Infectious Disease Reports 2014; volume 6:5496

A case of chronic progressive North America and Europe. Early LNB can cause lymphocytic ; involvement of Correspondence: Mohamed H. Yassin, University Lyme as a cranial and peripheral nerves is reported to of Pittsburgh Medical Center, Mercy Hospital, manifestation of late occur in 5-15% of untreated patients.2 Late 10550 Ermire Building, 1400 Locust Street, Lyme neuroborreliosis LNB, which is considerably rarer, can involve Pittsburgh, PA 15219, USA. brain/ parenchymal .2,3 Tel.: +1.412.232.7798 - Fax: +1.412.232.3292. E-mail: [email protected] Vivek Verma,1 Matthew Roman,1 There are important clinical consequences of these different species and their geographic Disha Shah,2 Marina Zaretskaya,2 Key words: Lyme neuroborreliosis, distributions, possibly as a result of differen- Mohamed H. Yassin1,3 burgdorferi, . tial species pathogenicity, as illustrated in one 1 2 Department of Medicine, Division 4 study. Neuroborreliosis is the most common Contributions: VV and MR analyzed data and of Neurology, 3Division of Infectious disseminated infection of in patient records, obtained references, prepared Diseases, University of Pittsburgh Europe, but is infrequently reported in the figures and table, and overall wrote the manu- Medical Center, PA, USA United States. Furthermore, even though all script; MZ and MHY supervised the aforemen- three aforementioned subspecies exist in tioned and took care of the patient in this case Europe, the same study notes that the North report in an inpatient and outpatient setting. American-predominant subspecies (B. Abstract burgdorferi sensu stricto) is responsible for Conflict of interests: the authors declare no only 8-11% of neuroborreliosis cases in potential conflict of interest. Europe.4 Thus, this could explain the fact that A 54-year-old female living in Europe pre- Received for publication: 21 July 2014. sented with gait , dizziness, and bilateral reports of neuroborreliosis reported in the US Revision received: 30 September 2014. hearing loss. Magnetic resonance imaging (particularly with encephalopathy, for Accepted for publication: 30 September 2014. (MRI) revealed non-specific white matter instance) are rare, especially in the adult pop- changes. The patient’s condition gradually ulation. As a result, optimal treatment regi- This work is licensed under a Creative Commons deteriorated over two years without diagnosis. mens of central (CNS) Attribution NonCommercial 3.0 License (CC BY- The patient continued to decline cognitively parenchymal neuroborreliosis are incomplete, NC 3.0). and neurologically with worsening ataxia and according to the American Academy of Neurology (AAN).3 The present case describes ©Copyright V. Verma et al., 2014 upper motor neuron signs. Repeat MRI showed Licensee PAGEPress, Italy worsening white matter changes. Lumbar a patient with chronic Lyme neuroborreliosis; Infectious Disease Reports 2014; 6:5496 puncture, not previously done, showed positive potentially adding much-needed evidence on doi:10.4081/idr.2014.5696 Lyme testing. Treatment with intravenous cef- effective management of this rare but serious disease. triaxone resulted in marked neurological tiform activity. Her workup was otherwise improvement. Four years after symptom, the unrevealing; it included complete blood count, patient has short-term memory deficits and basic metabolic panel, creatine phosphoki- chronic fatigue, but is otherwise neurological- Case Report nase, lactate, echocardiogram with bubble ly, cognitively, and functionally intact. Follow study, chest radiograph, vasculitis and hyper- up MRI findings remain largely unchanged. coagulable profiles. At that time, she was start- Because cases of intraparenchymal or A 54-year-old Caucasian female with past ed on aspirin 81 mg daily as well as levetirac- encephalopathic neuroborreliosis in America medical history of uncomplicated etam 250 mg twice daily. are lacking, so are treatment options. We pres- first noticed dizziness and ataxic gait in April The patient was then referred to our facility ent a rare case and discuss our experience 2009. The woman, American by nationality, for neurological evaluation. The patient report- with antibiotic treatment. This case lends evi- was living with her husband in the ed subjective generalized weakness/fatigue, dence to define optimal treatment of this dis- Netherlands at the time. Shortly thereafter, but denied any fevers, rash, joint pains, swal- ease, imperative for hastening neurological she developed bilateral hearing loss and