regimens is effective in Lyme neuroborreliosis, and patients with Neurology and the Infectious
Diseases Society of America for
early disease usually have excellent outcomes. Recovery is slower and may be in- the treatment of Lyme disease.
complete in patients with late disease. * 2015, American Academy
Summary: Nervous system involvement occurs in up to 15% of patients with un- of Neurology.
treated B. burgdorferi infection. This article reviews clinical aspects of the diagnosis
and treatment of Lyme neuroborreliosis, with focus on the United States.

Continuum (Minneap Minn) 2015;21(6):1729–1744.

DISCLAIMER
The findings and conclusions in this article are those of the author and do not necessarily
represent the official views of the National Institute of Allergy and Infectious Diseases.

INTRODUCTION pects of the diagnosis and treatment

Lyme disease, or Lyme borreliosis, is a
systemic illness caused by the spiro-
chete Borrelia burgdorferi and the
most common tick-borne illness in the
United States and Europe. While the B.
burgdorferi sensu lato group includes
at least 20 genospecies, the majority of
human infections are caused by three
genospecies: B. burgdorferi sensu stricto,
which causes disease in North America
and Europe, and Borrelia afzelii and
Borrelia garinii, which cause disease
in Europe and Asia.1 Evidence exists
that different genospecies (as well as
certain subtypes within a genospecies)
are more likely to be associated with
distinct clinical manifestations of Lyme
disease. This article reviews clinical as-
of Lyme neuroborreliosis, with focus
on the United States.
B. burgdorferi is transmitted by the
bite of infected ticks of the Ixodes ricinus
complex. Ixodes scapularis, the deer or
black-legged tick, is the main vector in
the United States. These ticks are small,
dark-colored ticks that have a 2-year life
cycle. In nature, B. burgdorferi cycles
among small mammals and birds, and I.
scapularis ticks acquire the infection by
feeding on infected hosts. Infected ticks
are then able to transmit the pathogen
during subsequent feedings (Figure 11-1).
Most cases of Lyme disease result from
a bite of an infected nymph, as they are
very small (about the size of a poppy
seed) and may easily go unnoticed; while

Continuum (Minneap Minn) 2015;21(6):1729–1744 www.ContinuumJournal.com 1729

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Lyme Neuroborreliosis

KEY POINTS
h The majority of human
Lyme disease infections
are caused by three
genospecies: Borrelia
burgdorferi sensu
stricto, which causes
disease in North America
and Europe, and Borrelia
afzelii and Borrelia garinii,
which cause disease in
Europe and Asia.
h Lyme disease is caused
by the spirochete
Borrelia burgdorferi and
transmitted by the bite
of the ticks of the Ixodes
ricinus complex. Ixodes
scapularis, the deer or
black-legged tick, is the
main vector in the
United States.
h In the United States, the
majority of cases of Lyme
disease occur in the
Mid-Atlantic, Northeast,
and Upper Midwest
regions. Both the number
of cases and the
geographic distribution
of the disease
FIGURE 11-1 Life cycle of Ixodes scapularis, the black-legged or deer tick that is the main
are increasing. vector of Borrelia burgdorferi in the United States.
1
Reprinted with permission from Mead PS, Infect Dis Clin North Am. www.id.theclinics.com/
article/S0891-5520(15)00024-0/abstract. B 2015 Elsevier, Inc.

adult Ixodes ticks are about the size of
a sesame seed (Figure 11-2). Transmis-
sion of B. burgdorferi takes at least
36 hours, as the spirochete moves from
the tick midgut to the salivary glands to
be transmitted to the host.2
In the United States, the majority of
cases of Lyme disease occur in the Mid-
Atlantic, Northeast, and Upper Midwest
regions (Figure 11-33).1 Highly endemic
areas include Connecticut, Delaware,
Maine, Maryland, Massachusetts,
Minnesota, New Hampshire, New Jersey,
New York, Pennsylvania, Rhode Island,
Vermont, Virginia, and Wisconsin. These
14 states accounted for more than 96%
1730 www.ContinuumJournal.com
of confirmed US cases in 2013. Evidence
exists that both the number of cases and
the geographic distribution of the dis-
ease are increasing. Newly revised esti-
mates from the Centers for Disease
Control and Prevention (CDC) suggest
an incidence of approximately 300,000
cases of Lyme disease per year in the
United States. Because people are more
active outdoors in the warmer months
when ticks are seeking hosts, most acute
cases of Lyme disease occur in late
spring and summer. Patients are most
likely to have illness in June, July, or
August and less likely from December
to March. The majority of patients with
December 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

FIGURE 11-2 Ixodes scapularis. From left to right: nymph, male, and female adult.
Courtesy of Utpal Pal, PhD.

FIGURE 11-3 Reported cases of Lyme disease in the United States in 2013. One dot is placed randomly within the county of
residence for each confirmed case. Although Lyme disease cases have been reported in nearly every state, cases are
reported based on the county of residence, not necessarily the county of infection.
3
Reprinted from Centers for Disease Control and Prevention, www.cdc.gov/lyme/stats/maps/map2013.html.

