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An Unusual Cluster of Neuroinvasive Lyme Disease Cases Presenting With Bannwarth Syndrome in the Midwest United States

An Unusual Cluster of Neuroinvasive Lyme Disease Cases Presenting With Bannwarth Syndrome in the... Open Forum Infectious Diseases BRIEF REPORT weeks prior, the patient observed an erythema migrans (EM) An Unusual Cluster of Neuroinvasive rash, treated with 5  days of twice-daily doxycycline. CSF and Lyme Disease Cases Presenting With serum were submitted for LD serologic testing using the stand- Bannwarth Syndrome in the Midwest ard 2-tiered testing algorithm and interpretive criteria (applied to serum) [2]. LD antibody index (AI), comparing the level of United States anti-Bbsl IgG in CSF and serum for determination of patho- 1 1,2 1 3 3 Aditya Shah, John C. O’Horo, John W. Wilson, Dane Granger, and Elitza S. Theel gen-specific IgG intrathecal antibody synthesis, was also per- 1 2 Division of Infectious Diseases and Division of Pulmonary and Critical Care, Department 3 formed [3]. LD IgM immunoblot was positive in serum, IgM of Medicine, and Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota and IgG antibodies to B.  burgdorferi senso stricto (B.  burg- dorferi) were detected in CSF, and LD AI was elevated at 5.28 Bannwarth syndrome (BWS), an infrequent manifestation of (reference range, 0.6–1.29), which, alongside CSF lymphocytic neuroinvasive Lyme disease (LD) characterized by radiculop- pleocytosis (77 white blood cells [WBCs], 86% lymphocytes), athy, neuropathy, and lymphocytic pleocytosis, is more com- led to a diagnosis of LNB/BWS (Table  1). The patient demon- monly documented in Europe than North America. Here, we strated significant neurologic improvement following 4 weeks describe a cluster of 5 neuroinvasive LD cases with BWS in the of intravenous (IV) ceftriaxone. upper Midwest United States between July and August 2017. Keywords. Lyme disease; neuroborreliosis; Bannwarth syn- Patient 2 drome; neuroinvasive; Garin-Bujadoux-Bannwarth syndrome. A 62-year-old female presented with subacute onset of lower extremity weakness, progressing to flaccid paralysis over a 3-week period, alongside radiating low back and abdominal pain Garin-Bujadoux-Bannwarth syndrome (Bannwarth syndrome with associated numbness. A magnetic resonance image (MRI) [BWS]) is an uncommon manifestation of neuroinvasive Lyme of her spine showed diffuse inflammation of the cauda equina. disease (LD) caused by infection with members of Borrelia CSF analysis was remarkable for lymphocytic pleocytosis (363 burgdorferi sensu lato (Bbsl) complex and is more frequently WBCs, 74% lymphocytes), elevated protein (649  mg/dL), described in patients with Lyme disease in Europe as compared and a high LD AI of 40.2. A Borrelia spp. real-time polymerase with the United States [1]. BWS is characterized by painful chain reaction (RT-PCR) assay was positive for B.  burgdorferi radiculopathy, neuropathy, varying degrees of motor weakness in CSF (Table  1) [4]. The patient was diagnosed with LNB/ and facial nerve palsy, and cerebrospinal fluid (CSF) lympho- BWS and discharged on a 4-week course of IV ceftriaxone. The cytic pleocytosis. patient reported improved mobility, though she still required Over 3 weeks between July and August 2017, Mayo Clinic extensive assistance 2 months post-treatment. campuses in Minnesota and Wisconsin identified 6 patients Patient 3 from the upper Midwest with Lyme neuroborreliosis (LNB), 5 A 65-year-old female presented with subacute progressive presenting with BWS. Here, we present the findings of these 5 ascending weakness and lower extremity paresthesias. Brain patients. and spine MRI imaging were negative; however, CSF evaluation CASES demonstrated lymphocytic pleocystosis (46 WBCs, 92% lym- phocytes), elevated protein (113 