Study

Population
limited to LNB

Length of follow‐up

Interventions

Antibiotic naïve

Clinical remission measurement

Time to remission

Patient‐reported outcomes

CSF remission
measured

Serology response
measured

Kohlhepp 1989

Yes

Up to 3 years

Penicillin

Doxycycline

Unknown

Complete/partial/no

No

No

Yes

No

Pfister 1989

Yes

Average of 7 months

Penicillin

Cefotaxime

Unknown

Yes/no

No

Yes: VAS, 0 to 10

Yes

No

Mullegger 1991

Yes (children only)

>6 months,

<12 months

Penicillin

Ceftriaxone

Yes

Yes/no

Yes; from treatment onset to complete remission

No

No

Yes

Pfister 1991

Yes

Average of 7.7

months

Ceftriaxone

Cefotaxime

Unknown

Yes/no

No

No

Yes

No

Karlsson 1994

Yes

12 months

Penicillin

Doxycycline

Past 4 weeks

Yes/no; by specific sign/symptom

No

Yes: Likert‐like scale, 0 to 3

Yes, at 2 weeks and 12 months

Yes

Oksi 2007

No (but large subgroup of LNB enrolled)

12 months

Ceftriaxone followed by

amoxicillin or placebo

Past 1 month

Physician VAS 0 to 100; scored as excellent/good, poor/none, controversial

No

Yes: VAS

Lumbar puncture and measurement of CSF antibody levels and PCR for Borrelia burgdorferi was repeated in selected cases during or after treatment.

Yes: scored as strong decline, mild, none

Ljostad 2008

Yes

Up to 4 months

Ceftriaxone

Doxycycline

Past 14 days

No/mild/more than mild;

also change in baseline deficits in past 3 months using own composite clinical score

No

Yes: 6 items, each scored 0 to 2

Yes

No

Criteria

Kohlhepp 1989

(N = 75)

Pfister 1989

(N = 21)

Mullegger 1991

(N = 23)

Pfister 1991

(N = 30)

Karlsson 1994

(N = 54)

Oksi 2007

(N = 145; 72% to 75% definite, 25% to 27% possible^a)

Ljostad 2008

(N = 102)

Clinical

Radicular pain, meningitic symptoms, cranial neuritis, sensory and/or motor radiculitis, arthritis, carditis, myelitis or peripheral neuritis, tick bite and/or erythema migrans

Radicular pain (15/21), headache (2/21), facial palsy (8/21), unilateral VI palsy (1/21), lower limb muscle weakness (9/21), sensory disturbance (12/21)

Presence of neurological signs and symptoms indicative of LNB

Radiculopathy (motor or sensory, or both), cranial neuropathy (facial palsy, ocular motor)

Headache (71% to 74%), subjective stiff neck (65%), paresis (55% to 57%) including facial palsy in 35% to 43%

Lymphocytic meningitis without radiculitis in 18 (all definite), meningoradiculitis (16 definite) or radiculitis (11 definite), paresis in 5, encephalomyelitis in 4, encephalopathy in 6, facial paresis in 21, sudden deafness in 6, tinnitus in 8, other cranial nerve involvement in 13, peripheral neuritis in 6, and other peripheral nervous system manifestations (9 peripheral mononeuropathy or polyneuropathy, 15 paresthesia, 39 with headache without meningitis, 29 with dizziness or vertigo, and 11 with memory impairment)

25% to 33% Bannwarth's syndrome, 19% to 22% facial palsy, 24% to 38% radiculopathy, various others (other cranial neuropathies, ataxia, myelopathy, limb paresis, paresthesias, cognitive deficits)

Laboratory

B. burgdorferi‐specific antibody titer in serum, B. burgdorferi‐specific antibody titer in CSF, lymphocytic pleocytosis, elevated CSF protein (>50 mg/dL), elevated CSF IgM‐, IgA‐, and/or IgG‐index, oligoclonal bands in CSF. Only group‐level information is given.

Elevated B. burgdorferi‐specific IgG and IgM antibody titers in serum (1:64 to 1:512): found in 11, of whom 4 had both elevated IgG and IgM, 6 had only elevated IgG, and 1 had only elevated IgM.