Continuum (Minneap Minn) 2015;21(6):1729–1744 www.ContinuumJournal.com 1731

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Lyme Neuroborreliosis
KEY POINTS
h The majority of cases of Lyme disease do not recall a tick bite.
early Lyme disease occur Lyme disease is a reportable disease in
in late spring and summer, the United States. A previous infection
and most patients do does not provide protective immunity,
not recall a tick bite. and reinfections may occur.
h A previous Lyme disease For clinical purposes, Lyme disease
infection does not provide is divided into early localized, early
protective immunity, and disseminated, and late stages. The early
reinfections can occur. localized stage is characterized by the
h Erythema migrans, a primary erythema migrans lesion and
gradually expanding, occurs in at least 80% of patients.4Y6
round or oval, flat, Erythema migrans occurs at the site of
erythematous skin lesion, the tick bite, usually 7 to 14 days after
occurs at the site of the the bite (range 2 to 28 days). It is char-
tick bite. The majority of acterized by a gradually expanding,
the rashes do not have
round or oval, flat, erythematous skin
central clearing.
lesion (Figure 11-4). Most often the rash
is homogenous in color, while central
erythema and central clearing (the clas-
sic bull’s-eye rash) are less common.5 A
punctum (the mark from the tick bite)
may be visible in the center of the le-
FIGURE 11-4 Erythema migrans. Primary
erythema migrans occurs at the
site of the tick bite. It is
characterized by a gradually expanding, round
or oval, flat, erythematous skin lesion. Most
often the rash is homogenous in color, rather
than the classic ‘‘bull’s-eye’’ appearance.
1732 www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
sion. Erythema migrans usually has few
(and mild) local symptoms. Systemic symp-
toms (predominantly malaise, myalgia,
arthralgia, fever/chills, and headache)
and regional lymphadenopathy may oc-
cur.7 Patients may also present during the
summer with nonspecific systemic symp-
toms (myalgia, arthralgia, headache, fever,
and chills) without erythema migrans.8
After several days or weeks, B.
burgdorferi may disseminate hematog-
enously from the initial site of infec-
tion, and patients may develop multiple
erythema migrans lesions as well as
neurologic, cardiac, and rheumatologic
involvement.9Y12 Multiple erythema mi-
grans lesions are similar in appearance
to the primary lesion but are usually
smaller, do not have a punctum, and
have no local symptoms. Some second-
ary lesions may be short-lived but may
recur.4 Cardiac involvement is observed
in 4% to 8% of patients, the most com-
mon feature being a fluctuating atrioven-
tricular block. Borrelial lymphocytoma
is a rare manifestation of Lyme disease,
predominantly seen in Europe. It pre-
sents as a painless bluish-red nodule or
plaque, usually localized in the earlobe
or nipple. Late manifestations include
Lyme arthritis, late Lyme neuroborrel-
iosis, and acrodermatitis chronica atro-
phicans. Lyme arthritis presents a mean
of 6 months after the onset of disease as
an asymmetric oligoarticular arthritis
usually involving the knees and occurs
in about 60% of untreated patients in the
United States. Acrodermatitis chronica
atrophicans, also predominantly seen in
Europe associated with infection with
B. afzelii, is characterized by slowly pro-
gressive skin lesions usually involving
the extensor surfaces of the extremities.13
CLINICAL MANIFESTATIONS OF
LYME NEUROBORRELIOSIS
Lyme neuroborreliosis is divided be-
tween early and late manifestations
(duration of signs and symptoms for
December 2015
 KEY POINTS
more than 6 months), as well as be- early Lyme neuroborreliosis in Europe, h From the site of infection,
tween central nervous system (CNS) where it is usually associated with Borrelia burgdorferi
and peripheral nervous system mani- B. garinii. The clinical features associ- may disseminate
festations.14 A combination of clinical ated with Lyme neuroborreliosis caused hematogenously. Patients
and laboratory findings has been rec- by B. afzelii are less specific.21 may present with multiple
ommended for the diagnosis of Lyme The most common presentation of erythema migrans
neuroborreliosis by the American Acad- early Lyme neuroborreliosis in the lesions as well as
emy of Neurology (AAN)10 (Appendix C) United States is facial palsy. The facial neurologic, cardiac, and
(Table 11-114) and by the European weakness begins acutely, usually during rheumatologic involvement.
Federation of Neurological Societies15 the summer months. About one-third h A combination of clinical
(Table 11-2). of the patients will also have CSF pleo- and laboratory findings
Early Lyme neuroborreliosis occurs cytosis.22 Involvement of other cranial is recommended for
in about 15% of patients with untreated nerves is less common. Patients with the diagnosis of
erythema migrans, with a median inter- Lyme neuroborreliosis.
early Lyme neuroborreliosis presenting
val between erythema migrans and neu- with facial palsy are commonly misdi- h The most common early
rologic disease of 4 weeks. Erythema agnosed as having Bell’s palsy. Systemic neurologic manifestations
migrans may still be present at the on- symptoms, headache, radicular pain, of Lyme disease are cranial
set of neurologic disease, thus, it is impor- neuropathy (particularly
presentation in late summer and fall, a
facial palsy), lymphocytic
tant to perform a full skin examination history of tick bite, and/or erythema
meningitis, and
when suspecting early Lyme neurobor- migrans point toward Lyme neurobor- radiculoneuritis,
reliosis. The majority of cases present in reliosis. Also, bilateral facial palsy, with which often occur
the summer and early fall. The most the two sides becoming paralyzed within in combination.
common manifestations are cranial a few days of each other, is common in
h When suspecting early
neuropathy (particularly facial palsy), Lyme neuroborreliosis but not seen in Lyme neuroborreliosis,
lymphocytic meningitis, and radiculo- Bell’s palsy. Many children with Lyme patients should have a
neuritis, which often occur in combi- diseaseYassociated facial nerve palsy complete skin examination
nation16Y20 (Case 11-1 and Case 11-2). have CSF abnormalities; in endemic to look for an erythema
This subacute painful meningoradiculitis, areas, the diagnosis of Lyme disease migrans lesion. Clues to
also known as Bannwarth syndrome or and occult meningitis should be strongly the diagnosis include a
Garin-Bujadoux-Bannwarth syndrome, considered in children with facial nerve history of tick bite; rash,
is the most common manifestation of palsy.23,24 malaise, or febrile illness
within the past 2 months;
the disease occurring in
the summer or early
TABLE 11-1 American Academy of Neurology Recommendations for
autumn; and the patient
the Diagnosis of Lyme Neuroborreliosisa,b
having been in an
endemic area.
1. Possible exposure to Ixodes ticks in Lyme-endemic area
h Facial paralysis is a common
2. One or more of the following: manifestation of Lyme
Erythema migrans neuroborreliosis. The
paralysis can be bilateral
Immunologic evidence of exposure to Borrelia burgdorferi
in 25% of the patients.
Histopathologic, microbiologic, or PCR proof of B. burgdorferi infection Patients with bilateral
3. Occurrence of a clinical disorder within the realm of those associated with involvement often have
Lyme disease, without other apparent cause CSF pleocytosis.

PCR = polymerase chain reaction.

a
Data from Halperin JJ, et al, Neurology.10 www.neurology.org/content/46/3/619.short.
b
Modified with permission from Halperin JJ, Infect Dis Clin North Am.14 www.sciencedirect.com/
science/article/pii/S0891552015000161. B 2015 Elsevier Inc.