mg/dL), and an LD AI of 2.49. Patient 1 The patient was positive for IgM and IgG antibodies to B. burg- A 61-year-old male with daily tick exposure presented with dorferi in serum, with both antibody classes also detected in progressive back pain, upper torso and extremity paresthesias, CSF (Table  1). The patient was diagnosed with LNB/BWS and right-sided facial droop, and blurry vision in the right eye. Four initiated on a 4-week course of IV ceftriaxone, and she reported significant improvement 2 weeks later. Received 14 November 2017; editorial decision 9 December 2017; accepted 20 December Patient 4 A 29-year-old male developed fever, myalgias, chills, headache, Open Forum Infectious Diseases © The Author(s) 2017. Published by Oxford University Press on behalf of Infectious Diseases fatigue, and a transient erythematous rash on his trunk in mid- Society of America. This is an Open Access article distributed under the terms of the Creative June 2017. Two weeks thereafter, he developed right foot drop, Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any Trendeleberg gait, lower extremity radiculopathy, and painful medium, provided the original work is not altered or transformed in any way, and that the work L5-S1 paresthesias. Over a 10-week period, he experienced con- is properly cited. For commercial re-use, please contact journals.permissions@oup.com DOI: 10.1093/ofid/ofx276 stitutional symptoms, including a 15-pound weight loss. MRI of BRIEF REPORT • OFID • 1 the lumbar spine showed nonspecific enhancement of the cauda equina roots. The patient was seropositive for both IgM and IgG to B.  burgdorferi; an LP was refused (Table  1). Based on clin- ical presentation, imaging studies, and seropositivity to B. burg- dorferi, the patient was diagnosed with LNB/BWS and initiated on IV ceftriaxone. At a 2-week follow-up, the patient indicated complete resolution of symptoms. Patient 5 A 69-year-old male presented with low-grade fevers, nausea, vomiting, diffuse arthralgias, headache, loss of smell, and blurry vision in the right eye. These symptoms were accompanied by neck and right upper extremity pain in a radicular pattern. The patient was seropositive for IgM and IgG antibodies to B. burgdorferi in serum, with both immunoglobulin classes also detected in CSF, which showed a lymphocytic pleocytosis (142 WBCs, 88% lymphocytes) (Table  1). An LD AI was not per- formed due to limited specimen volume. The patient’s constel- lation of symptoms, alongside CSF findings, led to a diagnosis of LNB/BWS, and IV ceftriaxone was initiated. Following com- pletion of treatment, the patient reported complete resolution of all symptoms. DISCUSSION LD is predominantly caused by 3 members of the B. burgdorferi sl complex: B. burgdorferi is responsible for the majority of cases in North America, whereas B. afzelii and B. garinii are predom- inant in Europe and Asia [5, 6]. Approximately 300 000 cases of LD are estimated annually in the United States [7]. LD can involve numerous organ systems, including the central nervous system (CNS), the peripheral nervous system (PNS), or both, with approximately 10% of untreated patients developing PNS involvement [5, 8]. While the clinical manifestations of LNB vary, the triad of painful radiculopathy, cranial neuropathy, and lymphocytic pleocytosis, often occurring in early-onset neuroinvasive LD, are encompassed by BWS [9]. Additionally, patients with LNB and BWS often experience paresis and show enhancement of the spinal nerve roots in the lower spinal cord and/or cauda equina on imaging [10]. While the precise inci- dence of BWS in the United States is unknown, literature sug- gests that LNB associated with BWS is more frequent in Europe, where it is primarily associated with B. garinii infections [1, 10]. In this brief communication, we report that among 6 patients