Late Lyme neuroborreliosis with predominant myelitis in a patient with neuropsychiatric presentation: a case report

Introduction

Lyme disease is considered one of the most common vector-borne diseases in North America and Europe (1,2). Lyme neuroborreliosis (LNB) can develop gradually over many months or years, a condition known as late LNB. Diagnosing late LNB is particularly challenging, resulting in treatment delay and higher risk of sequelae. We present a rare case of a patient with predominant myelitis in LNB, who had a long course of the disease before diagnosis was made. We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-202/rc).

Case presentation

A 54-year-old female presented to the neurological ward of the Kantonsspital Münsterlingen, Switzerland with a 1.5-year history of multiple nonspecific symptoms. She was referred to the Kantonsspital Münsterlingen from the psychiatric clinic, where she had been admitted to for suspected somatic symptom disorder. Because of evident neurological symptoms our colleagues prompted further evaluation.

On admission, the patient reported persistent vertigo and dizziness for over 18 months. For approximately a year, she had been experiencing progressive gait instability and reported constant neck pain as well as a recurrent tremor in both upper limbs, worsening under stress. A cranial magnetic resonance imaging (MRI) was requested twice because of her complaints, the first scan 14 months and the second scan 2 months before hospitalization. Both contrast MRIs showed sporadic patchy fluid-attenuated inversion recovery (FLAIR)-hyperintense medullary lesions subcortically and periventricularly. The findings were assessed as unspecific and the scans otherwise unremarkable.

Additionally, she experienced intermittent urinary and fecal incontinence over the previous six months. The tremor in both hands had worsened and she had new muscle twitches in the legs. She also reported unintentional weight loss of 15 kg within a year.

Around the time of the psychiatric evaluation her father as well as her son were diagnosed with a psychotic disorder, which caused her a lot of personal struggles. This, combined with negative MRI results, led to her complaints being attributed to psychosomatic causes.

On examination the patient was fully oriented and afebrile. Cranial nerve examination was unremarkable. Upper limb function showed no paresis, sensory deficits, or spasticity. Muscle reflexes were symmetrical and not increased. She showed a symmetrical, but inconsistent tremor in both arms, which increased under excitement or stress.

Lower limb examination revealed no signs of paresis either. However, reflexes were significantly increased, showing clonus with left-sided dominance and bilateral Babinski sign. The patient showed trunk instability in the Romberg test with atactic broad-based gait.

A whole-spine MRI was performed. The images showed a longitudinal myelopathy with a dull hyperintense T2 signal alteration in the spinal cord, starting at the level of the mid thoracic spine and continuing down to the conus medullaris, with varying segmental emphasis (Figure 1). Axial images of the thoracic spine revealed mild bilateral symmetric circular foci of high T2-weighted signals in the anterior horn cells of the spinal cord known as Owl’s Eyes Sign (Figure 2).

Figure 1 Sagittal magnetic resonance image of the spine. The arrow is pointing to a linear non-enhancing hyperintense central T2 signal, stretching from the thoracic myelon to the conus medullaris. Images by the Department of Radiology, Spital Thurgau, Münsterlingen, Switzerland.

Figure 2 Axial magnetic resonance image of the spine. The arrow is showing high T2-weighted signals in the anterior horn cells of the spinal cord (Owl’s Eyes Sign). Images by the Department of Radiology, Spital Thurgau, Münsterlingen, Switzerland.

Sagittal T1-weighted images with contrast showed no distinct enhancement in the myelon itself, but slight leptomeningeal contrast enhancement around the myelon (Figure 3).

Figure 3 A mild leptomeningeal contrast enhancement around the myelon on sagittal T1-weighted images with contrast (shown by the arrows). Images by the Department of Radiology, Spital Thurgau, Münsterlingen, Switzerland.

General laboratory investigations were normal, including complete blood cell count, electrolytes, inflammatory markers, liver enzymes and kidney function. Cerebrospinal fluid (CSF) showed a mononuclear pleocytosis (349/µL; reference range: <4/µL) with low glucose levels (1.3 mmol/L; reference range: 2.4–4.2 mmol/L) and high lactate (4.2 mmol/L; reference range: <1.9 mmol/L). Total protein was elevated (1,810 mg/L; reference range: 200–500 mg/L) with highly increased immunoglobulin G (IgG) levels (276 mg/L; reference range: <34 mg/L) and positive oligoclonal bands (19 bands). Culture showed no growth.

