Kolloori, Monika R. MD; Mejico, Luis J. MD; Corbo, Joseph MD, PhD; Sharma, Aseem MD; Ko, Melissa W. MD
Section Editor(s): Miller, Neil R. MD
Department of Medical Education (MRK), St. Joseph's Hospital and Health Center, Syracuse, New York
Departments of Neurology (LJM, MWK) and
Ophthalmology (LJM, MWK), Upstate Medical University, Syracuse, New York
Department of Pathology and Immunology (JC), Washington University School of Medicine, St Louis, Missouri
Mallinckrodt Institute of Radiology (AS), Washington University School of Medicine, St Louis, Missouri.
Address correspondence to Melissa W. Ko, MD, Upstate Medical University, Department of Neurology, 90 Presidential Plaza, Syracuse, NY 13202; E-mail: firstname.lastname@example.org
Supported by unrestricted grants from the Research to Prevent Blindness, Inc, New York, NY, and Lions District 20-Y1.
The authors report no conflict of interest.
A 62-year-old woman presented to a local emergency department with horizontal diplopia that she first noted upon awakening the previous day. She had experienced a mild headache the prior evening but was otherwise well and denied any constitutional symptoms, concurrent or recent illnesses, jaw claudication, or eye pain. She had a history of hypercholesterolemia. Physical examination revealed normal vital signs. The patient's visual acuity, intraocular pressures, and funduscopy were normal, and she had a mild abduction deficit of the left eye. Hematologic studies including complete blood count, metabolic panel, and sedimentation rate were normal. Noncontrast computed tomography (CT) of the head and magnetic resonance imaging (MRI) of the brain with and without contrast were performed.
Axial MRI with fluid-attenuated inversion recovery (FLAIR) technique demonstrates nonspecific hyperintense foci scattered in the white matter, without mass effect or loss of volume (Fig. 1). No enhancement or restricted diffusion was noted (scans not shown).
The patient was diagnosed with left sixth nerve palsy, most likely ischemic in origin. Six days later, her diplopia worsened, and she was referred for neuro-ophthalmic evaluation. Visual acuity, color vision, pupillary reactions, and visual fields were normal. She had no ptosis, and extraocular movements revealed a complete left abduction defect. Corneal and facial sensations were equal and normal bilaterally. Further testing was done, including C-reactive protein, reactive plasma regain, and Lyme titers.
Four days later, the patient developed left facial weakness consistent with a left seventh nerve palsy, and she was admitted to the hospital. Lumbar puncture demonstrated a cerebrospinal fluid (CSF) lymphocytic pleocytosis with an elevated protein concentration (Table 1, sample 1). Cytologic assessment revealed abundant atypical lymphocytes with plasmacytoid characteristics and mitotic figures. CSF electrophoresis was suspicious for a faint monoclonal band, but the sample was not viable for flow cytometry. Autoimmune panel and serological testing for fluorescent treponemal antibody absorption, cryptococcus, and herpes simplex virus were negative or gave normal results. Blood cultures were negative. Repeat brain MRI was unchanged, and magnetic resonance angiography was normal. The patient was given 1 gm of intravenous (IV) methylprednisolone for a possible inflammatory disorder of the central nervous system (CNS). The following evening, the enzyme-linked immunosorbent assay and Western blot IgM for Borrelia burgdorferi returned positive (2.81 Lyme Index Value and 41 and 23 kDa bands, respectively), with a negative IgG pattern. The patient was treated with 2 g of IV ceftriaxone and discharged home on 21 days of IV antibiotic therapy.
Three days following discharge from hospital, she underwent repeat lumbar puncture that demonstrated further increase in the CSF pleocytosis (Table 1, sample 2). Flow cytometry showed 84% T cells with a normal CD4:CD8 ratio and 11% B cells with a decreased kappa:lambda ratio of 0.4. Cytologic assessment of the CSF again was performed.
As in the first CSF sample, numerous atypical lymphocytes are present. The cells have plasmacytoid features including prominent juxtanuclear areas of clearing that correspond to the Golgi apparatus (Fig. 2A).
Immunoglobulin heavy chain polymerase chain reaction (PCR) of the CSF revealed a monoclonal band of approximately 240 base pairs using primers for the framework 2 region (Fig. 2B). Because these findings raised the concern of a B-cell lymphoma, the patient was referred to hematology-oncology, and a bone marrow biopsy was performed.
In contrast to the CSF samples, the bone marrow biopsy shows normal trilineage hematopoiesis without evidence of malignancy (Fig. 3).
On serum protein electrophoresis, a vague clonal band of similar size to that found in the patient's second CSF sample was detected (Fig. 4). CT of the neck, chest, abdomen, and pelvis revealed a thyroid nodule but were otherwise negative for malignancy. Ultrasound-guided biopsy of the thyroid nodule was not performed because of the nodule's close proximity to the patient's internal carotid artery.
With completion of a 3-week course of antibiotics, the patient's diplopia and left peripheral seventh nerve palsy improved, such that the treatment for a possible lymphoproliferative disorder was withheld. A third spinal tap performed 10 days following the completion of therapy revealed a reduced lymphocytic pleocytosis, small lymphocytes, and monocytes of normal appearance, with no evidence of malignancy (Table 1, sample 3).
Two months following the patient's initial presentation, the Western blot IgG returned positive (58, 45, 41, 39, and 23 kDa) for B. burgdorferi.
