Introduction
Lyme disease is a zoonotic infection caused by Borrelia burgdorferi sensu lato complex genospecies (Bbsl), B. afzelii , and B. garinii .[ 1 ] It is transmitted via the bite of infected Ixodes tick species across the Eurasian and North American subcontinents. As per Centers for Disease Control and Prevention (CDC) reports, roughly 89,468 cases of Lyme disease were reported in 2023, with higher incidence in the mid-Atlantic, Northeast, and Upper Midwest regions in the United States.[ 2 , 3 ]
Lyme disease, if untreated, typically progresses through stages: early localized (erythema migrans, regional lymphadenopathy), early disseminated (cardiac, ophthalmologic, or musculoskeletal manifestations), and late disseminated (neurological and dermatological).[ 4 , 5 ] The key neurological manifestations include lymphocytic meningitis, radiculoneuritis, cranial neuropathies (commonly of cranial nerves VII, VIII, III, V, or VI), myelitis, radiculitis, or mononeuropathy multiplex.[ 6 , 7 , 8 , 9 ]
Stroke and other cerebrovascular events secondary to Lyme neuroborreliosis (LNB) are infrequent and often mistaken for other common etiologies. Because presentations are scattered across multiple case reports and small series, clinicians lack a consolidated clinical picture. The diagnostic approach (2020 American Academy of Neurology (AAN)/American College of Rheumatology(ACR)/Infectious Diseases Society of America (IDSA) Guidelines) for suspected LNB, while nonlinear in clinical practice, begins with an assessment of presentation and exposure risk [ Figure 1 ].[ 10 ]
This review focuses on the current evidence of clinical features, serological and cerebrospinal fluid (CSF) analyses, and traditional and novel approaches in the management of vasculitides and neurovascular sequelae associated with Lyme disease, with an aim to map existing consensus and bridge knowledge gaps. Given its complex diagnostic approach and potential for morbidity, LNB remains a challenging topic for clinical research and systematic evaluation.
Methods
The review followed the recommendations and criteria by the Joanna Briggs Institute Manual for Evidence Synthesis for scoping reviews and reported results as per Preferred Reporting Items for Systematic Reviews and Meta Analyses ( PRISMA ) Extension for Scoping Reviews guidelines.[ 11 , 12 ] The protocol was pre-registered on the Open Science Framework with the DOI: https://doi.org/10.17605/OSF.IO/M476S .
PRISMA Checklist
JBI=Joanna Briggs Institute; PRISMA-ScR=Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews. *Where sources of evidence (see second footnote) are compiled from, such as bibliographic databases, social media platforms, and Web sites. † A more inclusive/heterogeneous term used to account for the different types of evidence or data sources (e.g., quantitative and/or qualitative research, expert opinion, and policy documents) that may be eligible in a scoping review as opposed to only studies. This is not to be confused with information sources (see first footnote). ‡ The frameworks by Arksey and O’Malley (6) and Levac and colleagues (7) and the JBI guidance (4, 5) refer to the process of data extraction in a scoping review as data charting. § The process of systematically examining research evidence to assess its validity, results, and relevance before using it to inform a decision. This term is used for items 12 and 19 instead of “risk of bias” (which is more applicable to systematic reviews of interventions) to include and acknowledge the various sources of evidence that may be used in a scoping review (e.g., quantitative and/or qualitative research, expert opinion, and policy document). From: Tricco AC, Lillie E, Zarin W, O’Brien KK, Colquhoun H, Levac D, et al. PRISMA Extension for Scoping Reviews (PRISMAScR): Checklist and Explanation. Ann Intern Med. 2018;169:467–473. doi: 10.7326/M18-0850.
| Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist | |||
| SECTION | ITEM | PRISMA-ScR CHECKLIST ITEM | REPORTED ON PAGE # |
| TITLE | |||
| Title | 1 | Identify the report as a scoping review. | 1 |
| ABSTRACT | |||
| Structured summary | 2 | Provide a structured summary that includes (as applicable): background, objectives, eligibility criteria, sources of evidence, charting methods, results, and conclusions that relate to the review questions and objectives. | 1 |
| INTRODUCTION | |||
| Rationale | 3 | Describe the rationale for the review in the context of what is already known. Explain why the review questions/objectives lend themselves to a scoping review approach. | 3 |
| Objectives | 4 | Provide an explicit statement of the questions and objectives being addressed with reference to their key elements (e.g., population or participants, concepts, and context) or other relevant key elements used to conceptualize the review questions and/or objectives. | 3 |
| METHODS | |||
| Protocol and registration | 5 | Indicate whether a review protocol exists; state if and where it can be accessed (e.g., a Web address); and if available, provide registration information, including the registration number. | 4 |
| Eligibility criteria | 6 | Specify characteristics of the sources of evidence used as eligibility criteria (e.g., years considered, language, and publication status), and provide a rationale. | 4 |
| Information sources* | 7 | Describe all information sources in the search (e.g., databases with dates of coverage and contact with authors to identify additional sources), as well as the date the most recent search was executed. | 4 |
| Search | 8 | Present the full electronic search strategy for at least 1 database, including any limits used, such that it could be repeated. | 4 |
| Selection of sources of evidence † | 9 | State the process for selecting sources of evidence (i.e., screening and eligibility) included in the scoping review. | 5 |
| Data charting process ‡ | 10 | Describe the methods of charting data from the included sources of evidence (e.g., calibrated forms or forms that have been tested by the team before their use, and whether data charting was done independently or in duplicate) and any processes for obtaining and confirming data from investigators. | 5 |
| Data items | 11 | List and define all variables for which data were sought and any assumptions and simplifications made. | 5-6 |
| Critical appraisal of individual sources of evidence § | 12 | If done, provide a rationale for conducting a critical appraisal of included sources of evidence; describe the methods used and how this information was used in any data synthesis (if appropriate). | 5 |
| Synthesis of results | 13 | Describe the methods of handling and summarizing the data that were charted. | 5-6 |
| RESULTS | |||
| Selection of sources of evidence | 14 | Give numbers of sources of evidence screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally using a flow diagram. | 6 |
| Characteristics of sources of evidence | 15 | For each source of evidence, present characteristics for which data were charted and provide the citations. | 6 |
| Critical appraisal within sources of evidence | 16 | If done, present data on critical appraisal of included sources of evidence (see item 12). | 6 |
| Results of individual sources of evidence | 17 | For each included source of evidence, present the relevant data that were charted that relate to the review questions and objectives. | 6-8 |
| Synthesis of results | 18 | Summarize and/or present the charting results as they relate to the review questions and objectives. | 6-8 |
| DISCUSSION | |||
| Summary of evidence | 19 | Summarize the main results (including an overview of concepts, themes, and types of evidence available), link to the review questions and objectives, and consider the relevance to key groups. | 8-13 |
| Limitations | 20 | Discuss the limitations of the scoping review process. | 13 |
| Conclusions | 21 | Provide a general interpretation of the results with respect to the review questions and objectives, as well as potential implications and/or next steps. | 8-13 |
| FUNDING | |||
| Funding | 22 | Describe sources of funding for the included sources of evidence, as well as sources of funding for the scoping review. Describe the role of the funders of the scoping review. | 13-14 |
Search strategy
A comprehensive literature search was conducted to identify studies on neurovascular manifestations of LNB published from the inception of major databases up to February 2025 [Supplementary Tables 1 - 6 ] and was performed across PubMed, Embase, Google Scholar, CORE, Directory of Open Access Journals, and BASE using combinations of the following terms: “neuroborreliosis,” “cerebral vasculitis,” “intracranial hemorrhage,” “subarachnoid hemorrhage,” “venous thrombosis,” “aneurysm,” “transient ischemic attack,” “hemorrhagic stroke,” and “ischemic stroke.” The complete search strategy is provided in the Supplementary Tables 1 - 6 .