4 were seropositive in CSF but not in blood; 6 had negative serology in both serum and CSF (seronegative LNB), but 4 had EM and 2 a history of insect bites.

1 or more of the following specific CSF laboratory parameters: elevated B. burgdorferi‐specific IgG antibody titer, intrathecally produced B. burgdorferi‐specific antibodies, and/or direct cultivation of B. burgdorferi from the CSF in a modified Barbour‐Stoenner‐Kelly medium

Elevated B. burgdorferi‐specific IgG and IgM antibody titers in serum: found in 22 and 8, respectively.

13 had positive B. burgdorferi‐specific CSF/serum antibody index.

Elevated B. burgdorferi‐specific IgM or IgG concentration, or both in 83% to 90%; all had positive serology or B. burgdorferi‐specific CSF antibodies, except for 1 participant who had a positive CSF culture.

Only 3 of the 145 study participants were seronegative.

Presence of inflammatory changes in the CSF or intrathecal antibodies against B. burgdorferi, or both supported a diagnosis of definite LNB; 124/145 participants had lumbar puncture performed at diagnosis.

Intrathecal production of B. burgdorferi‐specific antibodies or B. burgdorferi‐specific antibodies in serum, or both were required for enrollment.

Study

Kohlhepp 1989 Penicillin

Kohlhepp 1989 Doxycycline

Pfister 1989 Penicillin G

Pfister 1989 Cefotaxime

Pfister 1991 Ceftriaxone

Pfister 1991 Cefotaxime

Mullegger 1991 Penicillin G

Mullegger 1991 Ceftriaxone

Karlsson 1994

Penicillin G

Karlsson 1994 Doxycycline

Oksi 2007 Amoxicillin post‐ceftriaxone

Oksi 2007 Placebo

post‐ceftriaxone

Ljostad 2008 Doxycycline

Ljostad 2008 Ceftriaxone

Number of participants (evaluable)

36

39

10

11

14

16

11

12

23

31

73

72

54

48

Age

mean (SD) unless specified

Men 55 (12.6); women 54.1 (16.3)

Men 49.6 (14); women 55.7 (14.3)

56.7 (15)

55.4 (10.8)

58.7 (19.5)

53.7 (16.8)

8.1 (3.1)

Median 55 (range 16 to 88)

Median 49 (range 18 to 74)

Mean 52.3, range 19 to 87

Mean 50.5, range 16 to 80

54 (13)

52 (13)

Percentage males

44%

51%

50%

64%

64%

44%

36%

42%

44%

29%

48%

50%

52%

65%

History of erythema migrans

36%

31%

80%

45%

50%

56%

Not reported

61%

42%

26% (probable)

31%

10%

Mean (SD) time from onset of LNB to treatment

5.2 (13.6) months

4.1 (11.1) months

28.7 (33.8) days

23.5 (16.3) days

64.5 (84.7) days

38.6 (23.1) days

All included children were admitted to the hospital within 5 ± 1.8 days from onset of symptoms.

3.5 weeks (1 week to 25 months)

4 weeks (1 week to 18 months)

Unknown

10 (19) weeks

8 (13) weeks

Previous treatment with antibiotics

11%

8%

Not reported

Not reported

Not

reported (mentioned for 1 participant)

Was an exclusion criteria

None for the 4 weeks prior to enrollment

Yes, in all participants with EM, 24 adequately and 14 not adequately

Treatment with cephalosporin, penicillin, tetracycline in past 14 days exclusion criterion

Concomitant treatment with steroids

28%

26%

None

Not reported

Not reported

Not reported

Not

reported

Not

reported

CSF leukocytes

mean (SD) cells/uL

186 (75)

145 (58)

280.9 (212)

435.7 (528)

86.4 (128.4)

135.3 (299.2)

Not reported

Median 96, range 6 to 1190

Median 117, range 8 to 910

59% with available CSF showed lymphocytic pleocytosis.

