Lyme neuroborreliosis with encephalitis: A rare case

Encephalitis caused by Borrelia burgdorferi sensu lato is a rare clinical manifestation of Lyme neuroborreliosis and only in few cases have brain parenchymal inflammation been documented. Here, we present a case of Lyme neuroborreliosis with encephalitis with significant parenchymal inflammation on magnetic resonance imaging (MRI) in an immunosuppressed patient.


Background
Lyme neuroborreliosis (LNB) is a tick-borne neurological infection, caused by the spirochetes of the Borrelia burgdorferi sensu latu complex.
In Europe, LNB is among the most common bacterial neurological infections and mainly caused by B. garinii. In adults, typical nervous system manifestations include radiculoneuritis, cranial neuritis or lymphocytic meningitis. The combination of painful meningoradiculitis, peripheral motor paresis and spinal fluid inflammation is known as the Bannworth triad [1]. Diagnosis of definite LNB by criteria from the European Federation of Neurological Societies (EFNS) [2] requires 1) neurological symptoms compatible with LNB, 2) cerebrospinal fluid (CSF) pleocytosis, and 3) detection of intrathecal B. burgdorferi specific IgG and/or IgM antibody synthesis.
Probable or confirmed encephalitis, defined as altered mental state (major criterion) and ≥ 3 minor criteria including new onset of focal neurologic findings, CSF white blood cells (WBC) count ≥ 5/cubic mm and abnormality of brain parenchyma on neuroimaging [3,4], is a rare manifestation of LNB [5].

Case presentation
A 74 year-old woman with a history of systemic lupus erythematosus, myasthenia gravis (azathioprine and pyridostigmine treated), osteoporosis and atrial fibrillation was hospitalized four times within a period of three months from September to November. She had been admitted with confusion, paranoid delusions, a weight loss of 15 kg, back pains, history of fever and vomiting suspect of cancer and infection of unknown origin. During these admissions, she was treated with antibiotics for a urine tract infection. She underwent gastroscopy (normal), colonoscopy (showing diverticulosis and three benign polyps), computed tomography (CT) of the neck-thorax-abdomen and 18 F-fluorodeoxyglucose (FDG) PET/CT (which was normal except for a slightly enlarged spleen).
Previously, the patient was described with a high performance status, without any signs of dementia or known psychiatric diagnosis.
On the last admission in November, central nervous system (CNS) infection was suspected. Neurological examination disclosed disorientation, dysphasia, supranuclear signs with bilateral palmomental reflex, moderate vertical gaze paresis, significant postural tremor with superimposed intermittent myoclonus at the shoulders, elbow and fingers, universal mild hyperreflexia, and bilateral Babinski sign.
Brain MRI performed two days after admission showed symmetric FLAIR hyperintensities in basal gangliae, thalami, medial temporal lobes and mesencephalon without abnormal contrast enhancement (Fig. 1). EEG was without obvious abnormalities.
The patient reported no history of tick-bite, erythema migrans or painful meningoradiculitis. However, approximately three months prior the patient was efficiently treated for a non-itching universal skin rash with a topical steroid and antihistamines.
A diagnosis of LNB was confirmed by detection of a positive B. burgdorferi intrathecal antibody index of IgM (2.946) and IgG (2.058; IDEIA™ EIA Test -Oxoid). Serum B. burgdorferi IgG antibodies were also positive (125.8 AU/mL; LIAISON® DiaSorin CLIA-test). Neurosyphilis, Tick Borne Encephalitis, cryptococcus, Herpes Simplex Virus (HSV) and autoimmune encephalitis as well as several other viral and bacterial infections that can present as meningitis were ruled out (Table 1).
Benzylpenicilline and dexamethasone were discontinued after one and acyclovir after five days. Antibiotic treatment with high doses of ceftriaxone (4 g daily) was continued until acute bacterial meningitis could be ruled out and the patient was diagnosed with LNB. The patient received a total of 14 days of antibiotic therapy for LNB: seven days of intravenous ceftriaxone (4 g once daily) followed by seven days of oral doxycycline (200 mg b.i.d. for one day and then 100 mg b.i.d. the last six days) with good recovery.
At follow-up two weeks after completed antibiotic therapy for LNB the patient reported clinical improvement and a new lumbar puncture showed decreasing CSF pleocytosis (Table 1). At follow-up 2 months after the LNB diagnosis the patient still experienced cognitive problems such as memory loss. Mini Mental State Examination (MMSE) and Addenbrooke's Cognitive Test (ACE) were completed with 26/30 and 78/100 points, respectively. Follow-up brain MRI showed complete remission of previous hyperintensities in basal gangliae and thalamus. At 6 months follow-up, the patient had improved but still reported some memory problems (MMSE 29/30 points).