Supplementary Table 1
PubMed
| PubMed | |
| Search | Results |
| “Cerebrovascular”[All Fields] OR (“vasculitis, central nervous system”[MeSH Terms] OR (“vasculitis”[All Fields] AND “central”[All Fields] AND “nervous”[All Fields] AND “system”[All Fields]) OR “central nervous system vasculitis”[All Fields] OR (“cerebral”[All Fields] AND “vasculitis”[All Fields]) OR “cerebral vasculitis”[All Fields]) OR (“vascular diseases”[MeSH Terms] OR (“vascular”[All Fields] AND “diseases”[All Fields]) OR “vascular diseases”[All Fields] OR “vasculopathy”[All Fields] OR “vasculopathies”[All Fields]) OR (“angiopathies”[All Fields] OR “vascular diseases”[MeSH Terms] OR (“vascular”[All Fields] AND “diseases”[All Fields]) OR “vascular diseases”[All Fields] OR “angiopathy”[All Fields]) OR (“intracranial hemorrhage”[All Fields] OR “intracranial hemorrhages”[MeSH Terms] OR (“intracranial”[All Fields] AND “hemorrhages”[All Fields]) OR “intracranial hemorrhages”[All Fields] OR (“intracranial”[All Fields] AND “hemorrhage”[All Fields]) OR “intracranial hemorrhage”[All Fields]) OR (“subarachnoid hemorrhage”[All Fields] OR “subarachnoid hemorrhage”[MeSH Terms] OR (“subarachnoid”[All Fields] AND “hemorrhage”[All Fields]) OR “subarachnoid hemorrhage”[All Fields]) OR (“venous thrombosis”[MeSH Terms] OR (“venous”[All Fields] AND “thrombosis”[All Fields]) OR “venous thrombosis”[All Fields]) OR (“aneurysm”[MeSH Terms] OR “aneurysm”[All Fields] OR “aneurysms”[All Fields] OR “aneurysm s”[All Fields] OR “aneurysmal”[All Fields] OR “aneurysmally”[All Fields] OR “aneurysmic”[All Fields]) OR (“transient ischaemic attack”[All Fields] OR “ischemic attack, transient”[MeSH Terms] OR (“ischemic”[All Fields] AND “attack”[All Fields] AND “transient”[All Fields]) OR “transient ischemic attack”[All Fields] OR (“transient”[All Fields] AND “ischemic”[All Fields] AND “attack”[All Fields])) OR (“hemorrhagic stroke”[MeSH Terms] OR (“hemorrhagic”[All Fields] AND “stroke”[All Fields]) OR “hemorrhagic stroke”[All Fields]) OR (“ischemic stroke”[MeSH Terms] OR (“ischemic”[All Fields] AND “stroke”[All Fields]) OR “ischemic stroke”[All Fields]) OR (“vasospasm, intracranial”[MeSH Terms] OR (“vasospasm”[All Fields] AND “intracranial”[All Fields]) OR “intracranial vasospasm”[All Fields] OR (“cerebral”[All Fields] AND “vasospasm”[All Fields]) OR “cerebral vasospasm”[All Fields]) OR (“syncopal”[All Fields] OR “syncope”[MeSH Terms] OR “syncope”[All Fields] OR “syncopes”[All Fields] OR “syncopic”[All Fields]) AND “Neuroborreliosis”[All Fields] OR (“lyme disease”[MeSH Terms] OR (“lyme”[All Fields] AND “disease”[All Fields]) OR “lyme disease”[All Fields]) OR (“borrelia infections”[MeSH Terms] OR (“borrelia”[All Fields] AND “infections”[All Fields]) OR “borrelia infections”[All Fields] OR “borreliosis”[All Fields]) OR (“borrelia”[MeSH Terms] OR “borrelia”[All Fields] OR “borreliae”[All Fields] OR “borrelias”[All Fields]) OR (“borrelia burgdorferi group”[MeSH Terms] OR (“borrelia”[All Fields] AND “burgdorferi”[All Fields] AND “group”[All Fields]) OR “borrelia burgdorferi group”[All Fields] OR (“borrelia”[All Fields] AND “garinii”[All Fields]) OR “borrelia garinii”[All Fields]) OR (“borrelia burgdorferi group”[MeSH Terms] OR (“borrelia”[All Fields] AND “burgdorferi”[All Fields] AND “group”[All Fields]) OR “borrelia burgdorferi group”[All Fields] OR (“borrelia”[All Fields] AND “afzelii”[All Fields]) OR “borrelia afzelii”[All Fields]) OR (“b”[All Fields] AND (“burgdorferi”[All Fields] OR “burgdorferi s”[All Fields])) OR (“b”[All Fields] AND “garinii”[All Fields]) OR (“b”[All Fields] AND “afzelii”[All Fields]) OR (“post lyme disease syndrome”[MeSH Terms] OR (“post lyme”[All Fields] AND “disease”[All Fields] AND “syndrome”[All Fields]) OR “post lyme disease syndrome”[All Fields] OR (“chronic”[All Fields] AND “lyme”[All Fields] AND “disease”[All Fields]) OR “chronic lyme disease”[All Fields]) OR (“post lyme disease syndrome”[MeSH Terms] OR (“post lyme”[All Fields] AND “disease”[All Fields] AND “syndrome”[All Fields]) OR “post lyme disease syndrome”[All Fields] OR (“chronic”[All Fields] AND “lyme”[All Fields] AND “disease”[All Fields]) OR “chronic lyme disease”[All Fields]) | 462 |
Supplementary Table 6
BASE
| BASE | |
| Search | Results |
| Search terms: Neuroborreliosis, lymes, vasculitis, cerebrovascular Boolean operators: (“neuroborreliosis” OR “lyme” OR “borrelia” OR “Borrelia burgdorferi”) AND (“vasculitis” OR “cerebrovascular” OR “stroke”) | 521 |
Supplementary Table 2
Embase
| Embase | |
| Search query | Results |
| (‘neuroborreliosis’/exp OR ‘neuroborreliosis’ OR ‘lyme’ OR ‘borreliella’/exp OR ‘borreliella’) AND (‘stroke’/exp OR ‘stroke’ OR ‘vasculitis’/exp OR ‘vasculitis’ OR ‘intracranial hemorrhage’/exp OR ‘intracranial hemorrhage’ OR ‘subarachnoid hemorrhage’/exp OR ‘subarachnoid hemorrhage’ OR ‘transient ischaemic attack’/exp OR ‘transient ischaemic attack’ OR ‘cerebral sinus thrombosis’/exp OR ‘cerebral sinus thrombosis’) AND ([embase]/lim OR [medline]/lim) | 857 |
Supplementary Table 3
Google Scholar
| Google Scholar | |
| Search | Results |
| Search terms: Neuroborreliosis, lymes, vasculitis, cerebrovascular Boolean operators: (“Neuroborreliosis” OR “Lyme”) AND (“vasculitis” OR “cerebrovascular”) | 660 |
Supplementary Table 4
CORE
| CORE | |
| Search | Results |
| Search terms: Neuroborreliosis, lymes, vasculitis, cerebrovascular Boolean operators: (“neuroborreliosis” OR “lyme” OR “borrelia” OR “Borrelia burgdorferi”) AND (“vasculitis” OR “cerebrovascular” OR “stroke”) | 1667 |
| Filters applied: 1. Field of Interest: Medicine 2. Language: English | 47 |
Supplementary Table 5
DOAJ
| DOAJ | |
| Search | Results |
| Search terms: neuroborreliosis, cerebrovascular Boolean operators: neuroborreliosis AND cerebrovascular | 15 |
Eligibility criteria
This scoping review included studies published from the inception of the database to February 2025. Studies were eligible if they described pediatric (ages 18 or below) or adult patients diagnosed with LNB based on European Federation of Neurological Societies or IDSA/AAN/ACR guidelines.[ 13 , 14 ] The study had to document neurovascular involvement with a causal association proposed by clinical reasoning, diagnostic workup, or imaging. Studies reporting co-infections (e.g., syphilis, babesiosis), autoimmune or neurodegenerative disorders (e.g., multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, and dementia), psychiatric disorders, seizure disorders, or other cerebrovascular etiologies without exposure or serological evidence of LNB were excluded. The primary outcomes consisted of demographic, endemic, and clinical features; serological and CSF analyses; medical and/or surgical interventions; and patient outcomes.