194 (237)

178 (187)

CSF total protein

mean (SD) in mg/dL

133 (110)

119 (112)

115 (69)

136 (67.4)

72.7 (42)

79.1 (48.4)

Not reported

Median 110, range 40 to 360

Median 120, range 50 to 580

Not

reported

120 (70)

130 (80)

Presence of CSF oligoclonal bands

78%

62%

70%

64%

64%

Not

reported

Not

reported

Not

reported

Detected in 24/58 (41%) participants with definite LNB and CSF examined

Not

reported

Study

Tool

Signs assessed

Subjective symptoms elicited

Oksi 2007

Visual analogue scale

Yes

Possibly

Ljostad 2008

Composite clinical score

Yes

Yes

Mullegger 1991

Change of clinical symptoms

Yes

No

Disease duration

Yes

No

Kohlhepp 1989

Change of clinical symptoms

(3‐level classification)

Yes

Unclear

Pfister 1989

Change of clinical symptoms

Yes

Yes

Pfister 1991

Change of clinical symptoms

Yes

Unclear

Karlsson 1994

Change of clinical symptoms

Yes

No

Study

Parameter

Oksi 2007

Decrease of B. burgdorferi‐specific antibody concentrations at 12 months of at least 20% ("moderate decline") or 50% ("strong decline")

Ljostad 2008

Resolution of CSF pleocytosis

Kohlhepp 1989

Cell count, protein, antibody index, B. burgdorferi‐specific antibody production

Pfister 1989

Abnormal CSF on repeated lumbar puncture¹

Pfister 1991

Abnormal CSF on repeated lumbar puncture²

Karlsson 1994

Cell count, B. burgdorferi‐specific antibody production

Mullegger 1991

Changes in intrathecally produced specific antibodies against B. burgdorferi

Oral amoxicillin versus placebo for people previously treated with ceftriaxone for Lyme neuroborreliosis (acute and late)

Patient or population: people previously treated with ceftriaxone for disseminated Lyme neuroborreliosis (acute and chronic)¹
Settings: Finland, hospital‐based neurology/internal medicine, outpatient
Intervention: oral amoxicillin
Comparison: placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk or score/value

Corresponding risk or score/value

Placebo

Oral amoxicillin

Improvement in a measure of overall disability in the long term (3 or more months) following treatment

See comment

See comment

Not estimable

‐

See comment

Not reported

Improvement or resolution of the person's presenting neurological deficits in the long term (3 or more months) following treatment²

Separate information on the LNB subgroup (N = 62), but not for intervention groups within this subgroup was provided at the review authors' request. 59/62 participants were classified as experiencing improvement of presenting neurological deficits at month 12 (dichotomous assessment: 'excellent or good' based on investigator VAS values and medical record information).³

Not estimable

62⁴
(1 study)

Low⁵

Improvement in a measure of overall disability in the short term (2 weeks) following treatment⁴

See comment

See comment

Not estimable

‐

See comment

Not reported

Resolution of CSF pleocytosis following treatment

See comment

See comment

Not estimable

‐

See comment

Not measured

All adverse events ‐ 12 months

24 adverse events for all 145 Lyme disease participants, mostly diarrhea and fever with no need for discontinuation. No serious adverse events reported. Attribution of adverse events to either pretreatment with ceftriaxone, or to amoxicillin or placebo, or both, is unclear.

Not estimable

145
(1 study)

Very low⁶

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; CSF: cerebrospinal fluid; LNB: Lyme neuroborreliosis; RR: risk ratio; VAS: visual analogue scale

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Evidence based on randomized controlled trials begins as high‐quality evidence, but confidence in the evidence was decreased for several reasons, including the following.

• Study limitations

• Inconsistency of results

• Indirectness of evidence

• Imprecision

• Reporting bias

Oral doxycycline compared to intravenous ceftriaxone for Lyme neuroborreliosis (LNB) (acute and chronic)

Patient or population: Lyme neuroborreliosis (acute and chronic)
Settings: Southern Norway, hospital
Intervention: oral doxycycline
Comparison: intravenous ceftriaxone

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk or score/value

Corresponding risk or score/value

Intravenous ceftriaxone

Oral doxycycline

Improvement in a measure of overall disability in the long term (3 or more months) following treatment

See comment

See comment

Not estimable

‐

See comment

Not reported

Resolution of the person's presenting neurological deficits in the long term (3 or more months) following treatment

333 per 1000

480 per 1000 (297 to 783)

RR 1.44 (0.89 to 2.35)

102
(1 study)

Moderate¹

Symptom resolution; composite clinical score of neurological signs and symptoms at 12 months²

Improvement in a measure of overall disability in the short term (2 weeks) following treatment

See comment

See comment

Not estimable

‐

See comment

Not reported

Resolution of CSF pleocytosis following treatment

CSF was analyzed in 88/102 participants; authors state that no significant between‐group difference was present at 13 days and 4 months, but data are not available for verification.