recovery. noticed a 20-pound unintentional weight loss lowing difficulty, or visual problems. She had over the previous couple months. She was no family history of any neurological disorders. admitted to a hospital in the Netherlands, Her examination revealed slowed speech, where reportedly blood work, electroen- bilateral decrease in hearing, and bilateral Introduction cephalography (EEG), and echocardiogram non-sustained nystagmus on horizontal gaze. were normal. Magnetic resonance imaging She was alert and oriented times three, but Lyme neuroborreliosis (LNB) is an infec- (MRI) at the time apparently showed nonspe- had poor cognition and insight into her dis- tious disorder of the nervous system caused by cific white matter changes present over both ease history. Bilateral dysmetria, ataxic gait, tick-borne spirochetes of the Borrelia burgdor- cerebral hemispheres. The patient remained hyperreflexia with nonsustained clonus and feri sensu lato complex. It can commonly start relatively stable until her next episode that bilateral Babinski reflexes were also found on with a bull’s eye rash () and occurred in April 2011. A new, sudden-onset exam. Repeat brain MRI at our facility (Figure can systemically spread, causing arthritis, gait imbalance triggered further workup. 1) showed relatively unchanged scattered heart block, and effects in both the central and Though magnetic resonance angiography round-oval hyperintensities in the subcortical peripheral nervous systems.1 In Europe, LNB is (MRA) was normal, MRI was initially read as and periventricular white matter, as well as most often caused by B. garinii, less frequently being suspicious of an apparent small, acute cerebellum and pons. Spinal MRI did not show by B. afzelii, and rarely by B. burgdorferi sensu non-hemorrhagic in the left cerebellar any lesions. B12 level was low-normal at 242 stricto (which is predominantly in North peduncle as well as progressive white matter pg/mL (normal range 200-900), for which she America).2 Borrelia subspecies are thus changes (on a reviewed re-read, it was not was empirically started on weekly subcuta- responsible for significant differences in the read as a stroke). EEG showed sharp waves neous B12 injections (1000 mcg) to make sure clinical presentations of LNB observed in over the left temporal lobe but no foci of epilep- B12 levels did not drop and potentially com-

[Infectious Disease Reports 2014; 6:5496] [page 51] Case Report pound symptoms. Lumbar puncture (LP) done Table 1. Negative infectious disease workup in this patient. at that time revealed normal opening pressure 1 Herpes simplex virus-1 and -2 PCR, CSF with 200 white blood cells (65% monocytes, 35% neutrophils), zero red blood cells, low glu- 2 Epstein-Barr virus PCR, CSF cose level of 11 (serum level 107), and elevated 3 Cytomegalovirus PCR, CSF protein 324 mg/dl (normal range 15-45). 4 Mycobacterial stain and culture, CSF The patient was admitted to the hospital and 5 , CSF the infectious diseases service was consulted. 6 Cryptococcus antigen, CSF Repeat LP two days post-admission showed similar results (yellow-colored fluid, 229 white 7 Histoplasma antigen, urine blood cells (55% monocytes, 45% neutrophils), 8 HIV ELISA, serum 12 red blood cells, glucose 14, protein 290). 9 West Nile virus serology, CSF Autoimmune workup was negative for antinu- 10 Lymphocytic choriomeningitis virus serology, CSF clear antibody, antineutrophil cytoplasmic 11 Coxsackievirus serology panel, CSF antibody, rheumatoid factor; angiotensin-con- 12 Measles serology, CSF verting enzyme, aldolase, erythrocyte sedimen- tation rate, and C-reactive protein levels were 13 Mumps serology, CSF normal. Antibodies to cardiolipin, myeloperox- 14 St. Louis encephalitis serology, CSF idase-3, proteinase-3, Sjogren-A/B, and para- 15 Eastern/Western equine encephalitis serology, CSF neoplastic antibodies against neuronal nuclei 16 California encephalitis serology, CSF and Purkinje cells anti-neuronal nuclear anti- 17 Echovirus serology, CSF body (ANNA), and Purkinje cell cytoplasmic 18 Adenovirus serology, CSF antibody (PCCA) were negative. Infectious dis- eases workup that was negative is listed in 19 Influenza A/B antibody testing, nasopharyngeal swab Table 1. Screening (CSF) PCR, polymerase chain reaction; CSF, cerebrospinal fluid. enzyme-linked immunosorbent assay (ELISA) for Lyme disease was positive at 4.42 (refer- ence range <1.1). A confirmatory Western blot subsequently revealed positive bands at 18, 23, AB 41, and 58 kDa. Though antibodies were detected in the CSF, polymerase chain