with LNB identified over a 3-week period in 2017, 5 presented with PNS involvement (primarily axonal in nature) consistent with BWS. This is an unexpectedly high incidence at our facility as compared with prior years, in which 1 or 2 cases of LNB with BWS are typically suspected annually. All 5 patients presented with symptoms including upper or lower extremity radiculopathy and/or paresthesias. Typically, BWS is associated with limited radicular pain, as observed for 2 patients presented here. The more widespread peripheral neu- ropathy observed for the remaining 3 patients in this series is 2 • OFID • BRIEF REPORT Table 1. Patient Characteristics and Exposures CSF B. burgdorferi Serology Serum B. burgdorferi Serology Recalls Tick Bite/Other Tick CSF WBC/mcL, % CSF Glucose, CSF Protein, IgM Bands IgG Bands IgM Bands IgG Bands Borrelia spp. IgG e a b b a b b c Pt. No. Age/Sex Exposure?, State Lymphocytes mg/dL mg/dL C6 ELISA Detected Detected C6 ELISA Detected Detected Antibody Index 1 61/M Y/Y (MN) 77 (86%) 72 158 Pos 23 18, 41 Pos 23, 39, 41 18, 23, 41, 45 5.28 2 62/F Y/Y (IA) 363 (74%) 60 649 Pos 23, 39, 41 18, 23, 30, 39, 41, Pos 23, 39, 41 18, 23, 30, 41, 66, 93 40.2 45, 58, 66, 93 3 65/F N/Y (WI) 46 (92%) 50 113 Pos 23, 41 18, 23, 41 Pos 23, 39, 41 18, 23, 30, 39, 41, 2.49 45, 66 4 29/M Y/Y (MN) ND ND ND ND ND ND Pos 23, 39, 41 18, 23, 39, 41, 58, 93 ND 5 69/M Y/Y (MN) 142 (88%) 58 133 Pos 41 18, 23, 41 Pos 23, 29, 41 18, 23, 39, 41, 45 ND Abbreviations: ND, not done; Pos, positive. C6 B. burgdorferi (Lyme) ELISA (Immunetics, Marlborough, MA). Borrelia IgM and IgG ViraStripe Immunoblots (ViraMed Biotech AG, Planegg/Steinkerchen, Germany). Lyme IgG Antibody Index performed using the anti-B. burgdorferi sensu lato IgG ELISA (Euroimmun Inc., Mountain Lakes, NJ) in CSF and serum and calculated according to Reiber and Lange method. Reference range is 0.6–1.29, interpreted as “Negative” for species-specific antibody synthesis (3). Patient was positive for B. burgdorferi by RT-PCR in CSF (4). Reference range: 0–35 mg/dL somewhat atypical. Additionally, 2 patients developed visual is consistent with previous studies showing that the sensitivity disturbances and nerve root enhancement in the cauda equina of RT-PCR in CSF for Bbsl is low, with a median sensitivity of or lumbar spine, and 1 presented with Lyme disease–associ- 22.5% [12]. ated facial nerve palsy. Four patients underwent CSF collection CONCLUSIONS showing significant lymphocytic pleocytosis and high protein, We report 5 cases of LNB with BWS in the upper Midwest consistent with BWS. The absence of CSF evaluation for patient United States. While this suggests an increased incidence of this 4 is a limitation for definitive LNB classification, although his presentation in our region, BWS associated with LD is not cur- presentation with improvement following treatment strongly rently a reportable disease, and comparison with prior years is supports the presence of neuroinvasive disease. Importantly, 4 not possible. It remains prudent, however, for clinicians to be out of 5 patients showed rapid response to antimicrobials, as aware of this infrequent and possibly increasing clinical mani- expected with LNB. For the fifth patient, although symptomatic festation of LNB in the United States. The constellation of neu- improvement was noted, the prolonged symptoms may be a rological symptoms, particularly when associated with a recent result of a concomitant neurologic process, though an alterna- or suspected tick bite in an LD-endemic region, should prompt tive explanation has not yet been identified. clinical evaluation for LNB and assessment for BWS as this While definitive laboratory diagnostic criteria have been syndrome may be more common than previously presumed in well-established for non-neuroinvasive LD, diagnostic testing North