Lyme Neuroborreliosis With Acute Encephalopathy Despite Early Antibiotic Therapy: A Case Report

Introduction

Lyme disease is a tick-borne infection caused by spirochetes of the Borrelia burgdorferi sensu lato species complex (Bb), which includes 5 distinct species: B. afzelii, B. garinii, B. burgdorferi sensu stricto, B. spielmanii, and B. bavariensis [1]. The disease often presents initially with cutaneous findings in the form of erythema migrans [1] and can progress to Lyme neuroborreliosis (LNB) in up to 15% of untreated cases [2–4]. It has typically been classified into early (symptoms <6 months) and late (≥6 months) disease [5], although classification by the presence of central nervous system (CNS) disease may be more practical [6].

LNB commonly presents with cranial neuropathy (predominantly facial nerve involvement), meningitis, and polyradiculopathy [3,4]. It typically presents 4 to 6 weeks after tick exposure, although cases as early as 1 to 2 weeks have been documented [2,3]. In a Danish retrospective cohort study of 431 patients with confirmed LNB – defined as having a positive Bb cerebrospinal fluid (CSF): serum antibody index – painful radiculitis (65.9%), cranial nerve palsy (43.4%), and headache (28.3%) were the most frequently reported symptoms [3]. Typical CSF findings in LNB include lymphocytic pleocytosis and protein elevation. Measurement of Bb-specific antibodies in CSF is recommended and can be used to calculate a Bb CSF: serum antibody index; this measures the concentration of Lyme-specific immunoglobulin G (IgG) in the CSF as compared with in the serum [2,4]. An index greater than 1 is highly specific for LNB, but a negative test does not exclude LNB, and Bb-specific antibodies in CSF can particularly be negative in the first 6 weeks from initial exposure [2,4]. Detection of Borrelia species DNA in CSF with polymerase chain reaction (PCR) is low (5–17%) and should be used adjunctively [2].

Encephalitis is an uncommon complication of LNB, occurring in 3.3% to 9% of LNB cases [3,4,7]. A systematic review by Knudtzen et al identified 42 studies with 45 patients meeting strict criteria for LNB-associated encephalitis [7]. Symptoms included somnolence (n=10), comatose state (n=8), and personality changes (n=17). In a subgroup analysis of 1019 patients with LNB, the prevalence of encephalitis was 3.3%, with most cases presenting with typical LNB symptoms, such as cranial neuropathy. The Danish retrospective cohort noted encephalitis in 3.7% of patients [3]. In Lithuania, Radzišauskienė et al reported encephalitis in 9% of 103 LNB cases, with ataxia as the most prevalent symptom (7/9 cases). Predictors of encephalitis or myelitis in their study included fever over 38 °C and CSF pleocytosis of more than 300×106 cells/L [4]. A subtype of LNB leading to brainstem encephalitis has been described, with the most common signs and symptoms being gait disorder/ataxia (74%), headache (71%), fatigue (48%), muscle wasting (48%), brainstem signs (45%), pyramidal signs (35%), dizziness (16%), and paresthesias (16%). Symmetric pontomesencephalic lesions were present in 56% of cases, while basal/cervical perimedullary leptomeningeal enhancement, diencephalic, and/or basal ganglia lesions were noted in a minority of patients [8,9].

We present here a case of probable LNB complicated by acute encephalitis and facial nerve palsy despite treatment of periocular erythema migrans with doxycycline after a tick was found in the patient’s eye. Although tick infestation of conjunctivae and eyelids has been described [10–12], this is the first reported case of periocular erythema migrans progressing to probable LNB as a complication of tick attachment to the eyelid.

Case Report

An 84-year-old man with obstructive sleep apnea, atrial fibrillation, hypertension, hyperlipidemia, and benign prostatic hyperplasia presented with acute encephalopathy.

His symptoms started after he developed discomfort in his right eye while working on his motorcycle, leading to swelling, redness, and pain around the eye (Figure 1). Two days later, an ophthalmologic evaluation revealed a dead tick under his lower eyelid. He completed 10 days of doxycycline, with improvement in periorbital swelling and eye-related symptoms.

About 2 weeks after his ophthalmologic evaluation, he developed constipation, abdominal pain, poor appetite, and a 6-kg weight loss. Over the next 3 weeks, he exhibited agitation, fidgeting, visual and auditory hallucinations, interrupted sleep, appendicular ataxia affecting his gait, right eye ptosis, and difficulty closing the right eye, prompting hospitalization.

Further discussion with the family and patient revealed no history of vision changes, numbness, extremity weakness, or sensation changes; review of systems was also negative for fevers, chills, cough, congestion, nausea, vomiting, diarrhea, and rashes. The patient was generally very active and healthy at baseline, managing all of his own activities of daily living. He frequently worked outside with motor vehicles, and had been spending time tearing down an old house. Figure 2 further summarizes the timeline of the patient’s presentation.