Not estimable

88
(1 study)

Low³

Resolution of CSF pleocytosis in all participants

All adverse events

464 per 1000

367 per 1000
(237 to 571)

RR 0.79 (0.51 to 1.23)

113
(1 study)

Moderate⁴

48 adverse events in all participants randomized to study drug. 3 participants on ceftriaxone and 1 on doxycycline experienced serious adverse events (as defined by trial authors); RR 0.33 (95% CI 0.04 to 3.05).

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; CSF: cerebrospinal fluid; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Evidence based on randomized controlled trials begins as high‐quality evidence, but confidence in the evidence was decreased for several reasons, including the following.

• Study limitations

• Inconsistency of results

• Indirectness of evidence

• Imprecision

• Reporting bias

Intravenous penicillin G compared to oral doxycyline for Lyme neuroborreliosis (acute and chronic)

Patient or population: Lyme neuroborreliosis (acute and chronic)
Settings: Southern Sweden, hospital
Intervention: intravenous penicillin G
Comparison: oral doxycycline

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk or score/value

Corresponding risk or score/value

Oral doxycycline

Intravenous penicillin G

Improvement in a measure of overall disability in the long term (3 or more months) following treatment

See comment

See comment

Not estimable

‐

See comment

Not measured

Improvement of the person's presenting neurological deficits in the long term (3 or more months) following treatment¹

1000 per 1000

1000 per 1000

(920 to 1000)

RR 1.0
(0.92 to 1.08)

51
(1 study)

Low²

Investigators rating symptom composite on Likert scale from 1 to 3 (no, mild, moderate to severe)²

Resolution of the person's presenting neurological deficits in the long term (3 or more months) following treatment¹

900 per 1000

855 per 1000

(693 to 1000)

RR 0.95
(0.77 to 1.18)

51
(1 study)

Low²

Investigators rating symptom composite on Likert scale from 1 to 3 (no, mild, moderate to severe)²

Improvement in a measure of overall disability in the short term (2 weeks) following treatment

See comment

See comment

Not estimable

‐

See comment

Not reported

Resolution of CSF pleocytosis following treatment
Follow‐up: 1 year

1000 per 1000

930 per 1000
(750 to 1000)

RR 0.93
(0.75 to 1.15)

29
(1 study)

Very low³

All adverse events

129 per 1000

130 per 1000
(32 to 526)

RR 1.01
(0.25 to 4.08)

54
(1 study)

Very low⁴

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; CSF: cerebrospinal fluid; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Evidence based on randomized controlled trials begins as high‐quality evidence, but confidence in the evidence was decreased for several reasons, including the following.

• Study limitations

• Inconsistency of results

• Indirectness of evidence

• Imprecision

• Reporting bias

Intravenous doxycycline compared to intravenous penicillin G for Lyme neuroborreliosis (acute and chronic)

Patient or population: Lyme neuroborreliosis (acute and chronic)
Settings: Southern Germany, hospital
Intervention: intravenous doxycycline
Comparison: intravenous penicillin G

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk or score/value

Corresponding risk or score/value

Intravenous penicillin G

Intravenous doxycycline

Improvement in a measure of overall disability in the long term (3 or more months) following treatment

See comment

See comment

Not estimable

‐

See comment

Not reported

Improvement of the person's presenting neurological deficits in the long term (3 or more months) following treatment¹

833 per 1000

817 per 1000
(667 to 1000)

RR 0.98 (0.80 to 1.21)

75 (1 study)

Low²

Clinical findings were classified as no remission, partial remission, or full remission.