America. guidelines are not as well defined for confirmation of LNB in the United States. Detection of IgM and/or IgG class antibodies Acknowledgments to B.  burgdorferi by immunoblot in CSF is oen p ft erformed, Potential conifl cts of interest. All authors: no reported conflicts of although there are no specific criteria established for interpre- interest. All authors have submitted the ICMJE Form for Disclosure of tation of banding patterns in CSF. Also, due to the possibility of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. passive immunoglobulin diffusion across the blood-CSF bar - rier or the presence of serum antibodies in CSF as a result of References a traumatic lumbar puncture, detection of antibodies to Bbsl 1. Murray TS, Shapiro ED. Lyme disease. Clin Lab Med 2010; 30:311–28. in CSF does not solely confirm intrathecal synthesis [8 ]. Anti- 2. CDC. Notice to readers: recommendations for test performance and interpre- tation from the Second National Conference on Serologic Diagnosis of Lyme Bbsl intrathecal antibody synthesis can be established by deter- Disease. MMWR 1995; 44:590–1. mining a pathogen-specific IgG AI. The AI is a ratio of the level 3. Reiber H, Lange P. Quantification of virus-specific antibodies in cerebrospinal fluid and serum: sensitive and specific detection of antibody synthesis in brain. of pathogen-specific IgG antibodies in CSF:serum following Clin Chem 1991; 37:1153–60. normalization for total IgG in both specimen sources. An AI 4. Babady NE, Sloan LM, Vetter EA, et  al. Percent positive rate of Lyme real-time polymerase chain reaction in blood, cerebrospinal fluid, synovial fluid, and tissue. ratio of ≥1.5 is considered indicative of true, pathogen-specific Diagn Microbiol Infect Dis 2008; 62:464–6. intrathecal antibody synthesis [3]. The diagnostic sensitivity 5. Stanek G, Wormser GP, Gray J, Strle F. Lyme borreliosis. Lancet 2012; 379:461–73. 6. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, of the LD AI is variable (range, 55%–100%), largely depend- and prevention of Lyme disease, human granulocytic anaplasmosis, and babesi- ent on the duration of symptoms prior to specimen collection osis: clinical practice guidelines by the Infectious Diseases Society of America. [11]. Importantly, although oer ff ed through a limited number Clin Infect Dis 2006; 43:1089–134. 7. Hinckley AF, Connally NP, Meek JI, et al. Lyme disease testing by large commer- of reference laboratories in the United States, determining an cial laboratories in the United States. Clin Infect Dis 2014; 59:676–81. LD AI is included in diagnostic and management guidelines 8. Halperin JJ. Nervous system Lyme disease. Clin Lab Med 2015; 35:779–95. 9. Ogrinc K, Lusa L, Lotrič-Furlan S, et al. Course and outcome of early European for neuroinvasive LD from both the Infectious Diseases Society lyme neuroborreliosis (Bannwarth Syndrome): clinical and laboratory findings. of America and the European Federation of Neurological Clin Infect Dis 2016; 63:346–53. 10. Hildenbrand P, Craven DE, Jones R, Nemeskal P. Lyme neuroborreliosis: man- Societies [6, 11]. In this case series, all 3 patients with sufficient ifestations of a rapidly emerging zoonosis. AJNR Am J Neuroradiol 2009; CSF for LD AI testing were positive, with AI ratios ranging 30:1079–87. 11. Mygland A, Ljostad U, Fingerle V, et al. EFNS guidelines on the diagnosis and man- from 2.49 to 40.2. Finally, while definitive evidence of neuroin- agement of European Lyme neuroborreliosis. Eur J Neurol 2010; 17:8–16, e1–4. vasive LD includes detection of Bbsl nucleic acid in CSF, only 1 12. Ružić-Sabljić E, Cerar T. Progress in the molecular diagnosis of Lyme disease. patient with LNB/BWS was RT-PCR positive in this series. This Expert Rev Mol Diagn 2017; 17:19–30. BRIEF REPORT • OFID • 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