Continuum (Minneap Minn) 2015;21(6):1729–1744 www.ContinuumJournal.com 1733

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Lyme Neuroborreliosis

TABLE 11-2 European Federation of Neurological Societies

Suggested Case Definitions for European
Lyme Neuroborreliosisa

Definite neuroborreliosisb: All three criteria fulfilled

Possible neuroborreliosisc: Two criteria fulfilled
b Criteria
1. Neurologic symptoms suggestive of Lyme neuroborreliosis without other
obvious reasons
2. CSF pleocytosis
3. Intrathecal Borrelia burgdorferi antibody production
CSF = cerebrospinal fluid.
a
Adapted with permission from Mygland A, et al, Eur J Neurol.15 onlinelibrary.wiley.com/doi/
10.1111/j.1468-1331.2009.02862.x/full. B 2009 The Author(s), B 2009 EFNS.
b
These criteria apply to all subclasses of Lyme neuroborreliosis except for late Lyme neuroborreliosis
with polyneuropathy where the following should be fulfilled for definite diagnosis: (1) peripheral
neuropathy, (2) acrodermatitis chronica atrophicans, and (3) Borrelia burgdorferiYspecific
antibodies in serum.
c
If criteria 3 is not fulfilled, after a duration of 6 weeks, B. burgdorferiYspecific IgG antibodies
in the serum must be present.

Lyme meningitis may begin acutely ache is the most common symptom,
or subacutely and may continue for with the pain ranging from mild to
weeks to months if not treated. Head- disabling and usually fluctuating in

Case 11-1
A 30-year-old man residing in a Lyme diseaseYendemic area developed an
expanding erythematous rash on his thigh in late May. He did not recall a tick
bite. The rash lasted for about 2 to 3 weeks and expanded to close to 20 cm in
diameter. About 3 weeks later, he developed a headache with neck and back
pain, which varied in intensity. Two weeks later, he developed a complete
facial palsy on the right side. He was diagnosed with Bell’s palsy and prescribed
prednisone and acyclovir. A Lyme titer in the serum was borderline. One week
later, he developed a facial palsy on the left side, and he presented for
evaluation. Examination showed bilateral facial palsies. There was no neck
stiffness, and the remainder of his neurologic examination was normal. CSF
showed 103 white blood cells/mm3 (88% lymphocytes, 12% other
mononuclear cells), protein was 94 mg/dL, and glucose was normal. Borrelia
polymerase chain reaction (PCR) and culture were negative. The opening
pressure was normal. Serology was positive for both IgM and IgG by the
two-tier criteria. He was treated with IV ceftriaxone for 21 days. The facial
palsies completely resolved over the next 4 months.
Comment. Facial palsy due to Lyme neuroborreliosis is often misdiagnosed
as Bell’s palsy. The history (or the presence) of an expanding skin rash as well
as other symptoms such as headache, back and neck pain, fevers, fatigue, and
joint or muscle pain, and the occurrence during late summer or early fall all
point toward early Lyme neuroborreliosis. While a history of a tick bite is helpful,
the majority of patients with Lyme disease do not remember a tick bite. Bilateral
involvement of the facial nerves also points to Lyme neuroborreliosis.

1734 www.ContinuumJournal.com December 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Case 11-2
In early June, a 45-year-old woman developed left arm pain that was
described as deep, severe, and aching. She lived in a Lyme diseaseYendemic
area and had exposure to ticks. There was no history of trauma. A primary
care provider prescribed ibuprofen. Over the next 5 to 6 days, the pain
became excruciating and involved her upper and lower back and was not
affected by movement. She was unable to sleep. She also had a low-grade
fever and chills. She developed severe headaches and photophobia. A
neurologist increased her ibuprofen dose and added nortriptyline for the
pain. The patient noticed multiple erythematous rashes that were
asymptomatic and could be best seen after a hot shower. She was initially
diagnosed with hives and was prescribed an antihistamine, as well as
narcotic analgesics for her severe back pain. Two days later, her examination
showed multiple erythematous expanding lesions that involved her arms,
legs, back, and abdomen, and bilateral facial palsies. Her neck was supple.
CSF showed 60 white blood cells/mm3 (80% lymphocytes), protein was
106 mg/dL, and glucose was normal. Borrelia polymerase chain reaction (PCR)
and culture were negative. She was diagnosed with early Lyme neuroborreliosis
and multiple erythema migrans and was treated with IV ceftriaxone 2 g/d
for 4 weeks. She had a complete recovery over the next 3 months.
Comment. This is a classic presentation of early Lyme neuroborreliosis
with the triad of radiculoneuropathy, cranial neuropathy, and lymphocytic
meningitis. Lyme radiculoneuropathy is commonly misdiagnosed. The
intense pain of Lyme meningoradiculitis often leads to initial suspicion of
muscle strain/injury or mechanical radiculopathy. Multiple erythema
migrans rashes may be misdiagnosed as hives, but hives are pruritic, while
erythema migrans skin lesions have very few or no local symptoms.

intensity. In a series of untreated patients, The opening pressure should be mea-

the typical pattern was intermittent at-
tacks of severe headaches for weeks
alternating with periods of mild head-
aches for weeks, which continued for
months.16 Usually, the pain is localized
(frontal or occipital headaches are most
frequently reported) but may be gener-
alized and persistent.4,19 Mild neck
stiffness occurs in 20% to 30% of pa-
tients, usually only on extreme flexion.
A high index of suspicion is required, as
symptoms and signs may be mild and
often vary in intensity. CSF examination
shows lymphocytic pleocytosis (usually
around 100 cells/2L, but can range
from 8 to more than 1000), moderate
increase of protein level, and a normal
glucose level. An increased albumin
quotient, indicating impairment of the
blood-brain barrier, may be present.
sured, as increased intracranial pressure
and papilledema may occur, particularly
in children.24
Compared with children with aseptic
meningitis, children with Lyme menin-
gitis had longer durations of illness and
headache but were less likely to have
had fever. Both the Avery clinical pre-
diction rule25 and the Rule of 7’s26,27
can help identify children at low risk of
Lyme meningitis in cases without other
manifestations of Lyme disease (for ex-
ample, patients without a documented
erythema migrans rash). The Avery pre-
diction model includes three factors (du-
ration of headache, presence or absence
of cranial neuritis, and percent of CSF
mononuclear cells), but requires a com-
plicated mathematical formula to esti-
mate the probability of Lyme meningitis.

