Diagnostic Challenges of Lyme Neuroborreliosis in Inpatient Neurology: A Case Series

Abstract

Lyme disease is a multisystem disorder transmitted through the Ixodes tick and is most commonly diagnosed in northeastern and mid-Atlantic states, Wisconsin, and Minnesota, though its disease borders are expanding in the setting of climate change. Approximately 10%–15% of untreated Lyme disease cases will develop neurologic manifestations of Lyme neuroborreliosis (LNB). Due to varying presentations, LNB presents diagnostic challenges and is associated with a delay to treatment. We discuss three cases of LNB admitted to our referral center in a traditionally low-incidence state to highlight clinical pearls in LNB diagnosis. Three patients from low-incidence areas with prior diagnostic evaluations presented in August with neurologic manifestations of radiculoneuritis, cranial neuropathies, and/or lymphocytic meningitis. MRI findings included cranial nerve, nerve root, and leptomeningeal enhancement leading to broad differential diagnoses. Lumbar puncture demonstrated lymphocytic pleocytosis (range 85-753 cells/uL) and elevated protein (87-318 mg/dL). Each patient tested positive for Lyme on two-tiered serum testing and was diagnosed with LNB. All three cases were associated with a delay to health care presentation (mean 20 days) and a delay to diagnosis and treatment (mean 54 days) due to under-recognition and ongoing evaluation. With the geographic expansion of Lyme disease, increasing awareness of LNB manifestations and acquiring detailed travel histories in low-incidence areas is crucial to prompt delivery of care. Clinicians should be aware of two-tiered serum diagnostic requirements and use adjunctive studies such as lumbar puncture and MRI to eliminate other diagnoses. Treatment with an appropriate course of antibiotics leads to robust improvement in neurological symptoms.

Introduction

Lyme disease is a multisystem disorder caused by the transmission of a Borrelia spirochete through the Ixodes tick. Borrelia burgdorferi is the most common spirochete species responsible for Lyme disease in the United States while other species are more prominent in Europe. ¹ Diagnosis follows a bimodal age distribution in children and older adults with a slight male predominance and is most common during the summer months, though tick bites occur spring through fall during temperate climates. ¹ In the United States, Lyme disease is most prevalent in the northeastern and mid-Atlantic states, Wisconsin, and Minnesota (Figure 1). ¹ However, a recent review demonstrated that climate change has expanded favorable conditions for neurologic zoonotic diseases beyond their traditional borders, increasing the risk of disease in previously unaffected populations. ² Over the past decade, Lyme disease is increasingly seen in low-incidence states with larger proportions of diagnoses outside summer months.^1,3,4

Figure 1.

Centers for Disease Control and Prevention (CDC) Lyme disease surveillance maps. ¹ Lyme disease increased in incidence and geographically expanded from 2001 (a) to 2021 (b). 1 green dot = 1 case of Lyme disease as reported to the CDC. Blue state = high incidence state.

Approximately 10%–15% of patients with untreated Lyme disease will develop neurologic manifestations consistent with Lyme neuroborreliosis (LNB) weeks to months after initial exposure. ⁵ LNB most commonly manifests as facial nerve palsy in the United States, but can also present as a wide range of pathologies including subacute lymphocytic meningitis and/or radiculoneuritis leading to a broad differential diagnosis. ¹ Due to its diagnostic challenges, LNB is associated with a delay to treatment. ⁶ We present three cases of LNB presenting at a center in a low-incidence state in which time to diagnosis of LNB was delayed due to unique patient presentation and under-recognition. We use these cases to highlight clinical pearls regarding the diagnosis of LNB.

Case 1

A 62-year-old female from northwest Ohio presented in August with progressive meningismus, diplopia, left facial weakness, right arm paresthesias and weakness with 20-pound weight loss and hyponatremia. MRI brain with contrast at a local hospital during a prior admission was reported to be unremarkable. On arrival to our hospital 6 weeks after symptom onset, examination showed left eye ptosis, left eye abduction palsy, and left nasolabial flattening. She had mild weakness throughout her right upper extremity and proximal right lower extremity muscles. Reflexes were diminished throughout. Repeat MRI showed enhancement bilaterally within multiple cranial nerves and diffuse leptomeningeal enhancement along all spinal cord segments and cauda equina nerve roots (Figure 2). Two lumbar punctures 2 days apart revealed persistent lymphocytic pleocytosis (443, 753 cells/uL [0-5 cells/uL]) and elevated protein (296, 318 mg/dL [14-45 mg/dL]) with negative cytology. Given concern for malignancy, she underwent positron emission tomography (PET) scan which showed corresponding fluorodeoxyglucose uptake in areas of enhancement and was considered for nerve root biopsy. Several days into hospitalization, her serum Lyme enzyme immunoassay (EIA) resulted positive. Reflex Western Blot was positive for IgG; IgM was negative. Her CSF was positive for Lyme IgM and IgG (Table 1). Six days after initiating ceftriaxone, repeat MRI and CSF evaluation showed resolving enhancement (Figure 2) and improved pleocytosis (220 cells/uL). She later disclosed a preceding rash on her foot and tick exposure at her secondary property near West Virginia. Two weeks after completion of 4 weeks of ceftriaxone, her neurological deficits resolved except for intermittent paresthesias and fatigue.