Selection and risk of bias of studies
A total of 2045 articles were identified using the search strategy in databases. After removal of 517 duplicate entries, 1528 titles and abstracts were screened using Rayyan (Rayyan Systems Inc., Cambridge, MA, USA)., followed by full-text review of 117 articles by two independent reviewers (S.S., J.L.).[ 15 ] Ninety articles were included in the qualitative assessment of the review. [ Figure 2 ] Risk of bias was analyzed using appropriate Joanna Briggs Institute (JBI) Critical Appraisal Tools for Case Series and Case Reports.[ 16 , 17 ] The standardized checklists served to assess the reporting rigor through 8–10 domains, including clarity of description of patient demographics and clinical management. Each included study was reviewed independently by a reviewer (S.S., A.D.), with disagreements resolved through discussion.
Data extraction and analysis
Data were extracted independently by two reviewers (S.S., G.O.) using a Microsoft Excel sheet (Microsoft Excel [Office Home and Student 2019]). The data extraction framework comprised: i) study and author details, ii) demographics (age, gender), iii) clinical features (presenting neurological signs, time since onset of first neurological symptom), iv) imaging modalities and findings, v) diagnostic analyses (CSF and serum findings), vi) medical (antibiotics, stroke prevention medications, anticoagulants, antiepileptics) and surgical treatment approaches, and vii) patient outcomes (neurological or serological). A descriptive analysis and synthesis were performed to summarize the patient characteristics and thematic patterns across studies due to the type of study designs and heterogeneous nature of data. Figure creation was done on RStudio (RStudio 2025.09.1+401) .
Results
A total of 71 manuscripts [IS1-IS71; Supplementary Table 7 ] was reviewed and studied 92 patients following the selection criteria [ Figure 2 ]. Two patients (Cases 1 and 3) were excluded due to poor quality of evidence of cerebrovascular involvement secondary to NB as per JBI checklists (IS40). The analyses included 90 patients, with a median age of 12 years (Interquartile Range (IQR): 9–14) in the pediatric population and a median age of 52 (IQR: 39–60) in the adult population. There was no gender predominance, with 54% of cases being male. The majority of the cases were reported from the European continent (Germany [25.6%] and France [8.9%]), followed by the United States (16.7%) [ Figure 3 , Supplementary Table 8 ]. The median time of onset of neurological symptoms was less than 1 day, ranging up to 730 days (IQR: 1–14). A history of residence or travel to a Lyme-endemic area was documented in 89% (n/N = 63/71) of cases, and 51% (n/N = 32/63) recalled a tick bite. Of the 35 patients where comorbidities were documented, hypertension was the most common (n = 15/35). Common neurological manifestations reported in the cases were unilateral or bilateral hemiparesis (51%), followed by cranial nerve palsies (38%), most notably lower motor neuron (LMN) facial paralysis (31%), cognitive impairment (26%), ataxia (23%), dysarthria (19%), and paraesthesia (17%). The least commonly reported symptoms were meningeal signs (7%), seizures (9%), and cerebellar signs (11%). It was interesting to note a few cases reporting tetraplegia (5.6%) and locked-in syndrome (2.2%) [ Table 1 ]. Radiologically confirmed final diagnoses showed that roughly three-quarters of the cases (n/N = 64/89) had evidence of vasculitis, 50.6% of cases had ischemic strokes, and 6.7% of cases had aneurysms. Rarer diagnoses of cerebrovascular involvement were cases with hemorrhagic-conversion strokes (5.6%), subarachnoid hemorrhage (6.7%), or cerebral venous sinus thromboses (5.6%). Two cases (2.2%) of isolated intracranial hemorrhage were reported. Only 2.2% of cases reported normal imaging findings. Brain regions most affected included the cerebral cortex (56.2%), particularly the parietal (16.9%), temporal (16.9%), and frontal lobes (11.2%). The brainstem was affected in 26/89 (29.2%) cases, and deeper brain structures such as the basal ganglia (23.6%), thalamus (13.5%), and internal capsule (7.9%) were involved in over two-fifth of reported cases [40/89]. Diencephalic (14.6%) and cerebellar (2.2%) regions were less commonly affected. In terms of vascular territories, the vertebrobasilar systems and the middle cerebral artery, or their territories, were involved in one-third of the cases, while anterior cerebral artery (21.1%) and posterior cerebral artery (11/90 [12.2%]) were less frequently affected. Multivessel involvement was seen in 23/90 cases (25.6%), and sinus thromboses (superior sagittal or transverse sinuses) were observed in 5/89 (5.6%) cases [ Table 2 ]. Imaging techniques commonly involved were computed tomography (CT) brain and angiography, magnetic resonance imaging (MRI) brain (Diffusion-Weighted Imaging [DWI], Apparent Diffusion Coefficient [ADC], Fluid-Attenuated Inversion Recovery [FLAIR], Vessel Wall Imaging [VWI]), MR angiography (MRA), MRA- Time of Flight [TOF], and transcranial Doppler. Serological data indicated that 41/62 (66.1%) of patients had Borrelia-specific (Bb) Immunoglobulin M (IgM), 38/74 cases (51.4%) had Bb Immunoglobulin G (IgG), and 16 cases had both antibodies. Bb DNA Polymerase Chain Reaction (PCR) positivity in serum was low (n/N = 4/16). CSF analyses revealed lymphocytic pleocytosis in 76/81 cases (93.8%), with a median White Blood Cells (WBC) count of 73 cells/microliter (IQR 28-220), low glucose (normal: 50–80 mg/dl) in 25/52 (48.1%) cases, and elevated protein (normal: 15–40 mg/dl) in 