Journal http://jcn.sagepub.com/ of Child Neurology

Protracted Symptoms in Lymphocytic Choriomeningitis: A Case Report Heather Tyrell Souders, Debra Byler, Neelima Marupudi, Rakesh Patel and George McSherry J Child Neurol published online 15 April 2014 DOI: 10.1177/0883073814529820 The online version of this article can be found at: http://jcn.sagepub.com/content/early/2014/04/14/0883073814529820

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Brief Communication

Protracted Symptoms in Lymphocytic Choriomeningitis: A Case Report

Journal of Child Neurology 1-4 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814529820 jcn.sagepub.com

Heather Tyrell Souders, DO1, Debra Byler, MD2, Neelima Marupudi, MD3, Rakesh Patel, MD4, and George McSherry, MD5

Abstract Assumed to be underreported and underrecognized, lymphocytic choriomeningitis presents as a febrile illness transmitted by the common house mouse, Mus musculus. Although asymptomatic or mild febrile illnesses are commonplace, meningitis and meningoencephalitis may develop after symptoms have seemed to improve. Neurologic sequelae are not typical but have been reported and can persist for months. We report a documented case of lymphocytic choriomeningitis in which a previously healthy 17-year-old girl experienced debilitating recurrent headaches and arthralgias for more than a year after discharge. Neuropsychological testing and visual changes were also documented. Further research is needed to estimate the prevalence of this infection, although it has been estimated that 5% of American adults have antibodies to lymphocytic choriomeningitis virus. Education and awareness of the medical community as well as the general public will be critical in prevention as well as advancing future treatment modalities of lymphocytic choriomeningitis virus. Keywords headache, lymphocytic choriomeningitis virus, lymphocytic pleocytosis Received November 05, 2013. Received revised January 06, 2014. Accepted for publication March 05, 2014.

Lymphocytic choriomeningitis virus appears to be a common but underrecognized cause of neurologic illness. The virus was first isolated in 1933 by Armstrong and Lillie from a patient thought to have St. Louis Encephalitis.1 Transmitted primarily via Mus Musculus and Mus domesticus, the common house mouse species,2 pet hamsters and guinea pigs have also been identified as sources of infection. It is estimated that 5% of American adults have antibodies to lymphocytic choriomeningitis virus.3,4 In 2005, 3 solid organ transplant recipients died and were later found to have lymphocytic choriomeningitis virus, tracing the source to a pet hamster of the organ donor.5 Intrauterine infection with lymphocytic choriomeningitis virus through vertical transmission presents similarly to congenital toxoplasmosis and cytomegalovirus with encephalopathy, microcephaly, and periventricular calcifications.6 There is an increased risk of spontaneous abortion if the virus is transmitted during the first trimester of pregnancy.7 Lymphocytic choriomeningitis virus should also be considered in cases of non-immune hydrops fetalis.8 A member of the arenavirus family, lymphocytic choriomeningitis virus is transmitted to humans by aerosol or by ingestion of dust or food contaminated with virus from rodent urine, feces, blood, or nasopharyngeal secretions.9 In the United States, it has previously been estimated that 10% to 15% of all aseptic meningitis cases are caused by lymphocytic choriomeningitis virus.10 Lymphocytic choriomeningitis virus

was diagnosed in 10% of cases of febrile illness between 1941 and 1958 at the Walter Reed Army Medical Center.4 Because of underreporting or missed diagnosis, the prevalence is suspected to be higher. Most cases are asymptomatic or present with mild febrile illnesses. Infection is more commonly seen in adolescents or young adults.10 Lymphocytic choriomeningitis typically presents as a biphasic illness with initial symptoms of fever, headache, general malaise, as well as nausea, vomiting, and photophobia. The entire course usually lasts 1 to 3 weeks, with symptoms improving initially, followed by worsening meningitic sequelae in severe cases. Fatalities have been reported, but are rare. Following the illness, symptoms can persist for months. We report a case of

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Developmental and Behavioral Pediatrics, Nationwide Children’s Hospital, Columbus, OH, USA 2 Pediatric Neurology, Penn State Hershey Children’s Hospital, Hershey, PA, USA 3 Penn State College of Medicine, Hershey, PA, USA 4 Department of Pediatrics, York Hospital, York, PA, USA 5 Pediatric Infectious Disease, Penn State Hershey Children’s Hospital, Hershey, PA, USA Corresponding Author: Debra L. Byler, MD, Department of Pediatrics, Penn State College of Medicine, 500 University Drive, Mail Code H085, Hershey, PA 17033, USA. Email: [email protected]