An Unusual Cluster of Neuroinvasive Lyme Disease Cases Presenting With Bannwarth Syndrome in the Midwest United States

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Abstract

Open Forum Infectious Diseases BRIEF REPORT weeks prior, the patient observed an erythema migrans (EM) An Unusual Cluster of Neuroinvasive rash, treated with 5  days of twice-daily doxycycline. CSF and Lyme Disease Cases Presenting With serum were submitted for LD serologic testing using the stand- Bannwarth Syndrome in the Midwest ard 2-tiered testing algorithm and interpretive criteria (applied to serum) [2]. LD antibody index (AI), comparing the level of United States anti-Bbsl IgG in CSF and serum for determination of patho- 1 1,2 1 3 3 Aditya Shah, John C. O’Horo, John W. Wilson, Dane Granger, and Elitza S. Theel gen-specific IgG intrathecal antibody synthesis, was also per- 1 2 Division of Infectious Diseases and Division of Pulmonary and Critical Care, Department 3 formed [3]. LD IgM immunoblot was positive in serum, IgM of Medicine, and Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota and IgG antibodies to B.  burgdorferi senso stricto (B.  burg- dorferi) were detected in CSF, and LD AI was elevated at 5.28 Bannwarth syndrome (BWS), an infrequent manifestation of (reference range, 0.6–1.29), which, alongside CSF lymphocytic neuroinvasive Lyme disease (LD) characterized by radiculop- pleocytosis (77 white blood cells [WBCs], 86% lymphocytes), athy, neuropathy, and lymphocytic pleocytosis, is more com- led to a diagnosis of LNB/BWS (Table  1). The patient demon- monly documented in Europe than North America. Here, we strated significant neurologic improvement following 4 weeks describe a cluster of 5 neuroinvasive LD cases with BWS in the of intravenous (IV) ceftriaxone. upper Midwest United States between July and August 2017. Keywords. Lyme disease; neuroborreliosis; Bannwarth syn- Patient 2 drome; neuroinvasive; Garin-Bujadoux-Bannwarth syndrome. A 62-year-old female presented with subacute onset of lower extremity weakness, progressing to flaccid paralysis over a 3-week period, alongside radiating low back and abdominal pain Garin-Bujadoux-Bannwarth syndrome (Bannwarth syndrome with associated numbness. A magnetic resonance image (MRI) [BWS]) is an uncommon manifestation of neuroinvasive Lyme of her spine showed diffuse inflammation of the cauda equina. disease (LD) caused by infection with members of Borrelia CSF analysis was remarkable for lymphocytic pleocytosis (363 burgdorferi sensu lato (Bbsl) complex and is more frequently WBCs, 74% lymphocytes), elevated protein (649  mg/dL), described in patients with Lyme disease in Europe as compared and a high LD AI of 40.2. A Borrelia spp. real-time polymerase with the United States [1]. BWS is characterized by painful chain reaction (RT-PCR) assay was positive for B.  burgdorferi radiculopathy, neuropathy, varying degrees of motor weakness in CSF (Table  1) [4]. The patient was diagnosed with LNB/ and facial nerve palsy, and cerebrospinal fluid (CSF) lympho- BWS and discharged on a 4-week course of IV ceftriaxone. The cytic pleocytosis. patient reported improved mobility, though she still required Over 3 weeks between July and August 2017, Mayo Clinic extensive assistance 2 months post-treatment. campuses in Minnesota and Wisconsin identified 6 patients Patient 3 from the upper Midwest with Lyme neuroborreliosis (LNB), 5 A 65-year-old female presented with subacute progressive presenting with BWS. Here, we present the findings of these 5 ascending weakness and lower extremity paresthesias. Brain patients. and spine MRI imaging were negative; however, CSF evaluation CASES demonstrated lymphocytic pleocystosis (46 WBCs, 92% lym- phocytes), elevated protein (113 mg/dL), and an LD AI of 2.49. Patient 1 The patient was positive for IgM and IgG