52/73 (71%) cases (median of 203 mg/dL, IQR 113.2–349). Borrrelia-specific IgM and IgG antibodies were present in 45/51 (88.2%) and 60/63 (95.2%) of CSF samples, respectively. An elevated CSF: serum antibody index (IgM) was seen in 13/22 cases (59.1%) and in 22/28 cases (78.6%) for IgG. CSF PCR positivity was higher at 6/20 (30%). Oligoclonal bands were detected in 29/33 (87.9%) cases reporting it, and elevated C-X-C motif chemokine ligand 13 (CXCL13) was reported in 7/90 cases (8.2%) [ Table 3 ]. Cephalosporins, mainly ceftriaxone (76.4%), were the primary antibiotics used in 85.4% (n = 76/89) of patients, followed by penicillin (16.9%) and doxycycline (11.2%). Stroke prophylaxis was initiated in 33.3% of patients, predominantly with aspirin (n = 24/30) or other antiplatelets. Anticoagulants were administered in 11.1% of people, antiepileptics in 6.7%, and acetazolamide in 1.1%. Surgical interventions were necessary in 12/90 patients and included intra-arterial thrombolysis (33.3%), aneurysm embolization or clipping (16.6%), and stenting and decompressive craniectomy ([16.6%] each) [ Table 4 ]. Regarding outcomes, the median follow-up was 4.5 months (IQR: 1.4–7.25 months) for serological monitoring and 6 months (IQR: 2–12 months) for neurological assessment. A reduction in serological markers was achieved in almost all cases (41/43 cases), while a majority (79/88 cases) showed improvement in neurological signs or imaging. Isolated clinical improvement was seen in 75% of cases, while radiological stabilization or improvement was noted in 39.8% of cases. Mortality was reported in 4/88 cases, and persistent tetraplegia occurred in another 3/83 cases [ Supplementary Table 9 ].
Supplementary Table 7
Included Studies
| IS1 | Back T, Grünig S. Neuroborreliosis-associated cerebral vasculitis—An update. Neurol Psychiatry Brain Res . 2016;22 (3-4):162-166. doi: 10.1016/J.NPBR.2016.09.002 |
| IS2 | Blažina K, Miletić V, Relja M, Bažadona D. Thrombose der zerebralen Blutleiter: seltene Komplikation einer Neuroborreliose. Wien Klin Wochenschr . 2015;127 (1-2):65-67. doi: 10.1007/S00508-014-0622-5, |
| IS3 | Matera G, Labate A, Quirino A, et al. Chronic neuroborreliosis by B. garinii an unusual case presenting with epilepsy and multifocal brain MRI lesions. New Microbiologica . Published online 2014. |
| IS4 | Vieira Afonso JFF, Santos MM, Vieira J, Oliveira R, Rodrigues AF. Borrelia burgdorferi: A Rare Cause of Stroke. Cureus . 2025;17 (1). doi: 10.7759/CUREUS.77061 |
| IS5 | Peter S, Anderson M, Conyers FG, Murali S. The case of a 38-year-old man with transient right arm weakness and dysarthria. Ann Clin Transl Neurol . 2024;11 (8):2230-2231. doi: 10.1002/ACN3.52130, |
| IS6 | Hajiyev K, Forsting M, Cimpoca A, Khanafer A, Bäzner H, Henkes H. Multiple Severe Intracranial Stenoses with Ischemic Stroke in Neuroborreliosis-associated Cerebral Vasculitis: Endovascular Treatment Strategies and Literature Review. Clin Neuroradiol . 2024;34 (4):959-972. doi: 10.1007/S00062-024-01447-7/FIGURES/16 |
| IS7 | Rosendahl SB, Ravn P, Lebech AM, Midtgaard Stenør CP. Lyme neuroborreliosis with encephalitis: A rare case. IDCases . 2023;31. doi: 10.1016/J.IDCR.2023.E01704, |
| IS8 | Černík D, Javornická K, Gligić S, et al. Lyme disease-associated vasculitis with fatal course. J Neurol Sci . 2023;455:122283. doi: 10.1016/J.JNS.2023.122283 |
| IS9 | Sathi S, Kim D, Duplan P, Kim P, Shenkamn C. Ischemic Stroke With Hemorrhagic Conversion in a Case of Lyme Neuroborreliosis. Cureus . 2022;14 (8):e28028. doi: 10.7759/CUREUS.28028 |
| IS10 | Palleis C, Forbrig R, Lehner L, et al. Lyme neuroborreliosis: An unusual case with extensive (peri) vasculitis of the middle cerebral artery. Eur J Neurol . 2023;30 (3):785-787. doi: 10.1111/ENE.15633;REQUESTEDJOURNAL: JOURNAL: 14681331;WGROUP: STRING: PUBLICATION |
| IS11 | Philipps J, Erdlenbruch B, Kuschnerow M, et al. Hyperacute treatment of childhood stroke in Lyme neuroborreliosis: report of two cases and systematic review of the literature. Ther Adv Neurol Disord . 2022;15. doi: 10.1177/17562864221102842, |
| IS12 | Savasta S, Fiorito I, Foiadelli T, et al. Abdominal pain as first manifestation of lyme neuroborreliosis in children, case report and review of literature. Ital J Pediatr . 2020;46 (1):1-5. doi: 10.1186/S13052-020-00936-Y/FIGURES/1 |
| IS13 | Rahangdale R, Lima AA, Tayal A, Bhanot N, Scott T. Lyme disease presenting as acute ischemic strokes with an embolic pattern. Interdisciplinary Neurosurgery . 2020;22:100838. doi: 10.1016/J.INAT.2020.100838 |
| IS14 | Niksefat M, Albashiti B, Burke D, Moshayedi P, Patira R, Knepper L. Extensive meningeal enhancement in acute central nervous system Lyme: Case series and review of literature. Journal of Clinical Neuroscience . 2019;64:25-27. doi: 10.1016/j.jocn. 2019.03.048 |
| IS15 | Khan S, Bhattal GK, Shah NH, Lascano J, Karki A. Neuroborreliosis with Unusual Presentation: A Case Report. Cureus . 2019;11 (9):e5758. doi: 10.7759/CUREUS.5758 |
| IS16 | Legast GM, Schnider A, Nicastro N. Ischemic Stroke: Do Not Forget Lyme Neuroborreliosis. Case Rep Neurol Med . 2018;2018 (1):1720725. doi: 10.1155/2018/1720725 |
| IS17 | Tiu J, Hanson RM, Staudinger R. Cerebral Aneurysm in Lyme Neuroborreliosis with Regression After Medical Treatment. Journal of Neuroinfectious Diseases 2017 8:2. 2017;8 (2):1-2. doi: 10.4172/2314-7326.1000252 |
| IS18 | Kortela E, Hytönen J, Numminen J, Overmyer M, Saxen H, Oksi J. Cerebral vasculitis and intracranial multiple aneurysms in a child with Lyme neuroborreliosis. JMM Case Rep . 2017;4 (4):e005090. doi: 10.1099/JMMCR.0.005090 |
