Lyme Neuroborreliosis: Known Knowns, Known Unknowns

John J. Halperin; Randi Eikeland; John A. Branda; Rick Dersch

Brain. 2022;145(8):2635-2647.

Conclusions

The goal of this paper has been to facilitate a common foundational understanding of LNB. Key to this is appreciating what does, and does not, constitute nervous system disease. As should be clear, it is highly unlikely that Bbsl infection causes neurodegenerative disorders—particularly in the absence of any evidence of CNS inflammation. A causal relationship with MUS or psychiatric disorders^{[114,125,137,138]} seems highly unlikely—although becoming ill with inflammatory or infectious disorders in general might precipitate or aggravate symptoms of such disorders in individuals otherwise predisposed to them—i.e. this might reflect a class effect, true of any infection. Many questions remain. By what mechanism do spirochetes reach the nervous system? If a very small bacterial load triggers LNB, by what amplifying mechanism does this occur? Does this suggest other, non-antimicrobial interventions? Might this inform treatment of other infections? And if post-infectious symptoms occur, what is the pathophysiological mechanism and might this explain other post-infectious states? Hopefully the framework provided here will allow more focus on these fundamental questions.

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Abbreviations
BBB=blood–brain barrier; BCB=blood–CSF barrier; Bbsl=Borrelia burgdorferi sensu lato; Bbss=Borrelia burgdorferi sensu stricto; EM=erythema migrans; ITAb=intrathecal antibody production; LNB =Lyme neuroborreliosis; PNS=peripheral nervous system

Data availability
Data sharing is not applicable to this article as no new data were created or analysed in this study.

Funding
No funding was received towards this work.

Table 1. European and US serological two-tiered testing algorithms
	First tier test	Second tier test	Immunoblot interpretive criteria for a positive result
	First tier test	Second tier test	IgM	IgG
European STTT One example of immunoblot criteria ⁵¹	ELISA (total antibody or separate IgM + IgG)	IgM, IgG immunoblots	B. afzelii: ≥1 of p39, OspC, p17 or a strong p41 B garinii: ≥ 1 of 39, OspC or a strong p41	B afzelii: ≥2 of p83/100, p58, p43, p39, p30, OspC, p21, p17, p14 B garinii: ≥1 of p83/100, p39, p30, OspC, p21, p17b
US STTT	ELISA (total antibody or separate IgM + IgG)	IgM, IgG immunoblots	≥2 of the following three bands must be present: 24 kDa (OspC), 39 kDa (BmpA), and 41 kDa (Fla). Positive results are disregarded if signs or symptoms present for >30 days.	≥5 of the following 10 bands must be present: 18 kDa, 21 kDa (OspC), 28 kDa, 30 kDa, 39 kDa (BmpA), 41 kDa (Fla), 45 kDa, 58 kDa (not GroEL), 66 kDa, and 93 kDa
US MTTT⁵⁶	ELISA (total antibody)	Orthogonal ELISA (total antibody or separate IgM + IgG)	NA	NA

IgM = immunoglobulin M; IgG = immunoglobulin G; STTT = standard two-tiered testing; MTTT = modified two-tiered testing, using two or more separate ELISAs that are sufficiently different from one another in their antigenic constituents or assay principles that using them together improves specificity compared with the individual tests ('orthogonal'); NA = not applicable.

Table 2. European Federation of Neurological Societies criteria for LNB ⁶⁷
Compatible neurological symptoms (Table 3)
CSF pleocytosis
Intrathecal production of Bb specific antibody
Definite LNB: 3/3 ^a
Possible LNB 2/3 ^b

Bb = Borrelia burgdorferi sensu lato, using antigens appropriate to that region in standard immunoassays.
^aIn European late LNB with peripheral neuropathy, considered definite if acrodermatitis chronica atrophicans (a unique cutaneous change, not described in North American patients) and positive peripheral blood serology.
^bIf no ITAb, positive serum IgG two-tier testing by 6 weeks after onset.

Table 3. Suggested testing algorithms in Europe and the USA
	Europe	USA
	Plausible exposure
Clinical signs/symptoms	Meningitis, cranial neuritis, painful radiculoneuritis, mononeuropathy, plexopathy, mononeuropathy multiplex; rarely myelitis or other parenchymal CNS inflammation

Recommended testing
Serum	STTT^a	STTT or MTTT^a
CSF
If strong clinical suspicion
First tier (ELISA) negative	Yes	Yes
First tier (ELISA) positive or borderline	Yes	Yes – if parenchymal CNS inflammationelse optional – particularly to exclude other diagnoses
CSF testing
CSF/serum Bb antibody index^b	Yes	Yes
CSF Bb antibody alone	No	No
CSF PCR or culture for Bb	No	No
CSF western blot	No	No
CSF cells, protein	Yes	Yes
CSF IgG synthesis	Reiber calculation	IgG index or synthesis rate
Oligoclonal bands	Yes	May be informative

^aSTTT/MTTT = standard and modified two-tiered testing (Table 1).
^bAntibody index, see Table 2.

