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\begin{document}

\title{Lyme Neuroborreliosis: A case report}



\author[1]{Babak Sayad}%
\author[2]{Arefeh Babazadeh}%
\author[3]{Mohammad Barary}%
\author[2]{Rezvan Hosseinzadeh}%
\author[2]{Soheil Ebrahimpour}%
\author[1]{Zeinab Mohseni Afshar}%
\affil[1]{Kermanshah University of Medical Sciences}%
\affil[2]{Babol University of Medical Science}%
\affil[3]{Shahid Beheshti University of Medical Sciences}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\textbf{Lyme Neuroborreliosis: A case report}

Babak Sayad\textsuperscript{1}, Arefeh Babazadeh\textsuperscript{2},
Mohammad Barary\textsuperscript{3}, Rezvan
Hosseinzadeh\textsuperscript{4}, Soheil Ebrahimpour\textsuperscript{2},
Zeinab Mohseni Afshar\textsuperscript{1, *}

\begin{enumerate}
\tightlist
\item
  Clinical Research Development Center, Imam Reza Hospital, Kermanshah
  University of Medical Sciences, Kermanshah, Iran
\item
  Infectious Diseases and Tropical Medicine Research Center, Health
  Research Institute, Babol University of Medical Sciences, Babol, Iran
\item
  Student Research Committee, Virtual School of Medical Education and
  Management, Shahid Beheshti University of Medical Sciences, Tehran,
  Iran
\item
  Student Research Committee, Babol University of Medical Sciences,
  Babol, Iran
\end{enumerate}

\textbf{Correspondence:}

Zeinab Mohseni Afshar, Clinical Research Development Center, Imam Reza
Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran.
Email: baboldr2019@gmail.com

\textbf{Abstract}

Central nervous system (CNS) infections constitute a significant
etiology of seizures. However, the likelihood of such infections is
contingent upon factors such as age, immunological status, and
geographic region. \emph{Borrelia burgdorferi} , a Spirochaete, is
responsible for the infectious etiology of seizures in Lyme disease. The
case under consideration pertains to a patient who exhibited seizures as
the initial manifestation of neuroborreliosis. A male patient, aged 55,
was admitted to the emergency department due to the sudden onset of
tonic-clonic seizures. All standard laboratory examinations yielded
unremarkable outcomes, except a favorable Wright and 2-mercaptoethanol
test. The examination of cerebrospinal fluid revealed the presence of
380 white blood cells per milliliter. Additionally, the protein level
was elevated, while the glucose level was within the normal range. The
results of the serologic tests indicated the presence of both IgG and
IgM antibodies to \emph{B. burgdorferi} . Following the administration
of ceftriaxone, a significant improvement was observed in the patient's
medical status, and he was subsequently discharged.

\textbf{Keywords:} Central Nervous System Infections; Borrelia
Infections; Lyme Neuroborreliosis

\textbf{Key Clinical Message}

Lyme neuroborreliosis is the manifestation of Lyme borreliosis that
impacts the nervous system. It gives rise to various neurological and
psychiatric conditions, and its diagnosis is challenging. The timely
administration of antibiotics is effective.

\textbf{Introduction}

Central nervous system (CNS) infections are a major cause of seizures
worldwide. Infectious causes of convulsions vary according to
geographical location. Nevertheless, globalization and international
travel have broken the boundaries, so we can expect any infection to
cause seizures in different parts of the world {[}1{]}. Bacterial
meningitis, malaria, herpes simplex virus (HSV), human immunodeficiency
virus (HIV), tuberculosis, toxoplasmosis, and neurocysticercosis are
infectious etiologies of seizures. Nevertheless, their probability as
the cause of seizures depends on the age and immunologic condition of
the patient and geographical location {[}2{]}. Lyme disease is another
infectious cause of seizures caused by the Spirochaete, \emph{Borrelia
burgdorferi} . The condition, known as neuroborreliosis, may occur at
the early or late stages of this disease and can even be its first
presentation. Other neurologic manifestations of borreliosis include
cranial neuritis, facial palsy, radiculoneuritis, pseudotumor cerebri,
myelitis, cerebellar ataxia and spastic paraparesis {[}3{]}. Lyme
disease is rarely suspected as the cause of neurologic manifestations in
Iran since most cases have been reported in America and Europe. Here, we
present a case of neuroborreliosis with seizures as the first
manifestation in a 55-year-old man.