Continuum (Minneap Minn) 2015;21(6):1729–1744 www.ContinuumJournal.com 1735

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Lyme Neuroborreliosis

KEY POINT
h The initial diagnosis of
Lyme radiculoneuritis is
often missed. The pain is
severe and can mimic a
mechanical radiculopathy.
The Rule of 7’s is easier to apply; children
who meet all of the following criteria are
considered to be at low risk of Lyme
meningitis: less than 7 days of headache,
less than 70% mononuclear cells, and no
seventh (or other) cranial nerve palsy.
Lyme radiculoneuritis presents with
pain in the distribution of the affected
nerves. The pain is severe, deep in the
musculature, and worse at night and
does not respond to common analge-
sics. Often, the distribution of symptoms
and signs is multifocal and asymmetric.
Further neurologic symptoms and def-
icits may develop after about 1 to 4 weeks,
with asymmetrically distributed paresis
and sensitivity disturbances. Lyme ra-
diculoneuritis is frequently misdiagnosed
as mechanical radiculopathy and, de-
pending of the distribution (eg, truncal,
abdominal), may lead to investigation
of visceral causes for the pain. Acute
mononeuropathies and plexopathies
may occur.16Y18,20 Parenchymal or me-
ningovascular involvement is rare.
Late Lyme neuroborreliosis occurs
much less frequently than early disease.
A subtle encephalopathic syndrome
affecting memory and cognition has
been reported in the United States,28
while a progressive encephalitis, mye-
litis, or encephalomyelitis has been
reported in Europe.20 The encephalo-
myelitis develops over a period of weeks
to months, with persistent and signifi-
cant CSF inflammation and highly pos-
itive intrathecal antibody production
against B. burgdorferi. Rarely, symptoms
may be caused by a borrelial-induced
cerebral vasculitis.
In the peripheral nervous system, a
chronic mononeuritis or polyneuritis
may occur18,29,30 (Case 11-3). Neuro-
logic deficits are predominantly sensory
and distally distributed, and the distri-
bution is more symmetric but may be
asymmetric and affect any segment. The
typical symptoms are paresthesia, which
may be intermittent, or radicular pain.
Electrophysiologic studies indicate that

Case 11-3
A 75-year-old man presented with a 2-year history of impaired balance and
stumbling, particularly when going up or down stairs and on uneven surfaces.
For the previous 5 months, he had noticed decreased strength in both hands
as well as tingling and numbness involving his hands and feet. The left side was
more affected than the right. He lived in an area endemic for Lyme disease and
had exposure to ticks but did not recall tick bites. A few months before his
symptoms started, he had multiple rashes that were diagnosed as hives. These
rashes were not pruritic and lasted for more than 1 week. On examination,
he had decreased vibratory, light touch, and temperature perception in a
stocking distribution, with the left side more severely affected than the right.
He had no muscle weakness. Nerve conduction studies were consistent with
a mild, predominantly sensory, axonal polyneuropathy. Lyme enzyme-linked
immunosorbent assay (ELISA) was strongly positive, and the IgG Western blot
had 8 of 10 bands positive in the serum. CSF showed 0 white blood cells and
normal protein and glucose. Borrelia polymerase chain reaction (PCR) and
culture were negative. B. burgdorferiYspecific intrathecal antibody
production, using the capture method assay, was negative for IgG and IgM,
but positive by IgA index. He was treated with IV ceftriaxone for 4 weeks. His
neuropathy slowly improved over the next year.
Comment. Patients with chronic forms of peripheral nerve involvement
caused by Lyme disease often have normal CSF examination. Response to
therapy can be slow and may be incomplete.

1736 www.ContinuumJournal.com December 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

the neuropathy is primarily axonal. The
pathogenesis is thought to be a
mononeuropathy multiplex, which
may be confluent. These patients will
often have normal CSF findings. Studies
have shown perivascular infiltration of
the epineurial vessels and axonal nerve
fiber degeneration,18 suggesting an
immune-mediated ischemic process
driven by infection with B. burgdorferi.
In Europe, distal axonal neuropathy is
associated with acrodermatitis chronica
atrophicans.29
LABORATORY TESTS FOR LYME
NEUROBORRELIOSIS
There are two main categories of lab-
oratory methods for the diagnosis of
Lyme disease: direct methods that
detect B. burgdorferi, and indirect
methods that detect the immune re-
sponse against it.
Direct Microbiological Tests
Direct detection of B. burgdorferi in
clinical specimens is difficult. Culture
for B. burgdorferi requires special media
and expertise, has a long incubation
period and relatively low sensitivity,
and is seldom used for diagnosis of
Lyme disease in clinical practice.31 Sen-
sitivity of culture and polymerase chain
reaction (PCR) in CSF samples of patients
with early neuroborreliosis is low (10%
to 30%) and even lower in late disease.15
Serologic Tests
The majority of laboratory tests per-
formed for Lyme disease are based on
detection of the antibody responses
against B. burgdorferi in serum. Cur-
rent CDC recommendations for sero-
logic testing for Lyme disease acquired
in the United States consist of a two-
tier approach (Figure 11-532) using a

FIGURE 11-5 Current Centers for Disease Control and Prevention recommendations on serologic
diagnosis of Lyme disease two-tier algorithm.
ELISA = enzyme-linked immunosorbent assay; IFA = immunofluorescence antibody
assay; IgG = immunoglobulin G; IgM = immunoglobulin M; WB = Western blot.
32
Data from Centers for Disease Control and Prevention, MMWR Morb Mortal Wkly Rep. www.cdc.gov/mmwr/
preview/mmwrhtml/00038469.htm.

