PRACTICE | CASES CPD

Neurosyphilis mimicking autoimmune encephalitis in a 52-year-old man

Adrian Budhram MD, Michael Silverman MD, Jorge G. Burneo MD MSPH n Cite as: CMAJ 2017 July 24;189:E962-5. doi: 10.1503/cmaj.170190

52-year-old man in a long-term, same-gender sexual relationship presented with agitation, confusion and KEY POINTS problems speaking for about two weeks. On assess- • The rate of syphilis infection in Canada has risen in recent years. ment,A his vital signs were normal, but he was agitated and had • Early neurosyphilis typically presents as meningitis or global aphasia. No other focal deficits were identified on a meningovascular disease, while late neurosyphilis classically screening neurologic examination. He suffered a witnessed gen- causes dementia or tabes dorsalis. eralized tonic–clonic seizure in the emergency department and • Neurosyphilis may rarely mimic autoimmune encephalitis, and was given a loading dose of phenytoin. Seizure activity stopped, recognition of this is critical to ensure accurate diagnosis and but his agitation, confusion and aphasia persisted. prompt treatment with antimicrobial therapy. Six months earlier, he had been admitted to hospital with agi- • Further study is needed to determine whether immunologic tation, disorientation and aphasia that had developed one month mechanisms contribute to this atypical presentation of neurosyphilis. after an episode of vertigo. Brain magnetic resonance imaging

(MRI) had shown T2 hyperintensity of the left thalamus and medial temporal lobe (Figure 1). An electroencephalogram during this initial hospital admission showed left posterior temporal slowing, subacute neurologic decline with seizures, medial temporal lobe but no seizure activity. Lumbar puncture had shown inflamma- signal abnormality on initial MRI, and positive serum anti-GAD tory cerebrospinal fluid (CSF) with a leukocyte count of 72 × 106 antibody, a diagnosis of autoimmune encephalitis was consid- cells/L with 86% lymphocytes (normal 0–5 × 106 cells/L), elevated ered. He received five days of 0.4 mg/kg per day intravenous protein of 1260 (normal 200–400) mg/L and normal glucose. His immunoglobulin with substantial improvement, facilitating dis- CSF bacterial culture and herpes simplex virus polymerase chain charge home with his partner. reaction were negative. Serum HIV testing was negative. Rheuma- Given his previous response to immunotherapy, we initiated tologic, paraneoplastic and autoimmune serology, including anti– five days of 0.4 mg/kg intravenous immunoglobulin per day, in N-methyl-D-aspartate receptor (NMDAR), anti–voltage-gated case his symptoms were owing to autoimmune encephalitis. We potassium channel, anti–glutamic acid decarboxylase (GAD), anti- also administered a seven-day course of piperacillin-tazobactam Hu, anti-Yo, anti-Ri, anti-Ma2, anti-CV2 and anti-amphiphysin anti- for possible aspiration pneumonia after his seizure. We noticed bodies, was remarkable only for positive anti-GAD antibody in low some improvement in his agitation and speech. However, in light titre at 2.5 (normal < 1.0) U/mL. of his recurrent symptoms and his relatively low anti-GAD anti- During that admission, he had improved without any antimi- body titre, we revisited the working diagnosis of autoimmune crobial or immunotherapy and been discharged with outpatient encephalitis. A repeat lumbar puncture (his third) still showed speech therapy for mild word-finding difficulties. Three months inflammatory cerebrospinal fluid, with a leukocyte count of 31 × later, however, he was again admitted with agitation, confusion 106 cells/L (65% lymphocytes) and elevated protein of 1669 mg/L. and aphasia. A repeat electroencephalogram showed intermit- His CSF immunoglobulin G (IgG) index was elevated and oligoclo- tent seizure activity (Figure 2) and he was started on lacosamide nal bands were present, suggesting intrathecal antibody produc- 200 mg and levetiracetam 500 mg, both administered orally tion that was compatible with autoimmune encephalitis. How- twice daily. Electrographic seizure activity ceased, but his agita- ever, anti-GAD antibody testing in the CSF was negative. tion, confusion and aphasia persisted. Repeat brain MRI at this We also wanted to rule out neurosyphilis, which remained on second hospital admission showed left hippocampal atrophy the differential diagnosis in the absence of serology during the without signal abnormality. Repeat serum anti-GAD antibody previous hospital admissions. Serum treponemal automated was again positive in low titre at 1.9 U/mL, and a repeat lumbar enzyme immunoassay and serum Treponema pallidum particle puncture yielded results similar to those described above. No agglutination assay were reactive and serum quantitative rapid empiric antimicrobial therapy was administered. Because of his plasma reagin was 128, and CSF quantitative venereal disease