Neuroborreliosis associated with a reactive lymphocytosis mimicking CNS lymphoma.
Five months after presentation, the patient had complete clinical resolution of her left sixth and seventh nerve palsies. CSF analysis at this time was entirely normal (Table 1, sample 4).
Lyme disease is the most common tick-borne illness in Europe and North America (1). In North America, only 1 strain, B. burgdorferi sensu stricto, is recognized as pathogenic (2). Approximately 10%–15% of all B. burgdorferi infections progress to neuroborreliosis (3). Symptoms may include radiculopathy, cranial neuropathies, with the seventh cranial nerve most often affected, and mononeuropathy multiplex (3). Involvement of the nervous system may occur anywhere from 3 to 12 weeks following infection, often in the presence of the classic erythema migrans (EM). Additional findings including peripheral neuropathy, encephalopathy, or encephalomyelitis may develop later (4). The patient's MRI findings of nonspecific white matter FLAIR hyperintensity have been described in Lyme disease. Prior case reports have documented nonspecific demyelinating lesions with brain, nerve root, and spinal cord imaging that may be clinically asymptomatic (3,5 7).
The possibility of coexisting lymphoma with positive B. burgdorferi serology is an important diagnostic consideration. Of particular interest in our case was the possibility of malignancy versus infection raised by the patient's initial CSF and PCR findings. There are reports of neuroborreliosis mimicking lymphoma, but flow cytometric analyses were not performed in those cases (5,8). In neuroborreliosis, alteration of the blood-brain barrier allows for intrathecal antibody formation, which may appear as oligoclonal bands on PCR. Typical CSF findings in neuroborreliosis include elevated protein, normal glucose, and a lymphocytic pleocytosis (9). Cellular atypia suggestive of non-Hodgkin lymphoma may simply represent a lymphocytic response to antigenic stimulation by B. burgdorferi (5). In rare cases, B. burgdorferi causes a persistent antigenic stimulation that leads to malignant transformation of cells (10), although in our patient, the monoclonal B-cell expansion was self-limited. An association between Lyme disease and B-cell lymphoma may result from specific B-cell lymphocyte chemoattractants released in Borrelia infections. CXCL13, a B-cell chemoattractant, has been found to be increased in the CSF of neuroborreliosis patients (11). Upon exposure to Borrelia garinii antigen (a pathogenic European strain causing Lyme disease), monocytes release CXCL13, which may be a significant chemoattractant for B-cell migration to the CSF (12,13).
In distinguishing between neuroborreliosis and lymphoma, high-grade cellular atypia, monomorphism, and large numbers of lymphoid cells are characteristics of lymphoma, whereas polyclonality and elevated protein fractions are more likely because of infection (5). Utilizing these criteria, our patient's initial cytology and CSF analysis had components consistent with either diagnosis. A further confounding factor in our case was the use of methylprednisolone, leading to potential steroid suppression of lymphoma.
Our patient exhibited signs of monoclonality on PCR analysis of serum and CSF. Although the B-cell kappa:lambda ratio was abnormal, consistent with monoclonal expansion, the absolute number of B cells was small compared with the number of T lymphocytes. This monoclonality diminished in the patient's bone marrow 10 days following antibiotic administration. As a result, the final pathologic interpretation of these findings was one of the infections causing a reactive CSF lymphocytosis with transient monoclonal B-cells production. B-cell lymphocytosis with monoclonal or oligoclonal expansion in blood and bone marrow occurs in approximately 3.5% of individuals older than 40 years (14). There are no known clinical consequences if the following criteria are met: lack of cytopenias, lymphocytosis with monoclonal B cells of chronic lymphocytic leukemia phenotype (CD5+) numbering less than 5,000 per microliter, or lymphocytosis lasting less than a 3-month duration. However, it remains unclear if this lymphocytosis is a precursor to lymphoma (14).
Although our patient clearly had neuroborreliosis, initially she denied a history of EM or tick exposure. Although EM is the most common symptom reported in B. burgdorferi infection, it is found in only 60%–80% of all infections (6). Despite absent history of EM on initial visit, the patient's transient headache the night before symptom onset may have been significant. In 1 clinical trial, patients with sixth or seventh nerve palsies and neuroborreliosis reported pain including headache more often than patients with cranial neuropathies of other etiologies (15). Possible tick exposure in our patient became apparent when her husband recalled that she frequently cleared brush in a local state park, known to be endemic for Lyme disease. Her husband remembered that the patient had complained of a red rash 3 months before the initial presentation, but his description was not typical EM. During the year of the patient's illness, 50% of Lyme disease cases reported in her county of residence were within the patient's home ZIP code. The greatest number occurred during the month of the patient's presentation (Morrow C, personal communication, November 2010).
In summary, Lyme neuroborreliosis can simulate CNS lymphoma. Despite concern for neoplastic process, clinical and diagnostic abnormalities can completely resolve with appropriate antibiotic treatment for neuroborreliosis. The reasons for overlap between Lyme infection and CNS lymphoma may be purely coincidental or because of a common etiology. In clinical practice, given the distinctive treatment for each condition, thoroughly pursuing evaluation for both etiologies would be our recommended diagnostic approach.
The authors thank Barbara Henriquez, MD, and Robert Hutchinson, MD, for their assistance and preparation of the neuroimaging and histopathologic figures, respectively.
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