| IS19 | Seelen M, van den Wijngaard IR, Rundervoort RS. Cerebral vasculitis and stroke due to Lyme neuroborreliosis: A favorable clinical outcome after early antibiotic treatment. J Neurol Sci . 2017;375:165-166. doi: 10.1016/J.JNS.2017.01.067, |
| IS20 | Huys ACML, Lalive PH, Haller S. Meningoencephalitis with microinfarcts in early neuroborreliosis. Neuroradiology . 2016;58 (5):533-534. doi: 10.1007/S00234-016-1657-2/METRICS |
| IS21 | Birlutiu V, Birlutiu MR. Lyme Borreliosis as a Trigger of Dermatomyositis and Cerebral Thrombosis. Clinical Presentations of This Unusual Manifestation of Lyme Disease. Lyme Disease SMGroup . Published online January 30, 2016. |
| IS22 | Zajkowska J, Garkowski A, Moniuszko A, et al. Vasculitis and stroke due to Lyme neuroborreliosis - a review. Infect Dis. 2015;47 (1):1-6. doi: 10.3109/00365548.2014.961544, |
| IS23 | Wittwer B, Pelletier S, Ducrocq X, Maillard L, Mione G, Richard S. Cerebrovascular events in lyme neuroborreliosis. Journal of Stroke and Cerebrovascular Diseases . 2015;24 (7):1671-1678. doi: 10.1016/j.jstrokecerebrovasdis. 2015.03.056 |
| IS24 | Sokolov AA, Lienhard R, Du Pasquier R, Erard V. Acute Lyme neuroborreliosis with transient hemiparesis and aphasia. Ann Emerg Med . 2015;66 (1):60-64. doi: 10.1016/j.annemergmed. 2015.01.011 |
| IS25 | Li S, Vytopil M, Hreib K, Craven DE. Lyme disease presenting as multiple ischaemic strokes. Pract Neurol . 2015;15 (4):284-288. doi: 10.1136/PRACTNEUROL-2014-001072, |
| IS26 | Lenherr N, Walther K, Schneider J, Woerner A, Hess M. Neuroborreliosis-Associated Cerebral Vasculitis: An Uncommon Manifestation of Lyme Disease in a 9-Year-Old Boy. Glob Pediatr Health . 2015;2. doi: 10.1177/2333794X15601840 |
| IS27 | Kurian M, Pereira VM, Vargas MI, Fluss J. Stroke-like phenomena revealing multifocal cerebral vasculitis in pediatric lyme neuroborreliosis. J Child Neurol . 2015;30 (9):1226-1229. doi: 10.1177/0883073814552104, |
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Supplementary Table 8
Demographics and country of origin of reported cases
*n=the number of cases with positive criteria/N=number of cases reporting positive or negative criteria. † % is percentage of mentioned criteria. ‡ Adult: People who are 18 years of age or above. § Child: People who are below 18 years of age. IQR: interquartile range, USA: United States of America, UK: United Kingdom
| Demographics | |
| Child, n/N* (%) † | 28/90 (31%) |
| Age, child, median (range; IQR) | 12 (4-17; 9-14) |
| Adult, n/N (%) | 62/90 (69%) |
| Age, adult, median (range; IQR) | 52 (18-83; 39-60) |
| Male, n/N (%) | 48/90 (54%) |
| Reported Countries | |
| Germany, n/N* (%) † | 23/90 (25.6%) |
| USA, n/N (%) | 15/90 (16.7%) |
| France, n/N (%) | 8/90 (8.9%) |
| Switzerland, n/N (%) | 7/90 (7.8%) |
| Austria, n/N (%) | 6/90 (6.7%) |
| Netherlands, n/N (%) | 4/90 (4.4%) |
| Italy, n/N (%) | 4/90 (4.4%) |
| Finland, n/N (%) | 4/90 (4.4%) |
| Poland, n/N (%) | 4/90 (4.4%) |
| Belgium, n/N (%) | 3/90 (3.3%) |
| Croatia, n/N (%) | 2/90 (2.2%) |
| Sweden, n/N (%) | 2/90 (2.2%) |
| Norway, n/N (%) | 2/90 (2.2%) |
| Portugal, n/N (%) | 2/90 (2.2%) |
| Denmark, n/N (%) | 1/90 (1.1%) |
| Czech Republic, n/N (%) | 1/90 (1.1%) |
| Romania, n/N (%) | 1/90 (1.1%) |
| UK, n/N (%) | 1/90 (1.1%) |
Table 1
Comorbidities and exposure risk, clinical symptoms or signs typical for neuroborreliosis
*n=the number of cases with positive criteria/N=the number of cases reporting positive or negative criteria. † % is the percentage of mentioned criteria. ‡ UMN signs: hyperreflexia, increased deep tendon reflexes, or positive Babinski sign. § Cerebellar signs: dysmetria, postural tremors, dysdiadokinesia, hand incoordination, cerebellar ataxia, or hemiballismus. || Cranial nerve palsies: involvement of CN V, VI, VII, VIII, IX, or X. ¶ Cognitive: altered or fluctuating mental status, confusion, memory impairment, mental slowing, learning difficulties, changes affecting attention, behavior, motivation, spatial orientation, and executive functions, psychomotor retardation, impaired execution of orders, hallucinations, or poor scholastic or work performance. **Ataxia: Cerebellar and/or peripheral. †† Paresthesia: numbness, tingling, pain in limbs. ‡‡ Visual disturbances: ptosis, diplopia or ophthalmoplegia, or papilledema/papillitis. §§ Meningeal signs: headache or with neck stiffness. IQR: Interquartile range, LMN: Lyme neuroborreliosis
| Comorbidities | |
| Hypertension, n/N* (%) † | 15/35 (43%) |
| Smoking, n/N (%) | 5/35 (14%) |
| Alcohol abuse, n/N (%) | 4/35 (11%) |
| Hypercoagulable states, n/N (%) | 4/35 (11%) |
| Diabetes mellitus, n/N (%) | 3/35 (9%) |
| Atrial fibrillation, n/N (%) | 3/35 (9%) |
| Exposure History | |
| Stay in endemic area, n/N (%) | 63/71 (89%) |
| History of tick bite present, n/N (%) | 32/63 (51%) |
| Clinical features | |
| Time of onset of earliest neurological symptoms, median (range; IQR) (days) | Less than a day (<1-730; 1–14) |
| Hemiparesis/diplegia/paraplegia, n/N (%) | 46/90 (51.1%) |
| Upper motor neuron signs ‡ , n/N (%) | 14/90 (15.6%) |
| Tetraplegia, n/N (%) | 5/90 (5.6%) |
| Locked in syndrome, n/N (%) | 2/90 (2.2%) |
| Ataxia**, n/N (%) | 21/90 (23%) |
| Cerebellar signs § , n/N (%) | 10/90 (11%) |
| Paraesthesia †† , n/N (%) | 15/90 (17%) |
| Cognitive impairment ¶ , n/N (%) | 24/90 (27%) |
| Aphasia, n/N (%) | 12/90 (13%) |
| Dysphagia, n/N (%) | 6/90 (7%) |
| Dysarthria, n/N (%) | 17/90 (19%) |
| Vertigo, n/N (%) | 4/90 (4%) |
| Nystagmus, n/N (%) | 11/90 (12%) |
| Visual symptoms ‡‡ , n/N (%) | 15/90 (17%) |
| Ptosis, n/N (%) | 3/90 (3%) |
| Diplopia, n/N (%) | 6/90 (7%) |
| Papilledema, n/N (%) | 3/90 (4%) |