Continuum (Minneap Minn) 2015;21(6):1729–1744 www.ContinuumJournal.com 1737

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Lyme Neuroborreliosis
KEY POINTS
h The majority of laboratory
tests performed for Lyme
disease are based on
detection of the antibody
responses against
Borrelia burgdorferi in
serum. The sensitivity of
antibody-based tests
increases with the duration
of the infection, as a lag
exists from infection to
the time when serum
contains enough
antibodies to be
detected. No current
assays distinguish
between active and
inactive infection.
h Patients with very early
Lyme disease (erythema
migrans) may have
negative serologic results.
Patients with erythema
migrans should receive
treatment based on the
clinical diagnosis.
h The majority of patients
with early neurologic
Lyme disease
are seropositive.
h Testing for Borrelia
burgdorferiYspecific
antibody synthesis in
the CSF should be
performed with a paired
serum sample to
measure the intrathecal
antibody index.
h Direct detection of
Borrelia burgdorferi in
clinical specimens is
difficult. Polymerase chain
reaction and culture of
CSF have low sensitivity in
Lyme neuroborreliosis.
1738 www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
sensitive enzyme immunoassay (EIA) or
indirect immunofluorescence assay
(IFA), followed by separate IgM and
IgG Western blots if the initial test is
borderline or positive. The IgM Western
blot results are used only for disease of
less than 4 weeks’ duration.31 Infection
acquired in Europe and Asia requires
testing and criteria that include other
species within the B. burgdorferi sensu
lato complex. A major advance has
been the discovery of VlsE and C6 pep-
tide as markers of antibody response in
Lyme disease.
While the current two-tier algorithm
works relatively well, many areas need
improvement.31 Negative results are
common in patients who present very
early in their illness. Patients with ery-
thema migrans should receive treat-
ment based on the clinical diagnosis,
as first-tier tests will be positive in less
than 50% of these patients. It has been
shown that the addition of the IgM
Western blot step decreases sensitivity
in early disease, while false-positive IgM
Western blots are common in commer-
cial laboratories. Patients with early Lyme
neuroborreliosis are highly likely to be
positive by first-tier test (more than 90%),
while the two-tier criteria decrease the
sensitivity to around 80%.31 No current
point-of-care tests exist for Lyme disease,
and such a test would be very helpful,
particularly for patients suspected of
early Lyme neuroborreliosis. At present,
if these patients do not have other man-
ifestations of Lyme disease or a sugges-
tive history, the diagnosis may depend
on serologic test results that usually
take a few days to become available, pos-
sibly resulting in a delay in appropriate
therapy. No current assays distinguish
between active and inactive infection,
and patients may continue to be sero-
positive for years, including an IgM re-
sponse, even after adequate antibiotic
treatment. As with any test, using the
assays in patients with a low probability
of having the disease will increase the
chance of false-positive results.
Intrathecal antibody production.
In cases where Lyme neuroborreliosis is
considered, testing for B. burgdorferiY
specific antibody synthesis in the CSF
(CSF/serum index) should be performed
in paired samples. Measuring only the
antibody concentration in the CSF can
be misleading, as a positive result may
be due to passive transfer of antibodies
from the serum. The tests available in
the United States use different techniques
to measure B. burgdorferiYspecific an-
tibody index than tests in Europe. Cur-
rent procedures include the use of an
antibody-capture immunoassay,33 or di-
luting the specimens to a similar final
immunoglobulin concentration and per-
forming B. burgdorferiYspecific enzyme-
linked immunosorbent assay (ELISA)
simultaneously.23 Intrathecal antibody
production is considered present if the
antibody titer in the CSF exceeds the
titer in serum, ie, the CSF index is above
1.3. Evidence of intrathecal antibody pro-
duction is considered the gold standard
for the diagnosis of Lyme neuroborre-
liosis in Europe, where the vast majority
of the studies originate and where B.
garinii is the genospecies most often
associated with neurologic disease.
Many difficulties exist in the interpre-
tation of results from the studies, but,
overall, the sensitivity of intrathecal anti-
body production in acute Lyme neu-
roborreliosis is around 50%.33Y42 While
very few studies exist, positive intra-
thecal antibody production seems to
be found less frequently in patients
with neuroborreliosis in the United
States.11,33,43 Intrathecal antibodies may
persist after therapy.
CXCL13. CXCL13 is a potent B lym-
phocyte chemoattractant. Levels of
CXCL13 are highly elevated in the
CSF of patients with early Lyme
neuroborreliosis and decline with treat-
ment, paralleling the resolution of the
lymphocytic pleocytosis. The value and
December 2015
practical aspects of using CXCL13 to
help in the diagnosis of Lyme neu-
roborreliosis remain to be deter-
mined.39,44,45 CXCL13 is not specific for
Lyme neuroborreliosis, and increased
levels in the CSF are found in other
diseases, including neurosyphilis, viral
infections, multiple sclerosis, antiYN-
methyl-D-aspartate (NMDA) receptor
encephalitis, CNS lymphoma, and neu-
romyelitis optica.
TREATMENT
Lyme disease is usually successfully treated
with antimicrobial therapy (Table 11-3
and Table 11-4). Treatment guidelines
for Lyme disease have been published
by the Infectious Diseases Society of
America46 and the AAN.47 (Refer to
Appendix D for a summary of the AAN’s
evidence-based guideline for clinicians.)
Oral therapy is recommended for early
and uncomplicated Lyme disease, in-
cluding isolated facial nerve palsy. Doxy-
cycline has the advantage of being
effective against the agent of human
granulocytic anaplasmosis (which can
also be transmitted by Ixodes ticks), but
it is contraindicated for children youn-
ger than 8 years of age and pregnant or
lactating women. During doxycycline
therapy, patients should be advised to
wear sunscreen and avoid sun expo-
sure, as it may cause photosensitivity.
Amoxicillin is the drug of choice for
a
TABLE 11-3 Treatment of Lyme Neuroborreliosis
Indication
Early disease
Meningitis or radiculoneuritis
Isolated facial nerve palsy
Late disease
a
Data from Wormser GP, et al, Clin Infect Dis,46 cid.oxfordjournals.org/content/43/9/1089.long;
Halperin JJ, et al, Neurology.47 www.neurology.org/content/69/1/91.long.
b
Doxycycline 200Y400 mg/d had similar results when compared to IV ceftriaxone in adult patients
with early Lyme neuroborreliosis in Europe.
Continuum (Minneap Minn) 2015;21(6):1729–1744
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
children younger than 8 years of age
and pregnant or lactating women. Ce-
furoxime axetil (500 mg 2 times a day
for adults) is a second-line alternative,
and it may be helpful in cases where
cellulitis cannot be ruled out. Oral mac-
rolides are considered third-line alter-
native agents as their clinical efficacy
seems to be less than other therapeutic
agents. The recommended duration of
therapy for all agents varies from 14 to
28 days.
Only a few studies comparing different
treatment regimens in neuroborreliosis
are available. The most commonly used
IV regimen for neuroborreliosis is 2 to
4 weeks of IV ceftriaxone (2 g once a
day), but IV cefotaxime (2 g 3 times a day)
and IV penicillin G (20 million units/d
in 4 divided doses) may also be used.
Doxycycline (200 mg once a day or
200 mg 2 times a day) has been shown to
be as effective as IV ceftriaxone in adult
patients with Lyme neuroborreliosis in
Europe. No studies have been performed
in the United States, but it is likely to be
effective as well. Duration of antibiotic
treatment is from 10 to 28 days. Patients
with facial palsy caused by Lyme dis-
ease have an excellent prognosis, with
complete or near-complete recovery
in the vast majority of patients. Patients
with radiculitis and meningitis will im-
prove within days to weeks. However,
an established nerve injury may not
Treatment Duration
Parenteral regimenb 14Y28 days
Oral regimen 14Y21 days
Parenteral regimen 14Y28 days
www.ContinuumJournal.com 1739
 Lyme Neuroborreliosis