antibodies to B. burg- A 61-year-old male with daily tick exposure presented with dorferi in serum, with both antibody classes also detected in progressive back pain, upper torso and extremity paresthesias, CSF (Table  1). The patient was diagnosed with LNB/BWS and right-sided facial droop, and blurry vision in the right eye. Four initiated on a 4-week course of IV ceftriaxone, and she reported significant improvement 2 weeks later. Received 14 November 2017; editorial decision 9 December 2017; accepted 20 December Patient 4 A 29-year-old male developed fever, myalgias, chills, headache, Open Forum Infectious Diseases © The Author(s) 2017. Published by Oxford University Press on behalf of Infectious Diseases fatigue, and a transient erythematous rash on his trunk in mid- Society of America. This is an Open Access article distributed under the terms of the Creative June 2017. Two weeks thereafter, he developed right foot drop, Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any Trendeleberg gait, lower extremity radiculopathy, and painful medium, provided the original work is not altered or transformed in any way, and that the work L5-S1 paresthesias. Over a 10-week period, he experienced con- is properly cited. For commercial re-use, please contact journals.permissions@oup.com DOI: 10.1093/ofid/ofx276 stitutional symptoms, including a 15-pound weight loss. MRI of BRIEF REPORT • OFID • 1 the lumbar spine showed nonspecific enhancement of the cauda equina roots. The patient was seropositive for both IgM and IgG to B.  burgdorferi; an LP was refused (Table  1). Based on clin- ical presentation, imaging studies, and seropositivity to B. burg- dorferi, the patient was diagnosed with LNB/BWS and initiated on IV ceftriaxone. At a 2-week follow-up, the patient indicated complete resolution of symptoms. Patient 5 A 69-year-old male presented with low-grade fevers, nausea, vomiting, diffuse arthralgias, headache, loss of smell, and blurry vision in the right eye. These symptoms were accompanied by neck and right upper extremity pain in a radicular pattern. The patient was seropositive for IgM and IgG antibodies to B. burgdorferi in serum, with both immunoglobulin classes also detected in CSF, which showed a lymphocytic pleocytosis (142 WBCs, 88% lymphocytes) (Table  1). An LD AI was not per- formed due to limited specimen volume. The patient’s constel- lation of symptoms, alongside CSF findings, led to a diagnosis of LNB/BWS, and IV ceftriaxone was initiated. Following com- pletion of treatment, the patient reported complete resolution of all symptoms. DISCUSSION LD is predominantly caused by 3 members of the B. burgdorferi sl complex: B. burgdorferi is responsible for the majority of cases in North America, whereas B. afzelii and B. garinii are predom- inant in Europe and Asia [5, 6]. Approximately 300 000 cases of LD are estimated annually in the United States [7]. LD can involve numerous organ systems, including the central nervous system (CNS), the peripheral nervous system (PNS), or both, with approximately 10% of untreated patients developing PNS involvement [5, 8]. While the clinical manifestations of LNB vary, the triad of painful radiculopathy, cranial neuropathy, and lymphocytic pleocytosis, often occurring in early-onset neuroinvasive LD, are encompassed by BWS [9]. Additionally, patients with LNB and BWS often experience paresis and show enhancement of the spinal nerve roots in the lower spinal cord and/or cauda equina on imaging [10]. While the precise inci- dence of BWS in the United States is unknown, literature sug- gests that LNB associated with BWS is more frequent in Europe, where it is primarily associated with B. garinii infections [1, 10]. In this brief communication, we report that among 6 patients with LNB identified over a 3-week period in 2017, 5 presented with PNS involvement (primarily axonal in nature) consistent with BWS. This is an unexpectedly high incidence at our facility as compared with prior years, in which 1 or 2 cases of LNB with BWS are typically suspected annually. All 5 patients presented with symptoms including upper or lower extremity radiculopathy and/or paresthesias. Typically, BWS is associated with limited radicular pain, as observed for 2 patients presented here. The more widespread peripheral neu- ropathy observed for the remaining 3 patients in this series is 2 • OFID • BRIEF REPORT Table 1. Patient Characteristics and Exposures CSF B. burgdorferi Serology Serum B. burgdorferi Serology Recalls Tick Bite/Other Tick CSF WBC/mcL, % CSF Glucose, CSF Protein, IgM Bands IgG Bands IgM Bands IgG Bands Borrelia spp. IgG e a b b a b b c Pt. No. Age/Sex Exposure?, State Lymphocytes mg/dL mg/dL C6 ELISA Detected Detected C6 ELISA Detected Detected Antibody Index 1 61/M Y/Y (MN) 77 (86%) 72 158 Pos 23 18, 41 Pos 23, 39, 41 18, 23, 41, 45 5.28 2 62/F Y/Y (IA) 363 (74%) 60 649 Pos 23, 39, 41 18, 23, 30, 39, 41, Pos 23, 39, 41 18, 23, 30, 41, 66, 93 40.2 45, 58, 66, 93 3 65/F N/Y (WI) 46 (92%) 50 113 Pos 23, 41 18, 23, 41 Pos 23, 39, 41 18, 23, 30, 39, 41, 2.49 45, 66 4 29/M Y/Y (MN) ND ND ND ND ND ND Pos 23, 39, 41 18, 23, 39, 41, 58, 93 ND 5 69/M Y/Y (MN) 142 (88%) 58 133 Pos 41 18, 23, 41 Pos 23, 29, 41 18, 23, 39, 41, 45 ND Abbreviations: ND, not done; Pos, positive. C6 B. burgdorferi (Lyme) ELISA (Immunetics, Marlborough, MA). Borrelia IgM and IgG ViraStripe Immunoblots (ViraMed Biotech AG, Planegg/Steinkerchen, Germany). Lyme IgG Antibody Index performed using the anti-B. burgdorferi sensu lato IgG ELISA (Euroimmun Inc., Mountain Lakes, NJ) in CSF and serum and calculated according to Reiber and Lange method. Reference range is 0.6–1.29, interpreted as “Negative” for species-specific antibody synthesis (3). Patient was positive for B. burgdorferi by RT-PCR in CSF (4). Reference range: 0–35 mg/dL somewhat atypical. Additionally, 2 patients developed visual is consistent with previous studies showing that the sensitivity disturbances and nerve root enhancement in the cauda equina of RT-PCR in CSF for Bbsl is low, with a median sensitivity of or lumbar spine, and 1 presented with Lyme disease–associ- 22.5% [12]. ated facial nerve palsy. Four patients underwent CSF collection CONCLUSIONS showing significant lymphocytic pleocytosis and high protein, We report 5 cases of LNB with BWS in the upper Midwest consistent with BWS. The absence of CSF evaluation for patient United States. While this suggests an increased incidence of this 4 is a limitation for definitive LNB classification, although his presentation in our region, BWS associated with LD is not cur- presentation with improvement following treatment strongly rently a reportable disease, and comparison with prior years is supports the presence of neuroinvasive disease. Importantly, 4 not possible. It remains prudent, however, for clinicians to be out of 5 patients showed rapid response to antimicrobials, as aware of this infrequent and possibly increasing clinical mani- expected with LNB. For the fifth patient, although symptomatic festation of LNB in the United States. The constellation of neu- improvement was noted, the prolonged symptoms may be a rological symptoms, particularly when associated with a recent result of a concomitant neurologic process, though an alterna- or suspected tick bite in an LD-endemic region, should prompt tive explanation has not yet been identified. clinical evaluation for LNB and assessment for BWS as this While definitive laboratory diagnostic criteria have been syndrome may be more common than previously presumed in well-established for non-neuroinvasive LD, diagnostic testing North America. guidelines are not as well defined for confirmation of LNB in the United