Initial computed tomography (CT) of the head and neck was unremarkable. Magnetic resonance imaging (MRI) of the brain without contrast did not show any acute findings. Given clinical signs of right-sided facial nerve palsy, he was started on doxycycline, prednisone, and valacyclovir. This was done to treat for both the LNB and herpesviral infection as possible causes of his facial nerve palsy. However, his mental status and agitation worsened. Ceftriaxone was added to his regimen given concern for worsening LNB, and he was transferred to a tertiary care center.

On arrival, the patient was afebrile and hemodynamically stable. His examination was significant for diffuse abdominal tenderness on palpation. He was lethargic but followed simple and complex commands, with facial weakness affecting the entire right side of the face in a lower motor neuron pattern, but no other focal neurological signs were noted on examination. He was started on vancomycin, ampicillin, and acyclovir for coverage of bacterial meningitis and herpes encephalitis along with ceftriaxone and doxycycline, and the inpatient infectious diseases service was consulted.

Initial laboratory investigations showed a white blood cell count of 15.5×109/L, with a neutrophilic predominance; mild hyponatremia; normal glucose level; total bilirubin of 1.8 mg/dL with normal transaminases; and a normal venous shock panel. Lyme serologies via Western blot from day 38 were negative, with P41 IgM and IgG positive, P18 total antibody positive, but other targets negative.

Lumbar puncture showed a CSF nucleated cell count of 145/mcL and 163/mcL in tubes 1 and 4 (92% and 84% lymphocytes, respectively), protein level of 240 mg/dL (upper limit 50 mg/dL), and glucose level of 67 mg/dL. CSF bacterial cultures, a community-acquired meningitis PCR panel, Venereal Disease Research Laboratory test, and herpes simplex virus and varicella zoster virus PCR were negative. A CSF: serum antibody index was not performed; however, its absence does not exclude LNB as a diagnosis. Blood cultures, syphilis serologies, and HIV screening were also negative.

A repeat MRI of the brain with and without contrast showed abnormal enhancement of multiple cranial nerves, most pronounced along the right trigeminal and facial nerves. There were no signs of basal leptomeningeal enhancement, M-sign, or Tarsier sign (Figure 3). An electroencephalogram (EEG) was obtained and demonstrated mild diffuse slowing consistent with a generalized brain dysfunction. Repeat total Lyme serum antibodies were now positive on enzyme immunoassay, with Western blot IgM positive and IgG negative. CSF Lyme PCR was negative for B. burgdorferi sensu stricto, B. mayonii, and B. garinii/B. afzelii, which does not exclude LNB. Rocky Mountain spotted fever and West Nile virus serologies were negative. An autoimmune encephalitis panel of the CSF detected anti-glial fibrillary acidic protein (GFAP)-1 antibodies (titer 1: 64).

Based on this constellation of findings, the patient received a diagnosis of probable LNB with acute encephalitis and facial nerve palsy. In the absence of concern for bacterial meningitis or herpes encephalitis, and given strong clinical suspicion for LNB, targeted treatment was initiated. Due to lack of data showing superiority of ceftriaxone over doxycycline for LNB [13], the patient was placed on a 21-day course of oral doxycycline after initially receiving 2 daily doses of intravenous ceftriaxone.

The patient reached his mental baseline rapidly upon further treatment in the hospital. Given rapid improvement of his clinical status without immunomodulatory therapy, autoimmune encephalitis was considered unlikely despite the above CSF findings. He was discharged successfully on hospital day 7. After discharge, the patient continued to experience a persistent burning sensation in his chest, abdomen, and back, with overall slow but steady improvement. These findings were interpreted as neurological sequelae of his resolving LNB. These symptoms did not inhibit daily activities but persisted for about 6 months after discharge. He also underwent a physical therapy program in the outpatient setting, from which he was discharged after meeting therapy goals. On post-discharge evaluation by neurology about 3 months from discharge, he had intermittent burning in his chest but no further neurological sequelae, except decreased sensation to pinprick and temperature in his bilateral distal lower extremities, which was attributed to diabetic neuropathy. On discussion with the patient 6 months after discharge, he continued to have the intermittent chest burning and some lingering issues with his balance, but felt otherwise that he had mostly recovered in every other aspect.

Discussion

It remains important to consider LNB in the differential diagnosis of compatible neurological findings, even if initial testing is indeterminant and erythema migrans has been treated appropriately. Early diagnosis of LNB is challenging due to the possibility of negative Lyme serologies early in the course, as initially seen in our case. The Infectious Diseases Society of America (IDSA) recommends 2-tiered serum serology testing for acute Lyme disease diagnosis, with LNB diagnosis based on a combination of multiple factors, including the presence of neurological symptoms, positive Lyme serologies, and abnormal CSF analysis, which can include measurement of a Bb CSF: serum antibody index [3,14]. The European Federation of Neurological Societies (EFNS) criteria [5] for definite LNB include (1) neurological symptoms; (2) CSF pleocytosis; and (3) Bb-specific antibodies in CSF. Two criteria suffice for possible LNB. Notably, 67% of patients with LNB in the Danish cohort had negative Lyme antibodies in serum at diagnosis, highlighting the importance of CSF testing in early disease. Therefore, false-negative Lyme serologies can occur in LNB, in particular in the initial 3 weeks of the disease [2,3].