Table 4. Available methods of determining antibody index
	Reiber^a	Capture ELISA	Standard ELISA
Samples
CSF, serum, within a day	Yes	Yes	Yes
Measure
Total CSF and serum [IgG] (other classes if needed)	Yes	No	Yes
Total CSF and serum [albumin]	Yes	No	No
Bb specific IgG (other classes if needed)	Yes	Yes	Yes
Technical:
Measure (each measure requires additional CSF)	CSF and serum [IgG], [albumin], [IgG(Bb)] Bb ELISAs at standard dilutions	Proportion CSF IgG specific to Bb Proportion serum IgG specific to Bb	CSF and serum [IgG], [IgG(Bb)].Dilute serum, CSF to same final [IgG] and Bb ELISAs on both
Measure (each measure requires additional CSF)	Optional: same for IgA, IgM	Optional: same for IgA, IgM	Optional: same for IgA, IgM
Calculations	AI = Q(Bb)_IgG/Q_IgG	AI = ([IgG(Bb)_CSF]/[[IgG_CSF])/([IgG(Bb)_ser]/[[IgG_ser])	AI = ratio of Bb ELISAs
Advantages
Volume of CSF needed	More	Least	More
Adjust for age, site CSF obtained	Yes	No	No
Adjust for very elevated total Q_IgG relative to Q_albumin	Yes, including replacing Q_IgG with a maximum Q_Lim when overall intrathecal IgG synthesis (Q_IgG > Q_Lim)	No	No
Technical concerns	Non-linear relation of ELISA value to concentration may distort at extremes; normative data with logarithmic relationships, potentially distorting at extremes	Assay more difficult to create	Measurements of IgG, albumin and subsequent dilution susceptible to error

AI = antibody index; [IgG] = concentration of IgG; [IgG] = total IgG; [IgG(Bb)] = IgG specific to Bbsl, using antigens relevant to geographic region; Q = ratios of [IgG] etc. in CSF to serum, both total and Bb specific; Q_IgG = [IgG_CSF]/[IgG_serum]; Q(Bb)_IgG = [IgG(Bb)_CSF]/[IgG(Bb)_serum]; Q_Albumin = [Albumin_CSF]/[Albumin_serum]
In capture assays, the single immunoassay readout is the proportion of immunoglobulin specific to the test antigen e.g. IgG(Bb)_CSF]/[[IgG_CSF] without a need to determine the two individual values.
^aWidely used in Europe⁶⁹ and some laboratories in the USA.⁷⁰

Authors and Disclosures

John J. Halperin^1–3, Randi Eikeland^4,5, John A. Branda^6,7 and Rick Dersch⁸

1 Department of Neurosciences, Overlook Medical Center, 99 Beauvoir Ave., Summit, NJ 07901, USA
2 Department of Medicine, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA 19107, USA
3 Department of Neurology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA 19107, USA
4 National Advisory on Tick-borne Diseases, Sørlandet Hospital Trust, Egvsveien 100, 4615 Kristiansand, Norway
5 Faculty of Health and Sport Sciences, University of Agder, 4879 Grimstad, Norway
6 Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
7 Department of Pathology, Harvard Medical School, Boston, MA 02114, USA
8 Clinic of Neurology and Neurophysiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany

Correspondence to
John J. Halperin MD Department of Neurosciences Overlook Medical Center 99 Beauvoir Ave Summit NJ 07901, USA E-mail: john.halperin@atlantichealth.org

Competing interests
The only commercial products mentioned are generic antibiotics, as recommended in multiple guidelines. J.J.H.: Grants: NIAID, Sub-PI, planning grant for Lyme meningitis clinical trial; NIAID co-investigator; pediatric Lyme meningitis clinical trial. Royalties: UpToDate for chapter on Lyme disease, CABI for book 'Lyme disease, an evidence-based approach' (2nd edition). Consulting: Pfizer, regarding Lyme vaccine (not pertinent to this paper). Honoraria: American Academy of Neurology, teaching in neuro-infectious disease course. Expert testimony: Defending physicians accused of delayed diagnosis of Lyme disease – not discussed in this paper. Stock: Abbott, Abbvie, Johnson & Johnson, Merck (no Lyme related products). R.E.: none. J.A.B.: Research Funding: Zeus Scientific, Immunetics, Pfizer. Consulting: T2 Biosystems, DiaSorin, Roche Diagnostics. Support for attending meetings: Diasorin: Support and payment for scientific advisory board (SAB) meeting attendance. Roche Diagnostics: Support and payment for SAB meeting attendance. Data Safety Monitoring Board or Advisory Board: Diasorin & Roche Diagnostics: Participation on SAB. R.D.: Honoraria: Lecture fees: Roche, Alexion, Bayer, Sanofi (not pertinent to this paper). Support for attending meetings: Biogen, travel grant to ECTRIMS 2019.

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Lyme Neuroborreliosis: Known Knowns, Known Unknowns

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