Results for tuberculosis (TB) [culture and polymerase chain reaction (PCR)], brucella, syphilis, tick-borne encephalitis (TBE), human immunodeficiency virus (HIV), human T-lymphotropic virus type 1 and 2 (HTLV1/2), herpes simplex virus (HSV), varicella-zoster virus (VZV), Epstein-Barr virus (EBV,) cytomegalovirus (CMV), enterovirus, West Nile virus (WNV), Zika virus (ZKV) and autoimmune diseases came back negative.

Testing for Borrelia burgdorferi antibodies was positive for IgG [enzyme-linked immunosorbent assay (ELISA)] in blood and CSF (Serion ELISA Classic, Virion Serion, Wetzlar, Germany), showing a clearly elevated antibody index of 5.37. Western blot (Borrelia Virachip, Viramed, Planegg, Germany) confirmed the positive ELISA (VIsE, OsP17, 45 kD). Borrelia-immunoglobulin M (IgM) was negative. The immunoglobulin response in CSF showed an intrathecal production of IgG (Reiber diagram) and a combined three-class reaction of IgG, immunoglobulin A (IgA) and IgM confirmed by isoelectric focusing (IEF). In addition, the B-cell chemokine CXCL13 was highly elevated (>487 pg/mL; reference range: <20 pg/mL), indicating active inflammation in the CSF.

Based on clinical findings and laboratory results, the diagnosis of late LNB with predominant myelitis was made. The patient did not remember a previous tick bite or typical skin lesions. She had never been tested or received treatment for suspected Lyme disease before. We treated her with intravenous ceftriaxone 2 g/day for 4 weeks, which led to clinical improvement, but not complete symptom resolution. Follow-up lumbar puncture 6 months post-treatment showed a significant decline of mononuclear pleocytosis (12/µL versus 349/µL), total protein (468 versus 1,810 mg/L), and IgG levels (38.8 versus 276 mg/L). The chemokine CXCL13 came back negative (<20 versus >487 pg/mL). However, MRI images of the spine 6 months after treatment revealed unchanged hyperintense T2 signal alterations in the grey matter.

Fifteen months after treatment and intensive physiotherapy, the patient is still suffering from fatigue, has gait disorders and is requiring walking aids.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

We present the case of a late LNB with predominant spinal affection.

Lyme disease is considered one of the most common vector-borne diseases in North America and Europe (1,2). There is some variability in the clinical presentation of Lyme disease between Europe and North America, explained by the different Borrelia-species causing the disease (1,3). In Europe, the frequency of neurological involvement seems higher, attributed to Borrelia garinii (4). LNB is reported in 10–23% of cases in Europe (1,2,5). Most patients present early (94–97%), a few weeks after presumed preceding event, showing polyradiculitis (Bannwarth syndrome) as the most common initial neurological syndrome in Europe, followed by peripheral facial palsy and lymphocytic meningitis (2,6).

Late LNB, defined as laboratory confirmed disease activity for more than 6 months, probably accounts for less than 3% of LNB cases (2,5). The term late LNB must be distinguished from so-called chronic neuroborreliosis or post-treatment Lyme disease syndrome (PTLDS), concepts of chronic subjective complaints associated with Lyme disease that cannot be proven using accepted diagnostic methods and are surrounded by controversy (5).

Central nervous system involvement, like encephalitis and myelitis (very rarely stroke, cerebral vasculitis or hemorrhage), accounts for 4–12% of reported LNB cases (1-3,5-7).

Myelitis can present in early or late LNB, most often together with signs of encephalitis and very rarely isolated (2,3). Kaiser et al. found 24 cases of transverse myelitis due to LNB in a literature search in 2019, 16 reports from Europe and only 6 from the US (3). Radzišauskienė et al. reported three cases of myelitis, one in late LNB and two in early LNB, one of which did not show encephalitis (2). The same authors identified fever of ≥38 ℃ and pleocytosis of ≥300×10⁶/L as predictors for encephalitis and/or myelitis in early LNB.

Findings in spinal MRI in patients with myelitis are heterogeneous and not specific (2,8,9). MRI shows segmental or longitudinal extensive spinal involvement in cervical or upper thoracic spinal cord, presenting as transverse myelitis or with localized non-enhancing T2 lesions (2,8,9). The findings suggest that LNB myelitis does not have a strong predilection to a specific part of the spinal cord (2,8-10).

Differential diagnosis of myelopathy is broad and includes non-infectious causes like spinal cord compression, vascular insult, demyelinating processes, sarcoidosis or malignancies and a variety of infectious agents, e.g., herpes-, flavi-, picornaviruses, HIV, HTLV, syphilis, TB, brucella, parasites like schistosomiasis or fungi, etc. (3,9,10).