States. Detection of IgM and/or IgG class antibodies Acknowledgments to B.  burgdorferi by immunoblot in CSF is oen p ft erformed, Potential conifl cts of interest. All authors: no reported conflicts of although there are no specific criteria established for interpre- interest. All authors have submitted the ICMJE Form for Disclosure of tation of banding patterns in CSF. Also, due to the possibility of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. passive immunoglobulin diffusion across the blood-CSF bar - rier or the presence of serum antibodies in CSF as a result of References a traumatic lumbar puncture, detection of antibodies to Bbsl 1. Murray TS, Shapiro ED. Lyme disease. Clin Lab Med 2010; 30:311–28. in CSF does not solely confirm intrathecal synthesis [8 ]. Anti- 2. CDC. Notice to readers: recommendations for test performance and interpre- tation from the Second National Conference on Serologic Diagnosis of Lyme Bbsl intrathecal antibody synthesis can be established by deter- Disease. MMWR 1995; 44:590–1. mining a pathogen-specific IgG AI. The AI is a ratio of the level 3. Reiber H, Lange P. Quantification of virus-specific antibodies in cerebrospinal fluid and serum: sensitive and specific detection of antibody synthesis in brain. of pathogen-specific IgG antibodies in CSF:serum following Clin Chem 1991; 37:1153–60. normalization for total IgG in both specimen sources. An AI 4. Babady NE, Sloan LM, Vetter EA, et  al. Percent positive rate of Lyme real-time polymerase chain reaction in blood, cerebrospinal fluid, synovial fluid, and tissue. ratio of ≥1.5 is considered indicative of true, pathogen-specific Diagn Microbiol Infect Dis 2008; 62:464–6. intrathecal antibody synthesis [3]. The diagnostic sensitivity 5. Stanek G, Wormser GP, Gray J, Strle F. Lyme borreliosis. Lancet 2012; 379:461–73. 6. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, of the LD AI is variable (range, 55%–100%), largely depend- and prevention of Lyme disease, human granulocytic anaplasmosis, and babesi- ent on the duration of symptoms prior to specimen collection osis: clinical practice guidelines by the Infectious Diseases Society of America. [11]. Importantly, although oer ff ed through a limited number Clin Infect Dis 2006; 43:1089–134. 7. Hinckley AF, Connally NP, Meek JI, et al. Lyme disease testing by large commer- of reference laboratories in the United States, determining an cial laboratories in the United States. Clin Infect Dis 2014; 59:676–81. LD AI is included in diagnostic and management guidelines 8. Halperin JJ. Nervous system Lyme disease. Clin Lab Med 2015; 35:779–95. 9. Ogrinc K, Lusa L, Lotrič-Furlan S, et al. Course and outcome of early European for neuroinvasive LD from both the Infectious Diseases Society lyme neuroborreliosis (Bannwarth Syndrome): clinical and laboratory findings. of America and the European Federation of Neurological Clin Infect Dis 2016; 63:346–53. 10. Hildenbrand P, Craven DE, Jones R, Nemeskal P. Lyme neuroborreliosis: man- Societies [6, 11]. In this case series, all 3 patients with sufficient ifestations of a rapidly emerging zoonosis. AJNR Am J Neuroradiol 2009; CSF for LD AI testing were positive, with AI ratios ranging 30:1079–87. 11. Mygland A, Ljostad U, Fingerle V, et al. EFNS guidelines on the diagnosis and man- from 2.49 to 40.2. Finally, while definitive evidence of neuroin- agement of European Lyme neuroborreliosis. Eur J Neurol 2010; 17:8–16, e1–4. vasive LD includes detection of Bbsl nucleic acid in CSF, only 1 12. Ružić-Sabljić E, Cerar T. Progress in the molecular diagnosis of Lyme disease. patient with LNB/BWS was RT-PCR positive in this series. This Expert Rev Mol Diagn 2017; 17:19–30. BRIEF REPORT • OFID • 3

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Published: Dec 23, 2017

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