| Cranial nerve palsies || , n/N (%) | 34/90 (38%) |
| LMN Facial paralysis, n/N (%) | 28/90 (31%) |
| Seizures, n/N (%) | 8/90 (9%) |
| Meningeal signs §§ , n/N (%) | 6/90 (7%) |
Table 2
Final diagnoses with radiological confirmation and anatomical correlation
*n=the number of cases with positive criteria/N=the number of cases reporting positive or negative criteria. † % is the percentage of mentioned criteria. ACA: Anterior cerebral artery, MCA: Middle cerebral artery, PCA: Posterior cerebral artery
| Final diagnoses | |
| Vasculitis, n/N* (%) † | 64/89 (71.9%) |
| Stroke (ischemic), n/N (%) | 45/89 (50.6%) |
| Stroke (hemorrhagic), n/N (%) | 5/89 (5.6%) |
| Aneurysm, n/N (%) | 6/89 (6.7%) |
| Cerebral venous sinus thrombosis, n/N (%) | 5/89 (5.6%) |
| Subarachnoid hemorrhage, n/N (%) | 6/89 (6.7%) |
| Intracranial hemorrhage, n/N (%) | 2/89 (2.2%) |
| Normal radiological findings, n/N (%) | 2/89 (2.2%) |
| Anatomical correlation | |
| Cerebral cortex, n/N (%) | 50/89 (56.2%) |
| Parietal lobe, n/N (%) | 15/89 (16.9%) |
| Temporal lobe, n/N (%) | 15/89 (16.9%) |
| Frontal lobe, n/N (%) | 10/89 (11.2%) |
| Occipital lobe, n/N (%) | 8/89 (9%) |
| Insular lobe, n/N (%) | 2/89 (2.2%) |
| Brainstem, n/N (%) | 26/89 (29.2%) |
| Midbrain, n/N (%) | 5/89 (5.6%) |
| Pons, n/N (%) | 13/89 (14.6%) |
| Medulla, n/N (%) | 8/89 (9%) |
| Deeper brain structures, n/N (%) | 40/89 (44.9%) |
| Basal Ganglia, n/N (%) | 21/89 (23.6%) |
| Internal capsule, n/N (%) | 7/89 (7.9%) |
| Thalamus, n/N (%) | 12/89 (13.5%) |
| Diencephalon, n/N (%) | 13/89 (14.6%) |
| Hypothalamus, n/N (%) | 1/89 (1.1%) |
| Cerebellar, n/N (%) | 2/89 (2.2%) |
| Diffuse or multiple vessel wall involvement, n/N (%) | 23/90 (25.6%) |
| ACA, n/N (%) | 19/90 (21.1%) |
| MCA, n/N (%) | 25/90 (27.8%) |
| PCA, n/N (%) | 11/90 (12.2%) |
| Vertebrobasilar involvement, n/N (%) | 27/90 (30%) |
| Circle of Willis, n/N (%) | 2/90 (2.2%) |
| Sinus involvement, n/N (%) | 5/90 (5.6%) |
| Superior sagittal sinus, n/N (%) | 2/5 (40%) |
| Transverse sinus, n/N (%) | 2/5 (40%) |
Table 3
Results: serological and cerebrospinal fluid analyses
*n=the number of cases meeting positive criteria/N=number of cases reporting positive or negative criterion. † % is the proportion of studies meeting the specified criterion among those that reported it. CSF: Cerebrospinal fluid, CXCL13: C-X-C motif chemokine ligand 13, IgG: Immunoglobulin G, IgM: Immunoglobulin M, IQR: Interquartile range, PCR: Polymerase chain reaction
| Serological analyses | |
| Presence of Bb-specific IgM antibodies confirmed, n/N* (%) † | 41/62 (66.1%) |
| • Only IgM present, n/N (%) | 25/62 (40.3%) |
| • Both IgM and IgG present, n/N (%) | 16/62 (25.8%) |
| Presence of Bb-specific IgG antibodies confirmed, n/N (%) | 54/74 (72.9%) |
| • Only IgG present, n/N (%) | 38/74 (51.4%) |
| • Both IgM and IgG present, n/N (%) | 16/74 (21.6%) |
| Presence of Bb-specific unspecified antibodies confirmed, n/N (%) | 12/75 (16%) |
| Bb DNA PCR positive, n/N (%) | 4/16 (25%) |
| Cerebrospinal fluid analyses | |
| Lymphocytic pleocytosis present, n/N (%) | 76/81 (93.8%) |
| Lymphocytic pleocytosis present, median (range; IQR) | 73 (3-1152; 28-220) |
| Low glucose levels present, n/N (%) | 25/52 (48.1%) |
| Low glucose levels present, median (range ; IQR) | 39 (11-90; 26-57) |
| Elevated CSF protein, n/N (%) | 52/73 (71%) |
| Elevated CSF protein, median (range; IQR) | 203 (58.4-6486; 113.2-393) |
| CSF Serology | |
| Presence of Bb specific IgM antibodies confirmed, n/N (%) | 45/51 (88.2%) |
| Presence of Bb specific IgG antibodies confirmed, n/N (%) | 60/63 (95.2%) |
| Presence of Bb specific antibodies, unspecified whether IgM or IgG, n/N | 7/90 |
| CSF: Serum Antibody index Ratio elevated | |
| • IgM specific, n/N (%) | 13/22 (59.1%) |
| • IgG specific, n/N (%) | 22/28 (78.6%) |
| Bb DNA PCR, n/N (%) | 6/20 (30%) |
| Oligoclonal bands present, n/N (%) | 29/33 (87.9%) |
| CXCL13 elevated, n/N (%) | 7/90 (8.2%) |
Table 4
Medical and surgical interventions
*n=the number of cases with positive criteria/N=the number of cases reporting positive or negative criteria. † % is the percentage of mentioned criteria. ACE: Acetylcholine esterase, IVIG: Intravenous immunoglobulin, LMWH: Low molecular weight heparin
| Antibiotics | |
| Cephalosporins, n/N* (%) † | 76/89 (85.4%) |
| • Ceftriaxone, n/N (%) | 68/89 (76.4%) |
| • Cefotaxime, n/N (%) | 6/89 (6.7%) |
| • Cefuroxime, n/N (%) | 1/89 (1.1%) |
| Penicillin, n/N (%) | 15/89 (16.9%) |
| • Bencylpenicillin, n/N (%) | 7/89 (7.9%) |
| • Amoxicillin, n/N (%) | 5/89 (5.6%) |
| • Penicillin G, n/N (%) | 2/89 (2.2%) |
| • Ampicillin, n/N (%) | 1/89 (1.1%) |
| Doxycycline, n/N (%) | 10/89 (11.2%) |
| Stroke prophylaxis, n/N (%) | 30/89 (33.3%) |
| • Antiplatelet medication, n/N (%) | 25/27 (92.6%) |
| • Aspirin, n/N (%) | 24/30 (80%) |
| • Clopidogrel/ticagrelor, n/N (%) | 4/30 (13.3%) |
| Nimodipine, n/N (%) | 6/30 (20%) |
| Statins, n/N (%) | 3/30 (10%) |
| ACE inhibitors, n/N (%) | 1/30 (3.3%) |
| Immunomodulatory, n/N (%) | 25/90 (27.8%) |
| • Corticosteroids, n/N (%) | 28/30 (93%) |
| • Cyclophosphamide, n/N (%) | 4/30 (10%) |
| • IVIG, n/N (%) | 1/30 (3.3%) |
| Anticoagulants (LMWH, warfarin, apixaban), n/N (%) | 10/90 (11.1%) |
| Antiepileptics (diazepam, phenytoin, carbamazepine, levetiracetam), n/N (%) | 6/90 (6.7%) |
| Acetazolamide, n/N (%) | 1/90 (1.1%) |
| Surgical management, n/N (%) | 12/90 (13.3%) |
| Decompressive craniectomy, n/N (%) | 2/12 (16.6%) |
| Hemicraniectomy | 1/12 (8.3%) |
| Local intra-arterial thrombolysis or spasmolysis, n/N (%) | 4/12 (33.3%) |
| Endovascular embolization of aneurysm, n/N (%) | 2/12 (16.6%) |