Figure 2.

MRI brain and cervical spine images pre- and post-antibiotic treatment. Case 1 MRI brain pre- (a) and post-treatment (b) shows improvement in bilateral trigeminal nerve enhancement. Case 1 MRI cervical spine pre- (c) and post-treatment (d) shows resolving leptomeningeal enhancement.

Table 1.

Patient Clinical Presentations and Diagnostic Testing. CDC Criteria for a Positive Western Blot are the Presence of ≥2 bands for IgM or ≥5 bands for IgG in the serum or CSF. W = White Blood Cells (0-5 Cell/uL), P = Protein (14-45 mg/dL). Lyme serum and CSF Testing is Reported in Number of bands. LNB = Lyme Neuroborreliosis; EMG = electromyography; yo = Years-old; NW = Northwest; F = Female; EIA = Enzyme Immunoassay; IgM = Immunoglobulin M; IgG = Immunoglobulin G; IAC = Internal Auditory Canals; PET = Positron Emission Tomography; FDG = Fluorodeoxyglucose.

Case	Location	LNB Involvement	Serum Lyme Testing (bands)	CSF Lyme Testing Pre-treatment	MRI Results Pre-treatment	CSF Lyme Testing and MRI Results Post-treatment	EMG Results	Other Results	Time to Health care Contact	Time from Initial Contact to Treatment
Case 1 62 yo F	NW OH with property near WV	Cranial nerves Meningitis Radiculopathy	EIA positive Negative IgM (1) Positive IgG (6)	Initial W 443, P 296 IgG index 2.10 (.00-.61) Repeat pre-treatment W 753, P 318 Positive IgG (7) Positive IgM (4)	Enhancement of bilateral IAC, trigeminal and oculomotor nerves; diffuse leptomeningeal enhancement along cervical, thoracic, and lumbar spine, conus, and cauda equina	6 days post treatment CSF W 220, P 227 MRI Resolving trigeminal nerve and cord enhancement	Study of the right arm and leg showed C5 and C8-T1 radiculopathy	PET: FDG activity along the spinal cord corresponding to the leptomeningeal and nerve root enhancement seen on MRI	23 days	46 days
Case 2 55 yo F	Central OH	Meningitis Radiculopathy	EIA positive Positive IgM (3) Positive IgG (7)	W 85, P 134 Positive IgM (3) Positive IgG (9) IgG index 1.70 (.00-.61)	Smooth diffuse enhancement of the cauda equina nerve roots, punctate ischemic infarct of the left cerebellum	Not performed	Study of the right arm and leg was unremarkable but limited by pain	None	7 days	53 days
Case 3 51 yo F	SC with recent hike in upstate NY	Meningitis Radiculopathy	EIA positive Positive IgM (unavailable) Negative IgG (4)	Initial W 203, P 87 Repeat pre-treatment W 123, P 88	Cauda equina nerve root enhancement	Not performed	Study of the left arm and leg showed L2-L4 radiculopathy	None	30 days	62 days

Case 2

A 55-year-old female from central Ohio presented in August with progressive meningismus, lumbar back pain, paresthesias, and generalized weakness with 15-pound weight loss. She was previously evaluated at multiple emergency departments and treated for musculoskeletal pain and recurrent urinary tract infections without improvement. On arrival to our hospital 2 months after symptom onset, examination showed mild weakness in neck flexion and proximal upper and lower extremity muscles. Reflexes were brisk but symmetric throughout and attributed to her thin body habitus and generalized anxiety disorder. Further history revealed symptoms were preceded by an arthropod bite on her chest producing a circular erythematous rash, with a photograph consistent with erythema migrans. MRI of the lumbar spine showed smooth diffuse enhancement of the cauda equina nerve roots (Figure 3). CSF revealed lymphocytic pleocytosis (85 cells/uL) and elevated protein (134 mg/dL). Serum Lyme EIA was positive with reflex western blot resulting positive for IgM and IgG. CSF Lyme testing was positive for IgM and IgG (Table 1). She was diagnosed with LNB and finished 4 weeks of ceftriaxone, after which her symptoms completely resolved.

Figure 3.