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Table 1. Cerebrospinal Fluid Studies. CSF 1 day prior to admission Color Appearance WBCs per microliter RBCs per microliter Neutrophils, % Lymphocytes, % Glucose, mg/dL Protein, mg/dL Opening pressure, cm H2O Gram stain

Table 2. Diagnostic Workup. CSF on CSF on day 2 of day 9 of admission admission

Straw colored Cloudy 3135

Colorless Hazy 3208

Pink Hazy 402

145

367

4877

0 100 41 388

0 100 32 >600 23

0 100 31 195 12

4þ WBCs

3þ WBCs

Many mononuclear cells Few PMNs

Abbreviations: CSF, cerebrospinal fluid; PMN, polymorphonuclear cells; RBCs, red blood cells; WBCs, white blood cells.

lymphocytic choriomeningitis in which the patient continued to have persistent headache, developed significant arthralgias, and reported deficits in memory and concentration that persisted for more than a year after the initial admission.

Case Report A 17-year-old previously healthy female with no significant past medical history presented with the chief complaint of headache for 14 days. Temperatures of up to 100.4 F accompanied headaches, with photophobia, myalgias, and abdominal pain. Worsening headache and abdominal pain in addition to severe neck pain prompted admission to the referring hospital, where magnetic resonance imaging (MRI) of the brain and cervical and thoracic spine were normal. Lumbar puncture revealed straw-colored cloudy fluid with 3135 white blood cells per microliter, with a differential of 100% lymphocytes, 145 red blood cells per microliter, a glucose concentration of 41 mg/ dL, and a protein concentration of 388 mg/dL (see Table 1). Complete blood count was remarkable for leukopenia and thrombocytopenia. The patient was started on vancomycin, ceftriaxone, and acyclovir. Concern for altered mental status and decreased left grip strength prompted transfer to our facility. On admission to our institution, the patient was afebrile and bradycardic. Physical examination revealed nuchal rigidity and neurologic examination was significant for bilateral papilledema left greater than right as well as decreased deep tendon reflexes throughout. Motor, sensory, and coordination examinations were without deficit. Gait was not tested. Brain MRI was repeated and was suggestive of meningitis, revealing mildly increased T2 signals of the convexity and sulci in the fluid-attenuated inversion recovery sequence without abnormal leptomeningeal enhancement. Headache, neck stiffness, lower back pain, and photophobia persisted throughout the hospital stay. Repeat cerebrospinal fluid examination was

Infectious

Rheumatologic/autoimmune

CSF LCMV IgG, IgM CSF herpes simplex virus PCR CSF AFB culture CSF enterovirus PCR CSF cryptococcal antigen CSF fungal culture CSF culture Serum LCMV IgG, IgM Blood culture Serum Lyme IgM and IgG Serum Typhus IgM and IgG RPR Quantiferon- Gold IT assay Acanthamoeba/Naegleria culture Rocky Mountain spotted fever IgG, IgM Human monocytic ehrlichiosis IgG, IgM Human granulocytic anaplasmosis IgG, IgM Epstein-Barr virus Cytomegalovirus—serum, urine, PCR Urine histoplasma antigen Purified protein derivative

Lupus anticoagulant Rheumatoid factor Antinuclear Antibody Native DNA Anti-Smith Multiple sclerosis panel CSF Paraneoplastic antibodies Cardiolipin (IgA, IgG, IgM) Scl-70 (topoisomerase 1) SSA and SSB Anti-centromere Anti-histone ACE level NMDA antibodies Serum and CSF CSF neuromyelitis optica Anti Jo-1 antibody C3 C4

Abbreviations: ACE, angiotensin-converting enzyme; AFB, acid-fast bacilli; CSF, cerebrospinal fluid; DNA, deoxyribonucleic acid; IgG, immunoglobulin G; IgM, immunoglobulin M; LCMV, lymphocytic choriomeningitis virus; NMDA, N-methyl-D-aspartate; PCR, polymerase chain reaction; SSA, Sjo¨gren syndrome A; SSB, Sjo¨gren syndrome B.