a
TABLE 11-4 Antibiotics Used for the Treatment of Lyme Disease

Antibiotic Adult Dosage Pediatric Dosage Comments

Preferred oral agents
Doxycycline 100 mg 2 times/d Q8 years old: 1Y2 mg/kg Doxycycline is contraindicated in
2 times/d (maximum pregnancy, lactation, and in
100 mg/dose) children younger than 8 years
old. Doxycycline 200Y400 mg/d
has been shown to be as
effective as IV ceftriaxone in
adult patients with Lyme
neuroborreliosis in Europe.
Doxycycline is active against
human granulocytic anaplasmosis.
Amoxicillin 500 mg 3 times/d 50 mg/kg/d divided 3 times/d
(maximum 500 mg/dose)
Cefuroxime axetil 500 mg 2 times/d 30 mg/kg/d divided into 2 doses Useful when cellulitis cannot
(maximum 500 mg/dose) be ruled out.
Alternative oral agents
Azithromycin 500 mg once a day 10 mg/kg once a day Patients treated with macrolides
(maximum 500 mg/d) should be closely followed
because of the risk of treatment
Clarithromycin 500 mg 2 times/d 7.5 mg/kg 2 times/d
failure. In one trial, adults with
(maximum 500 mg/dose)
erythema migrans were more
Erythromycin 500 mg every 6 hours 12.5 mg/kg every 6 hours likely to fail therapy if treated
(maximum 500 mg/dose) with azithromycin for 7 days
than if treated with amoxicillin.51
Clarithromycin has not been
studied in a controlled trial.
Preferred IV agent
Ceftriaxone 2 g once per day 50Y75 mg/kg/d once a day Easy to administer and largest
(maximum 2 g/d) experience in Lyme disease.
Ceftriaxone can cause diarrhea
and biliary pseudolithiasis.
Alternative IV agents
Cefotaxime 2 g every 8 hours 150Y200 mg/kg/d given in Possibly same efficacy as
divided doses every 8 hours ceftriaxone, but requires more
(maximum 6 g/d) frequent administration.
Penicillin G 18Y24 million units/d 200,000Y400,000 units/kg/d
given in divided given in divided doses every
doses every 4 hours 4 hours (maximum
18Y24 million units/d)
a
Data from Wormser GP, et al, Clin Infect Dis,46 cid.oxfordjournals.org/content/43/9/1089.long; Halperin JJ, et al, Neurology.47
www.neurology.org/content/69/1/91.long.

recover or recover only partially. Patients usually starting a few months after
with late Lyme neuroborreliosis have a completion of therapy, and continue to
gradual improvement of their symptoms, slowly improve for up to 1 to 2 years.48

1740 www.ContinuumJournal.com December 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


Treatment decisions in patients with
neurologic syndromes not clearly es-
tablished as causally related to Lyme dis-
ease must be individualized depending
on the severity of symptoms and the
prognosis. In each case, the relative risks
and benefits of antimicrobial therapy
must be carefully weighed and reviewed
with the patient. Treatment with corti-
costeroids cannot be recommended at
this time.
‘‘CHRONIC LYME DISEASE’’ AND
POST-TREATMENT LYME
DISEASE SYNDROME
‘‘Chronic Lyme disease’’ is a confusing
term that is used to describe vastly dif-
ferent patient populations,49 including
patients with objective manifestations
of late Lyme disease, patients with post-
treatment Lyme disease syndrome
(PTLDS), and, most commonly, patients
with nonspecific signs and symptoms of
unclear cause who received this diag-
nosis based on unproven and nonvali-
dated clinical and laboratory criteria
(Table 11-5).50 PTLDS is defined by a
documented episode of Lyme disease,
treatment with an accepted antibiotic
regimen, resolution or stabilization of
the objective manifestation(s) of Lyme
disease, and persistent or relapsing
nonspecific symptoms for at least a
KEY POINTS
6-month period after completion of h Treatment with
antibiotic therapy in patients who have recommended antibiotic
no other condition that could explain regimens is effective in
their symptoms.46 It is characterized by Lyme neuroborreliosis,
nonspecific symptoms of fatigue, sleep and patients with early
disorders, headache, memory and con- disease usually have
centration difficulties, myalgia, and excellent outcomes.
arthralgia. PTLDS occurs in a small per- Recovery is slower and
centage of patients who have been ap- may be incomplete in
propriately treated for Lyme disease and patients with
late disease.
seems to correlate with having had dis-
seminated disease, a greater severity of h The cause of persisting
illness at presentation, and delayed anti- or relapsing nonspecific
biotic therapy. The cause of this syndrome symptoms after treatment
of Lyme disease is
is currently unknown, and it is likely that
unknown; no evidence
different factors play a role in individual
exists that these patients
patients, including natural evolution of benefit from additional
response after therapy, postinfective fa- antibiotic therapy.
tigue, and other conditions.49 Antibiotic
therapy, as tested in four randomized
placebo-controlled studies,52Y54 did not of-
fer durable or significant benefit in treating
patients with PTLDS and had considerable
risk of treatment-related adverse events.
CONCLUSION
Nervous system involvement occurs in
up to 15% of patients with untreated
B. burgdorferi infection. Patients with
early Lyme neuroborreliosis usually pres-
ent in the summer and early fall, with
cranial neuropathy (particularly seventh
nerve palsy), lymphocytic meningitis, or

a
TABLE 11-5 Categories of ‘‘Chronic Lyme Disease’’

Category Definition
1 Symptoms of unknown cause, with no evidence of Borrelia
burgdorferi infection
2 A well-defined illness unrelated to B. burgdorferi infection
3 Symptoms of unknown cause, with antibodies against B.
burgdorferi but no history of objective clinical findings that are
consistent with Lyme disease
4 Post-treatment Lyme disease syndrome

a
Modified with permission from Feder HM, et al, N Engl J Med.50 www.nejm.org/doi/full/10.1056/
NEJMra072023. B 2007 Massachusetts Medical Society.