MRI lumbar spine images. MRI lumbar spine pre- (a & c) and post-contrast (b & d) shows smooth diffuse enhancement of the cauda equina nerve roots in Case 2 and 3.

Case 3

A 51-year-old female from South Carolina presented in August with progressive left lower extremity weakness and numbness, back pain, and loss of bowel and bladder sensation. Symptoms were preceded by an erythematous rash on her left hip previously diagnosed as cellulitis. Workup during a prior hospitalization included MRI with cauda equina enhancement and CSF with lymphocytic pleocytosis (203 cells/uL) and elevated protein (87 mg/dL). She was diagnosed with autoimmune lumbosacral plexopathy and received high-dose intravenous methylprednisolone for 5 days without improvement. On arrival to our hospital 2 months after symptom onset, examination showed mild weakness in left finger abduction, hip flexion and thigh adduction, reduction of vibration and pinprick sensation in left L4-L5 distribution, saddle hypoesthesia to pinprick over left buttock, and absent left patellar reflex. Repeat CSF testing and MRI re-demonstrated previous findings (Table 1, Figure 3). Due to ongoing suspicion for an inflammatory or autoimmune process, she received three days of high-dose intravenous methylprednisolone with improvement in sensation and was discharged on a steroid taper. During follow-up locally, she disclosed onset of rash during a hiking trip in New York. She was then diagnosed with Lyme disease after testing positive for Lyme on serum EIA followed by IgM on reflex western blot and was treated with three months of oral doxycycline per her primary care physician, which completely resolved her symptoms.

Discussion

LNB remains a diagnostic challenge due to its various presentations. We describe three cases of LNB presenting with polyradiculoneuritis as well as variable additional findings such as cranial neuritis in Case 1 and systemic symptoms including weight loss, fatigue, and pain. According to the 2020 multidisciplinary Infectious Disease Society of America, American Academy of Neurology, and American College of Rheumatology Lyme Disease guidelines, patients with a possible tick exposure presenting with meningitis, radiculoneuritis, mononeuropathy multiplex, cranial neuropathies, encephalitis, and/or myelitis should be tested for LNB. ⁷ Erythema migrans is not essential for diagnosis as the rash can vary and be inconspicuous (ie, difficult to identify on various skin tones) and likely resolved by time of presentation.^8,9 Our three cases demonstrated that patients may have difficulty remembering travel history, arthropod bites, and/or rashes on initial presentation.

Two-tiered serum antibody testing, in which an EIA or indirect fluorescent antibody test is followed by IgM and/or IgG immunoblots in the standard protocol or two different EIAs are performed sequentially in the modified protocol, is the most sensitive and specific diagnostic testing.^7,10 IgM immunoblots are used for early diagnosis as it takes 1-2 months for IgG response to develop. ¹⁰ If CSF testing is pursued, serum should also be collected to calculate CSF to serum antibody index as this is a highly specific marker of intrathecal antibody production against B. burgdorferi. CSF antibody testing alone and CSF immunoblots are unreliable and not standardized,^7,10 though they are commonly ordered as demonstrated in our cases. Active central nervous system LNB is also usually associated with lymphocytic pleocytosis, which can be monitored for treatment efficacy. ⁷

Imaging findings supportive of LNB include meningeal, leptomeningeal, or neural enhancement though prevalence of these findings varies.^11-13 A prospective cohort study of 368 Danish patients with LNB showed only 12%–14% of MRIs demonstrated findings of LNB, ¹² but another prospective cohort study of 69 European LNB patients found 57% had cranial nerve enhancement. ¹³ Patients with longer duration of symptoms are more likely to have LNB findings on MRI, as in our cases. ¹² However, there is frequently lack of correlation between enhancement of cranial nerves or nerve roots and neurologic symptoms, which was also seen in our three cases.^5,13,14

Due to diagnostic challenges, LNB is commonly associated with delays to presentation and treatment. A retrospective cohort study in Denmark analyzing 431 patients over 20 years found a median delay of 20 days from neurological symptom debut to first hospital contact and a median delay of 24 days from symptom debut to treatment initiation. ⁶ Presentations outside of peak seasonal window and absence of rash are associated with longer delays.^6,15 Though our patients had similar times to health care contact (mean 20 days), their time to treatment was prolonged (mean 54 days). Longer treatment delays raise concern for under-recognition in low-incidence states.

Conclusion

We report three cases of LNB presenting in a low-incidence state in which under-recognition led to delays in diagnosis and treatment. With the geographic expansion of Lyme disease, increasing awareness of LNB manifestations and acquiring detailed travel histories in low-incidence areas is crucial to prompt delivery of patient care.

ORCID iD

Kaitlyn N. Palmer https://orcid.org/0009-0007-9885-0597