Discussion and conclusion
We describe a patient with definite LNB by EFNS criteria [2] and encephalitis (definite by international encephalitis consortium criteria (5). A recent Nordic systematic literature review and retrospective cohort study of LNB with encephalitis found a prevalence of encephalitis among LNB patients of 3.3 % (95 % confidence interval 2.2-4.4 %) and a yearly LNB encephalitis incidence of 0.93-1.35 cases/million inhabitants [5]. No specific pattern of brain or spinal cord involvement, like the characteristic involvement of temporal lobes and limbic system in HSV encephalitis, has been found in LNB encephalitis.
In this case, MRI showed hyperintensities in basal gangliae, thalami, medial temporal lobes and mesencephalon and hereby confirmed the diagnosis of encephalitis as the major and ≥ 3 minor criteria were fulfilled [4]. Our findings of significant parenchymal changes on MRI stands out in comparison to the aforementioned Nordic study [5], where varying CT and MRI changes were found in only 20.6 % of patients and were e.g. bilateral white matter changes, frontal left sided edema or vasculitis changes. The minor criteria of abnormal brain parenchyma on neuroimaging suggestive of encephalitis fulfilled here is not well characterized in other LNB cases with encephalitis described in the Nordic study [5]. However, similar MRI changes has been described in a Norwegian study [6].
The long disease course with uncharacteristic symptoms and subsequent diagnostic delay with lumbar puncture first performed three months after debut of symptoms emphasizes the importance of CSF examination in patients with unexplained CNS symptoms. The Nordic study found a median of 14 days from first neurological symptom onset to first hospital contact and from there an additional median of 7 days before initiation of antibiotic therapy. In this case we saw an expected decrease in CSF pleocytosis after intravenous antibiotic treatment and persistent high intrathecal B. burgdorferi antibody index as the latter often persists for years after successful antibiotic treatment and therefore cannot be used to monitor treatment efficacy [7,8]. Interestingly, the CSF glucose level was low at first CSF examination but normalized after antibiotic therapy. In the above mentioned Nordic study median CSF glucose was 3.1 mmol/L whereas a systematic review of LNB related cerebral vascular events reported a median CSF glucose of 1.7 mmol/L [5,9]. In the latter study median onset of symptoms to diagnosis was 3.5 months, similar to our case. Thus, duration of LNB might exacerbate hypoglycorrhachia as seen in other chronic CNS infections. Additional differential diagnoses must be considered in geriatric patients presenting with acute onset of confusion/altered mental status such as delirium, a wide range of infections (e.g. urinary tract infections, sepsis, pneumonia, CNS infections), stroke/transient cerebral ischemia, etc.
The patient was treated with azathioprine which affects both proliferating B-and T-cells resulting in broad immunosuppression. This could be a contributor to the widespread parenchymal changes seen on MRI and furthermore the atypical symptoms and signs including dysphasia, supranuclear signs, significant postural tremor and not classical signs of early stage LNB with radicular pains and/or peripheral paresis.
A limitation is that the patients was not tested for the presence of Borrelia miyamotoi. This tick-borne pathogen has recently been observed in Danish ticks [10] and can cause meningoencephalitis in immunocompromised patients [11]. In addition, patients infected with B. miyamotoi can be co-infected with Borrelia burgdorferi [12]. However, B.miyamotoi is also successfully treated with doxycycline.
In conclusion, we report the, to our knowledge, first case of confirmed LNB encephalitis with significant parenchymal MRI changes in a broadly immunosuppressed patient. Early diagnosis of this treatable infection is of great importance.

Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Ethical approval
The patient gave written consent for the publication of this case report.

Consent
The patient gave written consent for the publication of this case report.

Conflicts of interest
SBR, PR, CMS: none. AML: outside of the present work, AML reports unrestricted grants for Gilead, speakers honorarium/travel grants/ advisory board activity from Gilead/GSK and speakers honorarium/ advisory board activity from Pfizer.