Continuum (Minneap Minn) 2015;21(6):1729–1744 www.ContinuumJournal.com 1741

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Lyme Neuroborreliosis
a painful radiculoneuritis. These man-
ifestations often occur in combination.
Late Lyme neuroborreliosis is much less
frequent. Antibiotic therapy is successful
in the majority of patients, but recovery
can take weeks to months. The cause
of persisting or relapsing nonspecific
symptoms for more than 6 months after
treatment of Lyme disease is unknown;
however, no evidence exists that these
patients benefit from additional antibi-
otic therapy. Further research to eluci-
date the mechanisms underlying persistent
symptoms after Lyme disease and con-
trolled trials of new approaches of treat-
ment and management of these patients
are needed.
ACKNOWLEDGMENT
This research was supported by the
Intramural Research Program of the Na-
tional Institutes of Health and the Na-
tional Institute of Allergy and Infectious
Diseases.
REFERENCES
1. Mead PS. Epidemiology of Lyme
disease. Infect Dis Clin North Am
2015;29(2):187Y210. doi:10.1016/
j.idc.2015.02.010.
2. des Vignes F, Piesman J, Heffernan R, et al.
Effect of tick removal on transmission of
Borrelia burgdorferi and Ehrlichia
phagocytophila by Ixodes scapularis nymphs.
J Infect Dis 2001;183(5):773Y778.
3. Centers for Disease Control and Prevention.
Reported Cases of Lyme DiseaseVUnited
States, 2013. www.cdc.gov/lyme/stats/maps/
map2013.html. Updated March 4, 2015.
Accessed October 6, 2015.
4. Steere AC, Bartenhagen NH, Craft JE, et al.
The early clinical manifestations of Lyme
disease. Ann Intern Med 1983;99(1):76Y82.
5. Nadelman RB, Nowakowski J, Forseter G, et al.
The clinical spectrum of early Lyme borreliosis
in patients with culture-confirmed erythema
migrans. Am J Med 1996;100(5):502Y508.
6. Strle F, Nadelman RB, Cimperman J, et al.
Comparison of culture-confirmed erythema
migrans caused by Borrelia burgdorferi sensu
stricto in New York State and by Borrelia
afzelii in Slovenia. Ann Intern Med
1999;130(1):32Y36.
1742 www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
7. Nadelman RB. Erythema migrans. Infect Dis
Clin North Am 2015;29(2):211Y239.
doi:10.1016/j.idc.2015.02.001.
8. Steere AC, Sikand VK. The presenting
manifestations of Lyme disease and the
outcomes of treatment. N Engl J Med
2003;348(24):2472Y2474.
9. Kindstrand E, Nilsson BY, Hovmark A, et al.
Peripheral neuropathy in acrodermatitis
chronica atrophicansVa late Borrelia
manifestation. Acta Neurol Scand
1997;95(6):338Y345.
10. Halperin JJ, Logigian EL, Finkel MF, Pearl RA.
Practice parameters for the diagnosis of
patients with nervous system Lyme borreliosis
(Lyme disease). Quality Standards Subcommittee
of the American Academy of Neurology.
Neurology 1996;46(3):619Y627.
11. Logigian EL, Kaplan RF, Steere AC. Chronic
neurologic manifestations of Lyme disease.
N Engl J Med 1990;323(21):1438Y1444.
12. Steere AC, Schoen RT, Taylor E. The clinical
evolution of Lyme arthritis. Ann Intern Med
1987;107(5):725Y731.
13. Mullegger RR, Glatz M. Skin manifestations
of lyme borreliosis: diagnosis and management.
Am J Clin Dermatol 2008;9(6):355Y368.
doi:10.2165/0128071-200809060-00002.
14. Halperin JJ. Nervous system Lyme disease.
Infect Dis Clin North Am 2015;29(2):241Y253.
doi:10.1016/j.idc.2015.02.002.
15. Mygland A, Ljøstad U, Fingerle V, et al;
European Federation of Neurological Societies.
EFNS guidelines on the diagnosis and
management of European Lyme neuroborreliosis.
Eur J Neurol 2010;17(1):8Y16, e1Ye4.
doi:10.1111/j.1468-1331.2009.02862.x.
16. Reik L, Steere AC, Bartenhagen NH, et al.
Neurologic abnormalities of Lyme disease.
Medicine (Baltimore) 1979;58(4):281Y294.
17. Pachner AR, Steere AC. The triad of neurologic
manifestations of Lyme disease: meningitis,
cranial neuritis, and radiculoneuritis. Neurology
1985;35(1):47Y53.
18. Halperin JJ, Pass HL, Anand AK, et al.
Nervous system abnormalities in Lyme disease.
Ann N Y Acad Sci 1988;539:24Y34.
19. Belman AL, Iyer M, Coyle PK, Dattwyler R.
Neurologic manifestations in children with
North American Lyme disease. Neurology
1993;43(12):2609Y2614.
20. Oschmann P, Dorndorf W, Hornig C, et al.
Stages and syndromes of neuroborreliosis.
J Neurol 1998;245(5):262Y272.
21. Strle F, Ruzic-Sabljic E, Cimperman J, et al.
Comparison of findings for patients with
Borrelia garinii and Borrelia afzelii isolated
from cerebrospinal fluid. Clin Infect Dis
2006;43(6):704Y710.
December 2015
22. Halperin JJ. Facial nerve palsy associated
with lyme disease. Muscle Nerve
2003;28(4):516Y517.
23. Belman AL, Reynolds L, Preston T, et al.
Cerebrospinal fluid findings in children
with Lyme disease-associated facial
nerve palsy. Arch Pediatr Adolesc Med
1997;151(12):1224Y1228.
24. Sood SK. Lyme disease in children. Infect Dis
Clin North Am 2015;29(2):281Y294.
doi:10.1016/j.idc.2015.02.011.
25. Avery RA, Frank G, Glutting JJ, Eppes SC.
Prediction of Lyme meningitis in children
from a Lyme disease-endemic region: a
logistic-regression model using history,
physical, and laboratory findings. Pediatrics
2006;117(1):e1Ye7.
26. Garro AC, Rutman M, Simonsen K, et al.
Prospective validation of a clinical prediction