reaction (PCR) for Lyme DNA in CSF was negative times two. The overall CSF immunoglobulin (IgG) level was elevated to 65.6 (reference range 0.8 to 7.7), as was the IgG index (0.89, normal <0.6) with oligoclonal bands. CSF myelin basic protein was normal, however. All CSF cultures for bacteria (including mycobac- teria) and fungi remained negative. On review of these results, the patient was diagnosed with LNB. IV 2 g daily was administered via a peripherally inserted intra- venous catheter (PICC) for 28 days. The patient finished her course of ceftriaxone and followed up as outpatient with both Neurology and Infectious Diseases. After her antibiotic course, C D the patient noted complete resolution of her atax- ia, dizziness, hearing loss, and improvement of weakness/fatigue. Levetiracetam was stopped in March 2012. At the time of last follow-up (March 2013), almost four years after initial symptoms, the patient’s only reported symptoms were chron- ic fatigue (much improved relative to before antibiotics started), and some impairment in for- mation of short-term memories. On exam, she does display 0/3 word recall at five minutes, slight- ly decreased fine motor coordination, and is slightly hyperreflexic (albeit markedly less so compared to initial exam). Otherwise she remains neurologically, cognitively, and function- ally intact. Follow up brain MRI showed slight Figure 1. Fluid-attenuated inversion recovery - fast spin echo sequence images of the decrease in size of the pontine and cerebellar patient’s brain on initial presentation to our hospital. Lesions are present in the periven- peduncular lesions, but otherwise no changes tricular areas (A), white matter (A,B), pons (C, arrow), and middle cerebellar peduncle (Figure 2). (left>right, D).

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In this patient, the main distinction that differ from MS lesions that are largely around Discussion needed to be made was LNB versus MS. CSF/ventricular flow. Most importantly, the Though oligoclonal bands were present on CSF patient’s clinical status vastly and rapidly The present patient was probably infected analysis as well, it has been well established improved within weeks of IV antibiotic therapy with a European-specific species of Borrelia that this is an expected finding in LNB.6 The without any relapse or new symptoms at two (B. garinii or B. afzelii); although European in patient had a negative CSF myelin basic pro- year follow up.9 Chronically progressing neuro- origin, this case adds data to the overall data tein level, which is a relatively specific marker logical symptoms that disappeared without that is reported in the United States. Though for MS.7 Additionally, the CSF measles/mumps exacerbation after antibiotic use (no corticos- the causative agent was not specifically geno- antibody titer was not elevated, which is a reli- teroids or newer anti-inflammatory MS agents typed, it would not have changed clinical man- able indicator of differentiating LNB from were used) further points to LNB over MS. agement diagnostically nor therapeutically. MS.8,9 In our case CSF Lyme DNA PCR was neg- Overall, a salient point to glean from this clin- On radiological review, the main item on the ative, which is a common finding in chronic ical diagnostic process is that often in clinical differential diagnosis of the patient’s MRI neuroborreliosis; detection by PCR or CSF cul- medicine, some items on the differential diag- lesions, and certainly more common in North ture occurs in only 10-30% of patients.2,10 nosis can never be fully excluded (e.g. recur- America, included demyelinating conditions. Furthermore, radiologic findings in this rent or multiphasic disseminated Hence, (MS) should be at patient are not typical of MS lesions.11 The vast ), but based on a constella- the forefront of a differential diagnosis of sim- majority of MS cases have at least one tion of many diverse supporting factors (in ilar brain lesions, as should other infectious ovoid/round and well-demarcated lesion, and this patient, multiple laboratory tests, clinical causes (e.g., syphilis and other infectious periventricular lesions are often perpendicular picture, radiology, and treatment course), a causes in Table 1). Vitamin B12 deficiency and to the ventricles (Dawson’s fingers); this principal diagnosis can indeed be reached. autoimmune conditions such as systemic patient’s lesions were radiologically irregular Diagnosis in this patient was highly sus- lupus erythematosus are important to consid- with ragged borders and ill-defined