\textbf{Case presentation}

A 55-year-old man was admitted to the emergency department with
new-onset tonic-clinic generalized seizures. At the time of admission,
he was in the postictal phase. Soon after, his consciousness level
deteriorated, and he was intubated. His symptoms began one week prior to
presentation with a mild headache and low-grade fever, malaise, anorexia
and vomiting. Four days before admission, he developed his first
convulsive episode and was hospitalized. However, he was discharged with
personal consent. He had no history of recent trauma, drug overdose, or
travel. The patient was a butcher and had been treated for brucellosis
two times in recent two years. Neurologic examination was unreliable due
to decreased level of consciousness. Hypoglycemia and opium overdose
were excluded for the patient at admission, and he was started on
anticonvulsive therapy and broad-spectrum antibiotics.

Routine laboratory tests had normal results, except for a positive
Wright and 2-mercaptoethanol (2ME) tests results (Wright: 1:80, normal
range: [?] 1/160; 2ME: 1:40, normal range: [?] 1/160). Thyroid function
tests, vitamin B12 and folate, creatine kinase (CK), and C-reactive
protein (CRP) levels and erythrocyte sedimentation rate (ESR) were in
normal ranges. Autoantibodies, anti-HIV antibodies, and rapid plasma
reagin (RPR) tests were also negative. Chest computed tomography (CT)
scan demonstrated centrilobular opacities at the lower segments of both
lungs, indicative of aspiration pneumonia. A brain CT scan showed a
subarachnoid cyst in the left cerebellar hemisphere and opacification
and air-fluid levels in both maxillary paranasal sinuses. Brain magnetic
resonance imaging (MRI) revealed bilateral hypersignal changes on the
parietal lobes. Cerebrospinal fluid (CSF) examination showed white blood
cells (WBCs) of 380/mL (normal range: \textless{} 5/mL) with 68\%
lymphocytes, an elevated protein level (82 mg/dL, normal range: 15-60
mg/dL), and a normal glucose level. CSF gram stain, culture, and
polymerase chain reaction (PCR) tests were negative for HSV
and\emph{Mycobacterium tuberculosis} . The patient was first suspected
to be a case of neurobrucellosis.

Nonetheless, the presence of CSF pleocytosis with lymphocyte dominance
and inconclusive Wright and 2ME tests results ruled out this diagnosis,
and therefore, we suspected Lyme disease. Thus, we requested serologic
tests, which were positive for IgG and IgM antibodies to \emph{B.
burgdorferi} . Because of the high prevalence of cardiac and ocular
involvement in the settings of Lyme disease, we requested a cardiology
and an ophthalmology consultation. However, no abnormality was found.
The patient was started on ceftriaxone at a dose of 2 g daily. His
condition improved dramatically during the following days, and he was
discharged three weeks after admission with a favorable general
condition.

\textbf{Discussion}

Borreliosis is a tick-borne infection caused by Spirochetes of Borrelia
species. Depending upon the geographical location, the most common
causative agents for Lyme disease includes \emph{B. burgdorferi}
and\emph{B. garinii} . This spirochetal infection occurs as a result of
a tick bite. However, in disseminated or late infection, many patients
do not recall the insect bite {[}4, 5{]}. Neurological manifestations of
Lyme disease, known as neuroborreliosis, occur in up to 50\% of
borreliosis cases. Neurological involvement of Lyme disease can present
in various forms, ranging from simple neuropathy, neuritis or facial
palsy to seizures, psychosis, paraplegia, meningoencephalitis,
radiculomyelitis, and stroke {[}6-9{]}. Convulsion was our patient's
main manifestation, resulting from meningoencephalitis.

Diagnosis of Lyme disease is suspected in individuals with compatible
manifestations like characteristic cutaneous features (erythema migrans,
acrodermatitis chronica atrophicans, malar rash), musculoskeletal
presentations (migratory pain in the joints and muscles, arthritis,
panniculitis), neurologic symptoms (meningitis, ataxia, neuritis,
radiculopathy), cardiac complications (myopericarditis, AV block,
cardiomegaly) and ophthalmic abnormalities (iritis, keratitis,
conjunctivitis). However, paraclinical evaluation should confirm the
diagnosis {[}10-12{]}. CSF changes in Lyme disease with CNS involvement
are expected to include a pleocytosis, usually with lymphocyte
dominance, elevated protein, and normal glucose levels {[}13, 14{]}.
Microbiological tests (e.g., culture) and molecular tests (e.g., PCR)
yield low conclusive results in neurologic involvement of Lyme. Hence,
the definite diagnosis is based on serologic tests and a demonstration
of the patient's immune response {[}15{]}. Our patient was suspected of
neuroborreliosis due to aseptic meningitis with lymphocyte dominance.
Hence, we requested serum anti-Borrelia antibodies (IgM and IgG) tests,
both positive in high titers.