The patient’s CSF changes were significant and characteristic for LNB. In addition to the mononuclear pleocytosis and elevated total protein, CSF displayed a very low glucose level, as repeatedly demonstrated in LNB, which excludes most immune-mediated myelopathies (3,11,12). According to the guidelines of the European Federation of Neurological Societies (EFNS), the diagnosis of LNB is based on clinical symptoms, inflammatory changes in the CSF (lympho-monocytic pleocytosis, disruption of the blood-CSF barrier) and intrathecal immunoglobulin synthesis, e.g., Borrelia-specific IgG and IgM confirmed by Western blot. Normal CSF is mostly seen in very early stages of the disease (2,7,13). But even in established disease, classical inflammation can be absent, as outlined in EFNS guidelines. Pleocytosis tends to be higher in encephalomyelitis and cerebral vasculitis (2). However, literature on this is mixed.

Intrathecal antibodies without CSF pleocytosis exclude active late neuroborreliosis and point to previous infection or blood-brain-barrier disruption (4). Once established, specific IgG and IgM persist for years and do not correlate with disease activity or treatment response (13). PCR for Borrelia burgdorferi in CSF may be a complementary tool, but positivity rate is low (20%) (5).

The CXCL13 is a promising unspecific biomarker for the detection of intrathecal inflammation, especially in early LNB (5). CXCL13 is highly sensitive in spirochetal CNS infections and can be present in the CSF even before intrathecal antibody production. CXCL13 levels decrease significantly after antibiotic treatment, making it a possible marker for disease activity and treatment control (5,13). The chemokine, however, can also be present in other inflammatory and neurological disorders, making more studies necessary to standardize its use for diagnostic means (8,13). The initial CXCL13 level in our patient was remarkably high, well above established cutoff values for LNB, and declined to negative within 6 months after treatment.

Because of the broad spectrum and variability of symptoms, treatment delay and sequelae are common in patients with LNB. The longer it takes from symptom onset to the start of therapy, the greater the risk of residual symptoms (2,7). Every patient with aseptic encephalitis or myelitis in endemic areas should therefore be tested for LNB despite rarity of occurrence (2). Underdiagnosis of LNB is a relevant problem in patients with psychiatric history. In a study by Fallon et al. patients with neuropsychiatric symptoms reported signs of sickness for approximately one year and had to consult with a mean of two doctors prior to the diagnosis of LNB (14). On the other hand, there has been extensive media coverage about Lyme disease, which led to great concern about the disease, not only among the public but also among health professionals, resulting in overdiagnosis and unnecessary antimicrobial treatment (15).

The difficulty in diagnosing Lyme disease and the biased approach are evident in the presented case. More than 18 months had passed before the diagnosis of LNB was made. MRI images showed distinctive medullary findings. A longitudinal myelopathy starting at the level of the mid thoracic spine presented as “Owl’s Eyes Sign” on axial images. In contrast to the “H-sign”, which describes a hyperintensity in the anterior and posterior horns, the “Owl’s Eyes Sign” describes bilaterally symmetric circular to ovoid foci of high T2-weighted signals in the anterior horn cells of the spinal cord (16). While both signs can result from infectious myelitis, they are also observed in infarction and ultimately ischemia (16). In our case, the “Owl’s Eyes Sign” might suggest chronic ischemia because of vasculitis due to infection and may explain the patient’s persistent symptoms. Pathological examinations suggest that vasculitis is an important finding in central and peripheral nervous system involvement in LNB (1,17), but there are only a few cases that have been examined histologically (17). A combination of antimicrobial (or antiviral) therapy and corticosteroids has been tried in infectious myelopathies with suspected vasculitis with variable results (18).

MRI images acquired at the time of hospital admission showed mild leptomeningeal contrast enhancement around the myelon. This finding suggests that encephalitis was also present, which was not detected in previous images. It is likely that the patient’s history of neuropsychiatric symptoms was at least partly due to encephalitis.

Conclusions

Our patient showed predominant myelitis in LNB diagnosed late. She is a vivid example of the difficulties surrounding Lyme disease with its variability of symptoms in the context of pre-existing psychosomatic conditions and history of psychiatric disorders.

The case highlights the importance of a careful unbiased clinical approach combined with adequate and guideline-based diagnosis and treatment to prevent underdiagnosis as well as overtreatment of Lyme disease.

Acknowledgments

We sincerely thank Prof. Dr. Cornelia Brendle (Department of Radiology, Spital Thurgau, Münsterlingen, Switzerland) for assisting with MRI images selection.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-202/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-202/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-202/coif). S.M. has received payment for educational lectures in general practitioners’ quality circles and for educational lectures for medical doctors in other medical institutions, and has received financial support for attending the European Congress of Clinical Microbiology and Infectious Diseases 2023 and 2024 by Gilead Sciences. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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