Resolution of the person's presenting neurological deficits in the long term (3 or more months) following treatment¹

694 per 1000

667 per 1000
(486 to 910)

RR 0.96

(0.70 to 1.31)

75 (1 study)

Low²

Clinical findings were classified as no remission, partial remission, or full remission.

Improvement in a measure of overall disability in the short term (2 weeks) following treatment

See comment

See comment

Not estimable

‐

See comment

Not reported

Resolution of CSF pleocytosis following treatment

See comment

See comment

Not estimable

‐

‐

Measured but not reported in detail

All adverse events³

See comment

See comment

Not estimable

75
(1 study)

‐

'Adverse events' not reported. No serious adverse events occurred.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; CSF: cerebrospinal fluid; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Evidence based on randomized controlled trials begins as high‐quality evidence, but confidence in the evidence was decreased for several reasons, including the following.

• Study limitations

• Inconsistency of results

• Indirectness of evidence

• Imprecision

• Reporting bias

Intravenous cefotaxime compared to intravenous penicillin G for Lyme neuroborreliosis (acute)

Patient or population: Lyme neuroborreliosis (acute)
Settings: Southern Germany, hospital
Intervention: intravenous cefotaxime
Comparison: intravenous penicillin G

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk or score/value

Corresponding risk or score/value

Intravenous penicillin G

Intravenous cefotaxime

Improvement in a measure of overall disability in the long term (3 or more months) following treatment

See comment

See comment

Not estimable

‐

See comment

Not reported

Resolution of the person's presenting neurological deficits in the long term (3 or more months) following treatment¹

800 per 1000

816 per 1000

(536 to 1000)

RR 1.02
(0.67 to 1.55)

21
(1 study)

Low²

Investigators' nonstandardized judgement of improvement or resolution of symptoms reported at 7.7 months.

Improvement in a measure of overall disability in the short term (2 weeks) following treatment

See comment

See comment

Not estimable

‐

See comment

Not reported

Resolution of CSF pleocytosis following treatment

1000 per 1000

920 per 1000
(710 to 1000)

RR 0.92
(0.71 to 1.18)

21
(1 study)

Very low³

Follow‐up: mean 7.7 months

All adverse events

See comment

See comment

Not estimable

21
(1 study)

Low⁴

No adverse events occurred.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; CSF: cerebrospinal fluid; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Evidence based on randomized controlled trials begins as high‐quality evidence, but confidence in the evidence was decreased for several reasons, including the following.

• Study limitations

• Inconsistency of results

• Indirectness of evidence

• Imprecision

• Reporting bias

Intravenous ceftriaxone compared to intravenous cefotaxime for Lyme neuroborreliosis (acute)

Patient or population: acute Lyme neuroborreliosis
Settings: Southern Germany, hospital
Intervention: intravenous ceftriaxone
Comparison: intravenous cefotaxime

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk or score/value

Corresponding risk or score/value

Intravenous cefotaxime

Intravenous ceftriaxone

Improvement in a measure of overall disability in the long term (3 or more months) following treatment

See comment

See comment

Not estimable

‐

See comment

Not measured

Resolution of the person's presenting neurological deficits in the long term (3 or more months) following treatment

600 per 1000

666 per 1000

(378 to 1000)

RR 1.11 (0.63 to 1.97)

27
(1 study)

Low¹

Outcome reported at a mean of 8.1 months' follow‐up.

Improvement in a measure of overall disability in the short term (2 weeks) following treatment

See comment

See comment

Not estimable

‐

See comment

Not reported

Resolution of CSF pleocytosis following treatment

867 per 1000

988 per 1000
(780 to 1000)

RR 1.14 (0.90 to 1.44)

27
(1 study)

Very low²

All adverse events

188 per 1000

71 per 1000
(7 to 611)

RR 0.38
(0.04 to 3.26)

30
(1 study)

Low³

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; CSF: cerebrospinal fluid; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Evidence based on randomized controlled trials begins as high‐quality evidence, but confidence in the evidence was decreased for several reasons, including the following.

• Study limitations

• Inconsistency of results

• Indirectness of evidence

• Imprecision

• Reporting bias