| Surgical stenting, n/N (%) | 2/12 (16.6%) |
| Surgical aneurysm clipping, n/N (%) | 1/12 (8.3%) |
Supplementary Table 9
Outcomes recorded analysing serological or neurological outcomes
*n=the number of cases with positive criteria/N=number of cases reporting positive or negative criteria. † % is percentage of mentioned criteria. IQR: interquartile range
| Serology (N=43) | |
| Time (months) of start of treatment to last follow up visit, median (range; IQR) | 4.5 (<1 – 24; 1.4-7.25) |
| Neurological (N=88) | |
| Time (months) of start of treatment to last follow up visit, median (range; IQR) | 6 (<1 – 60; 2-12) |
| Reduction in serological markers achieved, n/N* (%) † | 41/43 (95%) |
| Reduction in neurological signs or imaging improvement achieved, n/N (%) | 79/88 (89.8%) |
| Reduction in neurological signs achieved, n/N (%) | 66/88 (75%) |
| Reduction or stabilization of radiological signs achieved, n/N (%) | 35/88 (39.8%) |
| Death, n/N (%) | 4/88 (4.5%) |
| Persistent tetraplegia, n/N (%) | 3/88 (3.4%) |
Discussion
This study reviews case studies and case series to provide clinicians with a descriptive review of expectations in a patient with probable LNB. A scoping review was undertaken to systematically identify reported cases and explore the heterogenous range of data, which could tend to be prone to bias due to the reliance of the review on case reports and series.
This extracellular spirochete causes a persistent infection by deploying specific virulence factors. In the tick midgut, it expresses outer surface protein (Osp) A and OspB, responsible for colonization and midgut adhesion, respectively. Once the tick feeds, OspC, shielded by the tick salivary protein Salp15, allows the spirochete to evade host antibodies and dampens the requirement for Natural Killer (NK) cells and macrophages.[ 18 ] In the human host, it survives through various adaptations, such as complement inhibition, antigenic variation, and immunomodulatory surface proteins.
The translocation of B. burgdorferi across the blood-brain barrier is a rare event, but its migration into brain parenchyma and the surrounding extracellular matrix can be influenced by chronic inflammation. The neurotropic nature is linked to the OspC, encoded by the ospC gene. Among the thirty-five identified genotypes, types A, B, I, and K strains have been implicated in cerebrovascular inflammation.[ 19 , 20 ] The presence of antibodies against particular antigens (IgM against VlsE, p41, and OspC, or IgG against p100, vIsE, and p18) could predict probable cerebrovascular NB involvement.[ 21 ]
NB was first identified in the 1920s.[ 22 ] It is notifiable only in a few European countries, reflecting a surveillance gap. The individual manifestations of Lyme disease are not tracked, and neurological estimates rely on proportions rather than individual counts.[ 23 ] A bimodal pattern was observed in the age group of less than 20 years or between 40 and 60 years in 30% of the cases. This could be attributed to a likelihood of longer outdoor exposure and more extensive workup performed in younger age groups.
Although the review has noticed no predominance of a particular gender, previous population-based cohorts have noticed male adults with a higher incidence of presentations of Lyme disease and women appearing to be more prone to post-treatment Lyme disease syndrome.[ 24 , 25 ] This discrepancy may reflect a limitation of the review’s reliance on case reports, which might have skewed gender representation. Most cases in the review have an exposure to endemic areas, but a recent trend of declining or stable incidence during nation-wide surveillance reports could be linked to environmental changes, vector ecology, or public health interventions.[ 26 , 27 ]
Hypertension was a common comorbidity, reflecting a baseline prevalence rather than an additive burden. The lower representation of traditional stroke risk factors suggests the role of Bb in vascular inflammation. Comorbid conditions can play a role in the reporting of long-term symptoms and overall quality of life of Lyme disease patients and could be considered in the evaluation of these patients.[ 28 ] A lower subset of studies with this statistic proposes inclusion of complete vascular risk profiles in prospective studies to understand Borrelia- specific pathology from coincidental stroke mechanisms. The predominance of hemiparesis and other upper motor neuron signs over other symptoms supports the hypothesis of Lyme being a stroke mimic. The relative scarcity of meningeal signs is reflective of a vasculitic over meningoencephalitic pathophysiology.
This review identified three vascular findings: (I) ischemic outnumbered hemorrhagic lesions, highlighting a probable inflammatory over hypertensive nature; (II) although the process is predominantly arterial, cerebral venous sinus thromboses can occur; and (III) Borrelia-mediated vasculitis can possibly weaken arterial walls to cause aneurysms, intracranial, and subarachnoid hemorrhages. Existing literature mentions that imaging in NB has heterogenous results, and its role is mainly to exclude other diagnoses.[ 29 , 30 , 31 ] A quarter of the imaging reports showed concentric enhancement across multiple vascular beds, indicating a diffuse inflammatory arteriopathy rather than single-territory atherosclerosis. Brain biopsy was done in two cases, one of which suspected intracranial masses as the cause of stroke (IS10, IS54). Although invasive, it provided an accurate diagnosis of the inflammatory origin of lesions, describing them as “perivascular cuffing with lymphocytes.”