margins. pected based the presence of intrathecal anti- er, as well as the rare but frequently missed Moreover, two prominent lesions in this Borrelia antibodies. In accordance with both acute disseminated encephalomyelitis.5 patient (in the cerebellar peduncle and pons) the European Federation of Neurological Societies and the AAN, the gold standard of LNB diagnosis involves intrathecal anti- Borrelia antibodies together with the clinical patient picture.9,12 Though serum Lyme serolo- ABgy was not checked due to initial suspicion for MS, both aforementioned guidelines endorse that clinically diagnosing LNB is essential. The patient’s rapid and relapse-free improvement for two years after IV ceftriaxone further sup- ports the diagnosis. Additionally, it was uncer- tain why hypoglycorrhachia was present, which is atypical of LNB, but it could possibly be related to the relatively long duration of the illness in this patient before the diagnosis was made. At the time of follow-up, neither Lyme serol- ogy nor repeat lumbar puncture for monitoring intrathecal antibodies was done. These have been shown to be of relatively lower yield as follow-up measures because they can be per- sistently elevated for years after treatment, C D irrespective of symptomatic remission.13,14 Recent research, however, has helped to iden- tify biomarkers such as CXCL13 with high sen- sitivity and specificity to identify acute LNB as well as monitor during follow-up.15 This is especially important in rare cases without intrathecal antibody production to cement a diagnosis without perpetuating neurological symptoms. Though further work will need to be done, novel biomarkers remain intriguing options as diagnostic aids for this disease. It is also noteworthy that at most recent (2 year) follow-up, the patient’s MRI signals have not changed for the most part (only the signal abnormalities in the pons and cerebellar Figure 2. Fluid-attenuated inversion recovery - conventional spin echo sequence images peduncle improved). More importantly, as long of the patient’s brain at two-year follow-up. Lesions persist in the periventricular areas as the patient’s clinical status is (and and white matter (A,B), but show decreased signal in the pons (C) and middle cerebellar remains) improved and nearly intact, this is in peduncle (D) relative to corresponding images in Figure 1. our opinion of little consequence. It could be

[Infectious Disease Reports 2014; 6:5496] [page 53] Case Report possible that because this patient had chronic antibiotics; management would be as if the Immunological differentiation between disease, and/or the nature of the infection, the patient were Lyme-naïve. neuroborreliosis and multiple sclerosis. J lesions may never change despite the patient Neurol 1990;237:465-70. being clinically normal. Indeed, there are radi- 9. Mygland Å, Ljøstad U, Fingerle V, et al. ology reports that support this notion, includ- EFNS guidelines on the diagnosis and ing one with a five-year follow-up.16 Conclusions management of European Lyme neurobor- This case supports the use of parenteral reliosis. Eur J Neurol 2010;17:8-16. antibiotics to treat this patient, since the The present case serves to show that a 10. Feder HM Jr, Johnson BJB, O’Connell S, et patient had an excellent clinical response with patient presenting with many neurological al. A critical appraisal of chronic Lyme dis- 2 g IV ceftriaxone. In terms of antibiotic thera- deficits not localized to one area must be ease. N Engl J Med 2007;357:1422-30. py, our treatment is consistent with recom- investigated thoroughly to rule out rare dis- 11. Miller DH, Kesselring J, McDonald I, et al. mendations from the Infectious Diseases eases such as LNB. In suspected cases, though Magnetic resonance in multiple sclerosis. Society of America and the AAN, though the data is greatly lacking in the USA, doing a 1st ed. Cambridge, UK: Cambridge latter report mentions that there is a dearth of prompt and deep investigation (also ruling out University Press; 1997. supportive data for cases involving the CNS other causes on the differential diagnosis such 12. Halperin JJ, Logigian EL, Finkel MF, Pearl 3,17 parenchyma. Though we continued as multiple sclerosis) is important to provide RA. Practice parameters for the diagnosis Levetiracetam for prophylaxis in this early treatment for the patient instead of caus- of patients with nervous system Lyme bor- patient, we did not use corticosteroids; it is ing lingering and possibly additive neurologi- reliosis (Lyme disease). Neurology apparent that more research needs to be done cal deficits. Once diagnosed, however, our 1996;46:619-27. on this issue, although the AAN hints that experience shows that parenteral antibiotic 13. Hammers-Berggren S, Hansen K, Lebech there may be no major impact of using corti- treatment works quite effectively for near-com- AM, Karlsson M. -spe- 3 costeroids. To prevent future cases of delayed plete resolution of clinical symptoms, regard- cific intrathecal antibody production in diagnosis while the patient has continuing less of the predictable persistence of radiologic neuroborreliosis. Neurology 1993;43:169- neurological symptoms, it is important for cli- findings. 