model for Lyme meningitis in children.
Pediatrics 2009;123(5):e829Ye834.
doi:10.1542/peds.2008-2048.
27. Cohn KA, Thompson AD, Shah SS, et al.
Validation of a clinical prediction rule to
distinguish Lyme meningitis from aseptic
meningitis. Pediatrics 2012;129(1):e46Ye53.
doi:10.1542/peds.2011-1215.
28. Halperin JJ, Krupp LB, Golightly MG, Volkman DJ.
Lyme borreliosis-associated encephalopathy.
Neurology 1990;40(9):1340Y1343.
29. Kristoferitsch W, Sluga E, Graf M,
et al. Neuropathy associated with
acrodermatitis chronica atrophicans. Clinical
and morphological features. Ann N Y Acad Sci
1988;539:35Y45.
30. Halperin J, Luft BJ, Volkman DJ, Dattwyler RJ.
Lyme neuroborreliosis. Peripheral nervous
system manifestations. Brain 1990;
113(pt 4):1207Y1221.
31. Marques AR. Laboratory diagnosis of Lyme
disease: advances and challenges. Infect Dis
Clin North Am 2015;29(2):295Y307.
doi:10.1016/j.idc.2015.02.005.
32. Centers for Disease Control and Prevention
(CDC). Recommendations for test performance
and interpretation from the Second National
Conference on Serologic Diagnosis of Lyme
Disease. MMWR Morb Mortal Wkly Rep
1995;44(31):590Y591.
33. Steere AC, Berardi VP, Weeks KE, et al.
Evaluation of the intrathecal antibody response
to Borrelia burgdorferi as a diagnostic test for
Lyme neuroborreliosis. J Infect Dis
1990;161(6):1203Y1209.
34. Ogrinc K, Lotric-Furlan S, Maraspin V, et al.
Suspected early Lyme neuroborreliosis in
patients with erythema migrans. Clin Infect Dis
2013;57(4):501Y509. doi:10.1093/cid/cit317.
Continuum (Minneap Minn) 2015;21(6):1729–1744
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
35. Djukic M, Schmidt-Samoa C, Lange P, et al.
Cerebrospinal fluid findings in adults with acute
Lyme neuroborreliosis. J Neurol 2012;259(4):
630Y636. doi:10.1007/s00415-011-6221-8.
36. Stanek G, Lusa L, Ogrinc K, et al. Intrathecally
produced IgG and IgM antibodies to
recombinant VlsE, VlsE peptide, recombinant
OspC and whole cell extracts in the diagnosis
of Lyme neuroborreliosis. Med Microbiol
Immunol 2013;203(2):125Y132. doi:10.1007/
s00430-013-0322-1.
37. Henningsson AJ, Christiansson M, Tjernberg I, et al.
Laboratory diagnosis of Lyme neuroborreliosis:
a comparison of three CSF anti-Borrelia antibody
assays. Eur J Clin Microbiol Infect Dis 2014;33(5):
797Y803. doi:10.1007/s10096-013-2014-6.
38. van Burgel ND, Brandenburg A, Gerritsen HJ, et al.
High sensitivity and specificity of the
C6-peptide ELISA on cerebrospinal fluid in
Lyme neuroborreliosis patients. Clin Microbiol
Infect 2011;17(10):1495Y1500. doi:10.1111/
j.1469-0691.2011.03459.x.
39. Cerar T, Ogrinc K, Lotric-Furlan S, et al.
Diagnostic value of cytokines and
chemokines in lyme neuroborreliosis. Clin
Vaccine Immunol 2013;20(10):1578Y1584.
doi:10.1128/CVI.00353-13.
40. Cerar T, Ogrinc K, Strle F, Ruzic-Sabljic E.
Humoral immune responses in patients with
Lyme neuroborreliosis. Clin Vaccine Immunol
2010;17(4):645Y650. doi:10.1128/CVI.00341-09.
41. Halperin JJ, Golightly M. Lyme borreliosis in
Bell’s palsy. Long Island Neuroborreliosis
Collaborative Study Group. Neurology
1992;42(7):1268Y1270.
42. Smouha EE, Coyle PK, Shukri S. Facial nerve
palsy in Lyme disease: evaluation of clinical
diagnostic criteria. Am J Otol 1997;18(2):257Y261.
43. Coyle PK, Schutzer SE, Deng Z, et al. Detection
of Borrelia burgdorferi-specific antigen in
antibody-negative cerebrospinal fluid in
neurologic Lyme disease. Neurology 1995;
45(11):2010Y2015. doi:10.1212/
WNL.0b013e318211c39a.
44. Bremell D, Mattsson N, Edsbagge M, et al.
Cerebrospinal fluid CXCL13 in Lyme
neuroborreliosis and asymptomatic HIV
infection. BMC Neurol 2013;13:2.
doi:10.1186/1471-2377-13-2.
45. Schmidt C, Plate A, Angele B, et al. A
prospective study on the role of CXCL13 in
Lyme neuroborreliosis. Neurology 2011;76(12):
1051Y1058. doi:10.1212/WNL.0b013e318211c39a.
46. Wormser GP, Dattwyler RJ, Shapiro ED, et al.
The clinical assessment, treatment, and
prevention of lyme disease, human granulocytic
anaplasmosis, and babesiosis: clinical practice
guidelines by the Infectious Diseases Society of
America. Clin Infect Dis 2006;43(9):1089Y1134.
www.ContinuumJournal.com 1743
 Lyme Neuroborreliosis
47. 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):91Y102.
48. Logigian EL, Kaplan RF, Steere AC. Successful
treatment of lyme encephalopathy with
intravenous ceftriaxone. J Infect Dis
1999;180(2):377Y383.
49. Marques A. Chronic Lyme disease: a review.
Infect Dis Clin North Am 2008;22(2):341Y360,
viiYviii. doi:10.1016/j.idc.2007.12.011.
50. Feder HM Jr, Johnson BJ, O’Connell S, et al.
A critical appraisal of ‘‘chronic Lyme disease’’.
N Engl J Med 2007;357(14):1422Y1430.
doi:10.1056/NEJMra072023.
1744 www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
51. Luft BJ, Dattwyler RJ, Johnson RC, et al.
Azithromycin compared with amoxicillin in
the treatment of erythema migrans: a
double-blind, randomized, controlled trial.
Ann Intern Med 1996;124(9):785Y791.
52. 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 2001;345(2):85Y92.
53. 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):1923Y1930.
54. 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):992Y1003.
December 2015