Nevertheless, the Western blot test should have been used as a secondary
test to exclude reactive IgG false positivity. However, due to our
inaccessibility to this confirmatory test, we started the patient on
Lyme treatment based on the initial ELISA positivity. Increased
oligoclonal bands in the CSF have also been reported to suggest
neuroborreliosis {[}16{]}, but it was not performed due to resource
shortage. On the other hand, some authorities only accept intrathecal
anti-Borrelia antibody production (ITAb) as the confirmatory diagnostic
test for neuroborreliosis {[}17{]}. Unfortunately, serological
evaluation of Borreliosis was not performed on our patient's CSF.
Recently, an increase in CXCL13 levels in the CSF and positive Borrelia
C6 peptide reaction have been suggested to be beneficial diagnostic
markers for neuroborreliosis {[}18, 19{]}. It should be acknowledged
that CSF pleocytosis, with lymphocytes dominance, also known as aseptic
meningitis, has several other differential diagnoses, including viral
CNS infections, late stages of tuberculosis meningitis,
neurobrucellosis, neurosyphilis, HIV infection, listeriosis, convulsion,
subarachnoid hemorrhage (SAH), neuroimmunogic and neurodegenerative
disorders, neoplasms, and vasculitis {[}20{]}. Nevertheless, most of
these diagnoses were excluded with corresponding laboratory tests in our
patient.

The treatment response of neuroborreliosis is more satisfactory with
intravenous antimicrobials. Ceftriaxone or penicillin G, alternatively,
are the most appropriate options, but oral doxycycline could also be
used {[}21{]}. Our patient responded favorably to antibiotics, improving
his condition within two weeks.

\textbf{Conclusion}

Lyme neuroborreliosis is Lyme borreliosis affecting the nervous system.
It can be difficult to diagnose unless it presents with typical
symptoms, and clinicians actively consider this diagnosis. If left
untreated, this disease can affect any part of the nervous system,
including the brain. It causes a wide range of neurological and
psychiatric disorders. There is no gold standard test that can be relied
upon for diagnosis. This illness can be successfully treated if
treatment starts early with antibiotics.

\textbf{Acknowledgments}

The authors would like to thank the Clinical Research Development
Center, Imam Reza Hospital, Kermanshah University of Medical Sciences,
and the Department of infectious diseases, School of Medicine, Babol
University of Medical Sciences.

\textbf{Data Availability Statement}

The data that support the findings of this study are available from the
corresponding author upon reasonable request.

\textbf{Conflict of interest disclosure}

All authors have no relevant financial interests to be declared.

\textbf{Author Contributions}

\begin{itemize}
\tightlist
\item
  \textbf{BS:} Data collection and writing of the manuscript.
\item
  \textbf{AB:} Data collection and writing of the manuscript.
\item
  \textbf{MB:} Data collection, helped with manuscript writing, and
  contributed substantial revisions to the manuscript's content.
\item
  \textbf{RH:} Data collection and writing of the manuscript.
\item
  \textbf{SE:} Data collection and writing of the manuscript.
\item
  \textbf{ZMA:} Design of the research study and supervision
\end{itemize}

\textbf{Informed consent}

Written informed consent was obtained from the patient to publish the
current case report.

\textbf{References}

1. Singhi P. Infectious causes of seizures and epilepsy in the
developing world. Dev Med Child Neurol. 2011;53(7):600-9. doi:
10.1111/j.1469-8749.2011.03928.x.

2. Lowenstein DH, Walker M, Waterhouse E. Status epilepticus in the
setting of acute encephalitis. Epilepsy Curr. 2014;14(1 Suppl):43-9.
doi: 10.5698/1535-7511-14.s2.43.

3. Roos KL. Neurologic Complications of Lyme Disease. Continuum (Minneap
Minn). 2021;27(4):1040-50. doi: 10.1212/CON.0000000000001015.

4. Wilske B. Epidemiology and diagnosis of Lyme borreliosis. Ann Med.
2005;37(8):568-79. doi: 10.1080/07853890500431934.

5. Schotthoefer AM, Frost HM. Ecology and Epidemiology of Lyme
Borreliosis. Clin Lab Med. 2015;35(4):723-43. doi:
10.1016/j.cll.2015.08.003.