performed on 2 occasions, revealing protein levels as high as 600 mg/dL and peak white blood cell count of 3208 per microliter (100% lymphocytes) (see Table 1). Pulse steroid treatment started on hospital day 13, which provided the patient significant improvement of headache and neck pain. On hospital day 15, the patient was discharged home on a 5-week course of tapering prednisone. After extensive workup (see Table 2), the diagnosis of lymphocytic choriomeningitis was established when serum (lymphocytic choriomeningitis virus immunoglobulin M > 1:80, lymphocytic choriomeningitis virus immunoglobulin G > 1:256) and cerebrospinal fluid (lymphocytic choriomeningitis virus immunoglobulin G > 1:128) titers returned positive. The patient was readmitted a month later for persistent headaches. This was treated with increased steroid dose and slower taper. Additional problems included nonspecific joint pain, thought to be related to chronic inflammation by rheumatology. A straight A student in honors classes previously, the patient reported new problems with memory and concentration. Outpatient neuropsychological testing revealed deficits in attention, concentration, and short-term memory out of proportion to the remainder of her cognitive skills. This was particularly evident on memorization tasks, with scores ranging as low as the 9th percentile for age. An acquired red color deficit was noted during pediatric ophthalmology follow-up. Examination of the optic nerves was normal.

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Four months after initial presentation, she returned to school part time. Full day attendance was limited by fatigue and headache for the remaining 2 months of the school year. Daily headaches persisted for 6 months after presentation. One year later, the patient had nondisabling headaches 2 or 3 times per week treated with over-the-counter medications. She had occasional joint pain that did not limit activity. She still noted difficulty with memorization and recall when compared to her prior level of function and used compensatory measures for continued academic success. She returned to full sports, band, and academic activities by 9 months after presentation and had graduated from high school with plans to attend college at last contact. She took no prescription medications and was no longer participating in medical care for sequelae of meningitis.

Discussion We report a case of lymphocytic choriomeningitis with protracted symptoms. Specific association of this illness with prolonged headache and persistent cognitive complaints is significant. Although this cause of meningitis is understood to be common, it is frequently overlooked and may be causally related to more persistent symptomatology. Our patient also experienced a wide variety of symptoms related to her primary infection, including persistent headaches, joint pain, red-color desaturation, and cognitive difficulties. The mechanism of these symptoms may be multifactorial, including direct effects of infection, sequelae of chronic inflammation, immune mechanisms, and possibly deconditioning. Although the typical course of lymphocytic choriomeningitis virus is relatively benign without complications in about one third of patients, meningitis or meningoencephalitis occurs in approximately one half of the remaining patients. There are few reported fatalities. Long-term neurologic sequelae include transient and permanent acquired hydrocephalus, deafness, and rarely Guillain-Barre´ syndrome and transverse myelitis.11 Current literature focuses on human transmission through organ donation and congenitally acquired infection and its complications. Green et al12 described 21 cases of acute lymphocytic choriomeningitis with headache persisting for more than 30 days in only 2 cases, average being 12.6 days. One patient 3 years after infection was not able to work consistently secondary to headaches. That patient was reported to have had increased intracranial pressure requiring lumbar puncture for relief on several occasions.12 Our patient had difficulties with persistent headaches and cognitive issues measurable by neuropsychological testing. During the acute febrile phase of the illness, leukopenia, thrombocytopenia, and mild transaminitis have been reported, in addition to a significant cerebral spinal fluid lymphocytic pleocytosis. In typical cases of viral meningoencephalitis, the white blood cell count ranges from 10 to 1000 cells/mm3, usually less than 300 cells/mm3, and is composed primarily of mononuclear cells.13 Elevated cerebrospinal fluid protein concentrations as well as hypoglycorrhachia have also been

described.13 Diagnosis is based on detection of antibodies for immunoglobulin M and immunoglobulin G in cerebrospinal fluid, but in severe infections live virus can also be detected in the serum, urine, and nasopharyngeal secretions.10 More research is necessary to determine whether there is a correlation between viral load and symptoms, particularly chronic headaches. In the case of our patient, the cerebrospinal fluid protein was notably and persistently high. Whether this is related to the degree of inflammatory response, and perhaps predictive of chronicity symptoms, is speculative (Table 1). Bonthius et al14 observed in experimental animal models lymphocytic choriomeningitis virus antigen to persist in neurons months after symptoms from initial infection had cleared. These findings, although limited to the developing rat brain, are noteworthy regarding the potential long-term sequelae of lymphocytic choriomeningitis virus. Presumably, testing for lymphocytic choriomeningitis has gone out of favor because of its generally benign course in adolescents and adults. It still, however, was previously the cause of a significant amount of aseptic meningitis, and is likely to be currently underreported and tested because of lack of knowledge about the virus. Although our patient lacked clear exposure to rodents, other cases in the literature have documented infection without revealing any exposure to mice or hamsters. Larsen et al15 reported 2 cases of hydrocephalus in a 12-month period secondary to infection with lymphocytic choriomeningitis without recognized exposure. This further emphasizes that lymphocytic choriomeningitis virus should be considered even in cases of unidentified exposure because of its potentially devastating effects on pregnant women through intrauterine transmission. Our patient was treated supportively, as current treatment is largely symptomatic. Use of antivirals such as ribavirin is considered off-label.3 Favipiravir has been shown to have activity against arenaviruses in cultures.3,16 In conclusion, we highlight this case to make other diagnosticians aware of the potential long-term complications of this typically benign pathogen. Although prevention is ideal, universal awareness may lead to advanced or earlier symptomatic treatment modalities after the infection is recognized. Acknowledgments This case was presented at the Southern Pediatric Neurology Society Meeting in New Orleans, Louisiana, on March 9, 2013, by HTS.