75. nicians to keep Lyme disease on the differen- 14. Hammers-Berggren S, Lebech AM, tial diagnosis of any lingering neurological Karlsson M, et al. Serological follow-up symptoms. This pathogen, possibly depending after treatment of patients with erythema on the strain, can be very difficult to clear by References migrans and neuroborreliosis. J Clin the immune system. Indeed, animal studies Microbiol 1994;32:1519-25. have showed that if Borrelia can survive the 1. Stanek G, Wormser GP, Gray J, Strle F. 15. Borde JP, Meier S, Fingerle V, et al. CXCL13 initial innate immune response, there are very Lyme borreliosis. Lancet 2012;379:461-73. may improve diagnosis in early neurobor- few barriers to developing long-term infection 2. Strle F, Stanek G. Clinical manifestations reliosis with atypical laboratory findings. within distant tissues such as the brain.18 and diagnosis of Lyme borreliosis. Curr BMC Infect Dis 2012;12:344. Clinically, this means Lyme disease should be Probl Dermatol 2009;37:51-110. 16. Hildenbrand P, Craven DE, Jones R, high on a lingering neurological disease differ- 3. Halperin JJ, Shapiro ED, Logigian E, et al. Nemeskal P. Lyme neuroborreliosis: mani- ential diagnosis. Practice parameter: treatment of nervous festations of a rapidly emerging zoonosis. Lastly, in patients with documented history system Lyme disease (an evidence-based Am J Neuroradiol 2009;30:1079-87. of LNB, there are salient complications for cli- review): report of the Quality Standards 17. Wormser GP, Dattwyler RJ, Shapiro ED, et nicians to regularly monitor, which this patient Subcommittee of the American Academy displayed as well. As many as 15% of patients of Neurology. Neurology 2007;69:91-102. al. The clinical assessment, treatment, and can experience chronic symptoms (such as 4. Wang G, van Dam AP, Schwartz I, Dankert prevention of Lyme disease, human granu- fatigue, depression, memory or concentration J. Molecular typing of Borrelia burgdorferi locytic anaplasmosis, and babesiosis: clin- defects, and musculoskeletal pain) which can sensu lato: taxonomic, epidemiological, ical practice guidelines by the Infectious occur years after completion of therapy, and clinical implications. Clin Microbiol Diseases Society of America. Clin Infect despite positive clinical response to initial Rev 1999;12:633-53. Dis 2006;43:1089-134. antibiotic therapy.10,19 Unfortunately, these 5. Rocha R, Lisboa L, Neves J, et al. 18. Troy EB, Lin T, Gao L, et al. Understanding symptoms do not respond to additional antibi- Neuroborreliosis presenting as acute dis- barriers to Borrelia burgdorferi dissemi- otics, so their administration is largely not seminated encephalomyelitis. Pediatr nation during infection using massively warranted; management is best done sympto- Emer Care 2012;28:1374-6. parallel sequencing. Infect Immun matically and with gentle reassurance/counsel- 6. Hansen K, Cruz M, Link H. Oligoclonal 2013;81:2347-57. ing.10 It is also important for physicians to not Borrelia burgdorferi-specific IgG antibod- 19. Eikeland R, Mygland Å, Herlofson K, completely ignore recurrence of Lyme-specific ies in cerebrospinal fluid in Lyme neu- Ljøstad U. European neuroborreliosis: symptoms (such as erythema migrans), roborreliosis. J Infect Dis 1990;161:1194- quality of life 30 months after treatment. because a small proportion of patients develop 202. Acta Neurol Scand 2011;124:349-54. recurrent Lyme disease, which is thought to be 7. Schmutzhard E. Multiple sclerosis and 20. Nadelman RB, Hanincova K, Mukherjee P, due to reinfection with a different strain Lyme borreliosis. Wien Klin Wochenschr et al. Differentiation of reinfection from rather than relapse from the previous strain.20 2002;114:539-43. relapse in recurrent Lyme disease. N Engl These cases would be managed with repeat 8. Heller J, Holzer G, Schimrigk K. J Med 2012;367:1883-90.

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