6. Allen NM, Jungbluth H. Lyme Neuroborreliosis: A Potentially
Preventable Cause of Stroke. J Pediatr. 2016;170:334-e1. doi:
10.1016/j.jpeds.2015.11.077.

7. Wendling D, Sevrin P, Bouchaud-Chabot A, Chabroux A, Toussirot E,
Bardin T, et al. Parsonage-Turner syndrome revealing Lyme borreliosis.
Joint Bone Spine. 2009;76(2):202-4. doi: 10.1016/j.jbspin.2008.07.013.

8. Fallon BA, Schwartzberg M, Bransfield R, Zimmerman B, Scotti A, Weber
CA, et al. Late-stage neuropsychiatric Lyme borreliosis. Differential
diagnosis and treatment. Psychosomatics. 1995;36(3):295-300. doi:
10.1016/S0033-3182(95)71669-3.

9. Blanc F, Gebly. {[}Neurologic and psychiatric manifestations of Lyme
disease{]}. Med Mal Infect. 2007;37(7-8):435-45. doi:
10.1016/j.medmal.2006.01.025.

10. Mullegger RR, Glatz M. Skin manifestations of lyme borreliosis:
diagnosis and management. Am J Clin Dermatol. 2008;9(6):355-68. doi:
10.2165/0128071-200809060-00002.

11. Kostic T, Momcilovic S, Perisic ZD, Apostolovic SR, Cvetkovic J,
Jovanovic A, et al. Manifestations of Lyme carditis. Int J Cardiol.
2017;232:24-32. doi: 10.1016/j.ijcard.2016.12.169.

12. Strle F, Stanek G. Clinical manifestations and diagnosis of lyme
borreliosis. Curr Probl Dermatol. 2009;37:51-110. doi:
10.1159/000213070.

13. Xing J, Radkay L, Monaco SE, Roth CG, Pantanowitz L. Cerebrospinal
Fluid Cytology of Lyme Neuroborreliosis: A Report of 3 Cases with
Literature Review. Acta Cytol. 2015;59(4):339-44. doi:
10.1159/000439160.

14. Morrison DG, Phuah HK, Reddy AT, Dure LS, Kline LB. Ophthalmologic
involvement in the syndrome of headache, neurologic deficits, and
cerebrospinal fluid lymphocytosis. Ophthalmology. 2003;110(1):115-8.
doi: 10.1016/s0161-6420(02)01444-6.

15. Branda JA, Linskey K, Kim YA, Steere AC, Ferraro MJ. Two-tiered
antibody testing for Lyme disease with use of 2 enzyme immunoassays, a
whole-cell sonicate enzyme immunoassay followed by a VlsE C6 peptide
enzyme immunoassay. Clin Infect Dis. 2011;53(6):541-7. doi:
10.1093/cid/cir464.

16. Djukic M, Schmidt-Samoa C, Lange P, Spreer A, Neubieser K, Eiffert
H, et al. Cerebrospinal fluid findings in adults with acute Lyme
neuroborreliosis. J Neurol. 2012;259(4):630-6. doi:
10.1007/s00415-011-6221-8.

17. Mygland A, Ljostad U, Fingerle V, Rupprecht T, Schmutzhard E,
Steiner I, et al. EFNS guidelines on the diagnosis and management of
European Lyme neuroborreliosis. Eur J Neurol. 2010;17(1):8-16, e1-4.
doi: 10.1111/j.1468-1331.2009.02862.x.

18. Remy MM, Schobi N, Kottanattu L, Pfister S, Duppenthaler A,
Suter-Riniker F. Cerebrospinal fluid CXCL13 as a diagnostic marker of
neuroborreliosis in children: a retrospective case-control study. J
Neuroinflammation. 2017;14(1):173. doi: 10.1186/s12974-017-0948-9.

19. Steere AC, McHugh G, Damle N, Sikand VK. Prospective study of
serologic tests for lyme disease. Clin Infect Dis. 2008;47(2):188-95.
doi: 10.1086/589242.

20. Baunbaek Egelund G, Ertner G, Langholz Kristensen K, Vestergaard
Jensen A, Benfield TL, Brandt CT. Cerebrospinal fluid pleocytosis in
infectious and noninfectious central nervous system disease: A
retrospective cohort study. Medicine (Baltimore). 2017;96(18):e6686.
doi: 10.1097/MD.0000000000006686.

21. Halperin JJ. Diagnosis and management of Lyme neuroborreliosis.
Expert Rev Anti Infect Ther. 2018;16(1):5-11. doi:
10.1080/14787210.2018.1417836.

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