As per guidelines, initial diagnostic testing should include two-tiered serologic testing (enzyme-linked immunosorbent assay followed by confirmatory Western blot analysis), followed by lumbar puncture if indicated.[ 10 ] The review found varying patterns of serological findings, and CSF findings were relied upon for Borrelia infection interpretation. CSF analyses should focus on identifying lymphocytic pleocytosis, elevated protein concentration, and an elevated CSF-to-serum Borrelia -specific antibody index ratio (AR). Increased Bb-specific CSF: serum (IgG) AR reflects ongoing intrathecal antibody production during NB. It was noticed that the LNB CSF findings were like a tuberculous meningitis profile. Our findings could reflect how the diagnostic yield of PCR testing is limited. Serum PCR positivity was low (4/16), and CSF PCR positivity was only modestly higher (6/20), consistent with the fact of low sensitivity of B. burgdorferi in CSF via PCR.[ 13 , 14 ] This reinforces the need to interpret diagnostic tests in the context of clinical features and exposure. Elevated levels of neurofilament or CXCL13 in CSF were reported in seven cases, reflecting axonal loss typically corelated with neurodegenerative processes. This is consistent with findings from a trial, which supports the utility of serum neurofilament biomarker for acute-phase LNB.[ 32 , 33 ] Future studies can focus on validating similar biomarkers for early diagnosis.
A diagnosis of definite LNB requires the convergence of clinical features, exposure history, positive CSF results, and supportive serologic findings. During tick-endemic seasons (i.e. summer, when people do tend to do more outdoor activities), most clinicians should try to include a tick profile: anything an Ixodes tick can transmit (identifying for Borrelia , Anaplasma , Babesia , and Ehrlichia ).
Treatment typically has a prolonged course of antibiotics, with doxycycline or ceftriaxone being first-line options for central nervous system involvement. Clinicians prefer cephalosporins over doxycycline in most situations because of the historical belief of better blood–brain barrier penetration. If chosen, patients tend to be on doxycycline for a longer time compared to its penicillin counterpart.[ 34 ] However, recent studies have proven doxycycline to be safe and as effective as beta-lactams for children and adults.[ 35 , 36 ] Uncertainty in the use of drugs for secondary prevention of stroke was reflected in this study, with only one-third of the cases utilizing them. The IDSA guidelines do not endorse routine corticosteroid use as adjunctive therapy, and anticoagulants, antiepileptics, or acetazolamide were noticed to be used for supportive reasons.[ 10 ] Surgical interventions (endovascular approaches such as intra-arterial thrombolysis or stenting, aneurysm embolization or clipping) were utilized in about one in nine patients in the review. Selective cases with elevated intracranial pressure underwent decompressive craniectomy or hemicraniectomy. This could suggest earlier initiation of antibiotic treatment to prevent disease from progressing to requiring salvage surgical intervention. Although medical and interventional treatments are effective, no vaccine has yet been approved for the prevention of Lyme disease.[ 37 ] The Valneva–Pfizer “VLA15” is currently the only Lyme disease (LD) vaccine candidate in advanced clinical development (Phase III), with potential for better preventive control.
As neurological outcomes normalize later than serological markers, they may be followed up longer for assessing recovery. This was the trend observed in our review as well. The outcomes tend to be favorable in treated patients. Effective pathogen clearance is observed in almost all cases (90%), with either neurological or radiological improvement. The review suggests that vessel wall or parenchymal normalization could persist longer after functional recovery, with only 40% of cases achieving stable or reversed lesions. Atypical presentations of LNB are frequently subject to misdiagnosis and increased morbidity and mortality.[ 38 , 39 ] A case reported an adult who presented with tetraplegia within hours. CSF analyses confirmed NB, and they were started on antibiotics. Although respiratory and autonomic functions recovered, they remained tetraplegic (IS59).[ 40 ] Another patient was identified to have NB and received oral doxycycline, steroids, and cyclophosphamide for refractory vasculitis. Within 3 weeks, severe bi-hemispheric infarctions led to worsening cerebral edema with transtentorial and subfalcine herniation (IS35).[ 41 ] The patient had a prolonged onset of symptoms. Their condition worsened despite initiation of antibiotics, with further progression from stenosis to thrombosis of the basilar artery. Tetraplegia persisted with anarthria and dysphagia (IS1).[ 42 ] The patient had multiple comorbidities, was admitted intubated and on vasopressors, and remained ventilator-dependent despite antibiotic therapy. Life support was withdrawn as per family wishes (IS15).[ 43 ] Another patient had escalating cerebral edema despite antibiotics and decompressive craniectomy and did not survive (IS8).[ 44 ] This patient had worsening of cerebral arterial stenoses and occurrence of a subdural hemorrhage despite interventional efforts, resulting in death (IS67).[ 45 ]
Another interesting presentation of NB with cerebrovascular manifestations is Syndrome of Inappropriate Anti-Diuretic Hormone (SIADH). In this review, Chehrenama et al.[ 46 ] reported a case in which the patient developed SIADH during the progression of the disease. Evidence for this association is limited, with a few case reports describing hyponatremia in conjunction with positive CSF findings for NB. This underscores the need to consider rare infections, such as borreliosis, as a possible cause of the neuroendocrine manifestation. The application of standardized clinical guidelines in LNB is not universally straightforward due to significant heterogeneity among reported cases. In instances of inconclusive labs or imaging, clinicians may have to rely on individual judgment. Although a comparison of preceding non-neurological manifestations would have been valuable in identifying early clinical scenarios that warrant suspicion for NB, most reported cases in our review either presented primarily with neurological symptoms or did not provide sufficient detail on earlier systemic features. This limited the ability to characterize pre-neurological presentations. The reliance on case series limits the capacity to draw causal associations and is prone to reporting bias. Quality appraisal, while performed, could not be used to weigh studies, ranking low-quality reports the same as higher-quality ones. As a result, the findings should be interpreted as exploratory, owing to the study design’s constraints on performing advanced statistical analyses. Advanced imaging modalities have a limitation in identifying subtle or early-stage vascular involvement, particularly of those with a small caliber. Furthermore, there is a limited body of evidence supporting interventional approaches or adjunctive therapies. Despite a comprehensive search strategy, exclusion of studies in non-English languages or without available English translations could have limited the diversity of cases discussed.
Conclusions
LNB can present with diverse cerebrovascular manifestations, mainly ischemic stroke. Given its potential for misdiagnosis, key diagnostic clues are essential for recognizing LNB. A high index of clinical suspicion and routine incorporation of Lyme serology and CSF analysis are recommended in the work-up of unexplained cerebrovascular events in individuals from endemic areas. Timely diagnosis and appropriate antimicrobial therapy should be considered to prevent irreversible neurological deficits and morbidity. Novel modalities of management, such as interventional techniques, could reduce morbidity and prevent mortality in affected patients.
Author contributions
ASD: conceptualization; methodology; investigation; writing – review and editing. SS: conceptualization; methodology; data curation; formal analysis; investigation; writing – original draft (lead); writing – review and editing. GO: formal analysis; investigation; writing – original draft (supporting). JL: methodology; data curation; formal analysis; writing – original draft (supporting).
Conflicts of interest
There are no conflicts of interest.
Data availability statement
All the data used to perform this analysis is publicly available in the referenced articles. The rest of the material is available upon request.
Funding Statement
Nil.
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Associated Data
Data Availability Statement
All the data used to perform this analysis is publicly available in the referenced articles. The rest of the material is available upon request.