Importantly, Bb-specific antibodies in CSF were not measured in our case; therefore, we cannot calculate a Bb CSF: serum antibody index. CSF PCR for detection of Borrelia species DNA was also negative in our case. Imaging and EEG can support diagnosis. For example, in Knudtzen et al’s substudy, only 20.6% of encephalitis cases had concordant imaging findings, whereas 15 of 16 had EEGs with encephalitis findings [7]. The EEG in our case demonstrated mild diffuse slowing, which is nonspecific. In the review of LNB imaging by Lindland et al [15], the authors describe heterogenous imaging findings, with historical reports of Lyme encephalitis showing white matter lesions on MRI in 15% to 63% of cases. Imaging, therefore, serves primarily to exclude other etiologies when the diagnosis of LNB is being considered.

Based on the EFNS criteria, our case would be defined as possible LNB given that the presence of Bb-specific antibodies in the CSF was not tested; however, this testing is not required for diagnosis based on the American Academy of Neurology, American College of Rheumatology, or IDSA guidelines, and there are no internationally recognized guidelines for diagnosis of LNB [5,14]. Given the combination of findings, our case may most appropriately be classified as probable LNB. The patient developed initial cutaneous symptoms typical for erythema migrans associated with exposure to a tick. He subsequently developed symptoms consistent with typical LNB, namely facial nerve palsy, which can be associated with development of ptosis without concomitant oculomotor nerve palsy [16]. This preceded further development of encephalopathy, with lymphocytic pleocytosis of the CSF and development of positive Lyme serologies. His symptoms improved with repeat treatment with doxycycline, and no other explanatory diagnosis was identified. For these reasons, Lyme encephalitis remains the most likely diagnosis. Importantly, given his frequent outdoors activities, it is possible that the patient had previous tick exposures prior to the index presentation, although this would not explain the periocular findings. Tick bites to the head and neck region have been postulated to increase the risk of subsequent LNB, although this remains a rare complication [17].

The primary treatment for LNB is oral doxycycline or intravenous ceftriaxone, with intravenous cefotaxime and penicillin as alternatives. Treatment choice depends on symptom duration and severity, with ceftriaxone often preferred for CNS involvement [2,5]. Recommended treatment duration ranges from 14 to 21 days, with longer courses for late LNB [2,5]. Interestingly, LNB has been described to develop despite initial appropriate treatment, although the explanation for this has not been robustly evaluated [18–20]. Strle et al [21] described development of LNB in 8 of 828 patients with erythema migrans initially treated with doxycycline, highlighting that this is a rare but significant clinical outcome. Development of LNB despite initial erythema migrans treatment could be explained by early dissemination of Bb into the CNS with insufficient drug penetration early in the course, or due to intrinsic immune dysregulation, which may have also precipitated development of LNB in the first place. Prognosis of LNB is generally favorable, although residual symptoms such as paresis, cognitive deficits, and ataxia can persist in 12% to 59% of patients [3,7]. Most long-term studies on LNB report no significant impact on mortality or overall function [2]. Among patients with encephalitis in Knudtzen et al’s substudy, 32 of 45 experienced full or partial recovery at last follow-up a median of 12 months after hospital discharge [7].

The detection of anti-GFAP-1 antibodies in the present case raises questions about potential autoimmune mechanisms in LNB. While anti-NMDAR encephalitis, one type of autoimmune encephalitis, has been linked to LNB in 3 case reports [22], the significance of anti-GFAP-1 antibodies remains unclear. Anti-GFAP-1 autoimmune astrocytopathy, characterized by anti-GFAP-1 IgG in serum or CSF, typically presents as meningoencephalomyelitis (81% of cases) [23]. While elevated CSF GFAP-1 levels have been linked to CNS Lyme disease in some studies [24], recent research suggests no significant differences in CSF GFAP-1 between individuals with and without LNB [25]. In our case, the anti-GFAP-1 antibodies were considered to be incidental and unrelated to the clinical presentation, primarily based on the improvement of the patient’s symptoms without immunomodulatory therapy.

Conclusions

This case highlights an unusual presentation of probable LNB with facial nerve palsy and acute encephalopathy following removal of a tick from the eyelid. Progression of neurologic signs and symptoms after appropriately treated erythema migrans should prompt consideration of LNB and further targeted diagnostic work-up. Ultimately, positive Lyme serologies and CSF lymphocytic pleocytosis supported the diagnosis, and the patient improved with extended antibiotic therapy. The incidental detection of anti-GFAP-1 antibodies underscores that autoimmune markers may be present in CNS infections without pathogenic significance, a finding that warrants further investigation. The mechanisms leading to progression of LNB despite early treatment remain incompletely understood and merit additional study to inform strategies for prevention and early intervention.