Author Contributions HTS was the primary author and wrote the first draft of the report and abstract. DB made subsequent revisions; NM performed chart review; RP provided case information and contributed content; and GM provided mentorship and final editorial guidance.

Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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Funding The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical Approval The institution review board granted exemption and determined the study did not require formal review.

References 1. Jahrling PB, Peters CJ. Lymphocytic choriomeningitis virus: a neglected pathogen of man. Arch Pathol Lab Med. 1992;116: 486-488. 2. Laposova K, Pastorekova S, Tomaskova J. Lymphocytic choriomeningitis virus: invisible but not innocent. Acta Virol. 2013;57: 160-170. 3. Bonthius DJ. Lymphocytic choriomeningitis virus: an underrecognized cause of neurologic disease in the fetus, child, and adult. Semin Pediatr Neurol. 2012;19:89-95. 4. Peters CJ. Lymphocytic choriomeningitis—an old enemy up to new tricks. N Engl J Med. 2006;354:2208-2211. 5. Centers for Disease Control and Prevention (CDC). Update: interim guidance for minimizing risk for human lymphocytic choriomeningitis virus infection associated with pet rodents. MMWR Morb Mortal Wkly Rep. 2005;54:799-801. 6. Wright R, Johnson D, Neumann M, et al. Congenital lymphocytic choriomeningitis virus syndrome: a disease that mimics congenital toxoplasmosis or Cytomegalovirus infection. Pediatrics. 1997;100:E9. 7. Barton LL, Mets MB. Lymphocytic choriomeningitis virus: pediatric pathogen and fetal teratogen. Pediatr Infect Dis J. 1999; 18:540-541.

8. Anderson J, Levy P, Leonard K, et al. Congenital lymphocytic choriomeningitis virus: when to consider the diagnosis. J Child Neurol. 2013;00:1-6. 9. Barton LL, Mets MB. Congenital lymphocytic choriomeningitis virus infection: decade of rediscovery. Clin Infect Dis. 2001;33: 370-374. 10. American Academy of Pediatrics. Lymphocytic choriomeningitis. In: Pickering LK, ed. Red Book: 2012 Report of the Committee on Infectious Diseases. 29th ed. Elk Grove, IL: American Academy of Pediatrics; 2012:481-482. 11. Lehmann-Grube F. Diseases of the nervous system caused by lymphocytic choriomeningitis virus and other arenaviruses. In: Bruyn GW, Klawans HL, Vinken PJ, McKendall RR, eds. Handbook of Clinical Neurology. Vol. 56. New York: Elsevier; 1989: 355-381. 12. Green WR, Sweet LK, Prichard RW. Acute lymphocytic choriomeningitis; a study of 21 cases. J Pediatr. 1949;35:688-701. 13. Rumbaugh JA, Nath A. Approach to the patient with a cerebrospinal fluid pleocytosis. In: Irani DN, ed. Cerebrospinal Fluid in Clinical Practice. Philadelphia, PA: Elsevier Health Sciences; 2009:273-280. 14. Bonthius DJ, Mahoney J, Buchmeier MJ, et al. Critical role for glial cells in the propagation and spread of lymphocytic choriomeningitis virus in the developing rat brain. J Virol. 2002;76: 6618-6635. 15. Larsen PD, Chartrand SA, Tomashek KM, et al. Hydrocephalus complicating lymphocytic choriomeningitis infection. Pediatr Infect Dis J. 1993;12:528-531. 16. Mendenhall M, Russell A, Juelich T, et al. T-705 (favipiravir) inhibition of arenavirus replication in cell culture. Antimicrob Agents Chemother. 2011;55:782-787.

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Protracted symptoms in lymphocytic choriomeningitis: a case report.

Assumed to be underreported and underrecognized, lymphocytic choriomeningitis presents as a febrile illness transmitted by the common house mouse, Mus...
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