E962 CMAJ | JULY 24, 2017 | VOLUME 189 | ISSUE 29 © 2017 Joule Inc. or its licensors PRACTICE E963 cognitive ­cognitive cells/L (100% lympho- immune encephalitis encephalitis ­immune 6 syphilis. The patient had patient had syphilis. The Autoimmune encephalitis Autoimmune encephalitis 2,3 which has rarely been reported in in reported been rarely has which 1 ), On follow-up assessment six months six months On follow-up assessment is the second most common cause of of is the second most common cause abnormali- temporal lobe with encephalitis cytes) and mildly elevated protein of 619 cytes) and mildly elevated protein of 619 had VDRL quantitative CSF the and mg/L, - fallen to 8, confirming response to antimi crobial therapy. Discussion - We present an unusual case of neurosyphi auto mimicking lis 1 (Box research laboratory test (VDRL) was 16, 16, (VDRL) was test laboratory research neuro­ confirming or treat- of syphilis testing no prior history tested long-term male partner ment. His history for syphilis. Focused seronegative and skin of the genitals and examination of primary or second- showed no evidence pupils ary syphilis, and Argyll-Robertson admission to hospital. were not present on 4 million units of intra- He was treated with penicillin G venous aqueous crystalline days. every four hours for 30 clinical improve- later, we noted sustained neuro mild only identifying ment, serum quantitative difficulties. Repeat fell fourfold, to 32. rapid plasma reagin Repeat CSF testing showed a leukocyte count of only 5 × 10 the literature. ISSUE 29 ISSUE | -weighted fluid- 2 VOLUME 189 VOLUME | JULY 24, 2017 JULY | CMAJ

ation at T5-O1 and O1-O2 (circle), with propagation Figure 2: Electroencephalogram showing onset of left temporal-occipital seizure in neurosyphilis throughout the left temporal lobe. Magnetic resonance imaging showing left thalamic and medial temporal lobe signal and medial temporal lobe signal Figure 1: Magnetic resonance imaging showing left thalamic Magnetic resonance imaging T abnormality in neurosyphilis in a 52-year-old man. attenuated inversion recovery (FLAIR) shows hyperintensity of the left dorsomedial thalamus on attenuated inversion recovery (FLAIR) shows hyperintensity anteromedial left the of hyperintensity Subtle images. arrow) (B, coronal and arrow) (A, axial the and coronal (D, arrow) images. temporal lobe is also seen on the axial (C, arrow) PRACTICE a diagnosis of autoimmune encephalitis. bands werepresentintheCSFofourpatient,whichmaysupport causes ofencephalitis.AnelevatedIgGindexandoligoclonal titre positivityinserumshouldmotivateinvestigationforother E964 ties afterherpessimplexvirusencephalitis, crobial therapy who haveneurologicworsening thatisattributed extend totheuncommoncase autoimmune encephalitisisunknown, andthisquestionmay role for immunotherapy in cases of neurosyphilismimicking mediated centralnervoussystem injury.Whetherthereisany occur, blurringthedistinction betweenbacterialandimmune- be requiredforthisunusualpresentationofneurosyphilis to including neurosyphilis. be seen with numerous central nervous systeminfections, in mind, however, that intrathecal antibody production may also of anti-GADantibodyinthecerebrospinalfluid; patients withtype1diabetesmellitus)andintrathecalsynthesis high serumtitres(usuallymorethan100-foldhigher logic disease related to anti-GAD antibody is associated with owing tohispositiveanti-GADserumantibody.However,neuro- initial workingdiagnosisofautoimmuneencephalitis,inpart of thisunusualpresentation. who presentsimilarly, and provide insight intothepathogenesis agnosis in the uncommon case of patients with neurosyphilis important observationsfromourcasemayhelptopreventmisdi- major diagnosticconsiderationinpatientssuchasours.Several infected withHIV. syphilis mimickingautoimmune encephalitisaretypicallynot frequently occursinHIV-infectedpersons,patientswithneuro - tion. Thisissupportedbythefactthatalthoughneurosyphilis nisms mayhavecontributedtoourpatient’sclinicalpresenta - apy in ourcase raises the possibility that immunologic mecha- intrathecal antibodyproductionandresponsetoimmunother - lin intheabsenceofanyantibiotictherapy.Thepresenceboth substantial initialimprovementafterintravenousimmunoglobu - Both our team and our patient’s previous clinicians had an Our patientrespondedtoimmunotherapytwice,includinga • • • been met: Diagnosis canbemadewhenallthreeofthefollowingcriteriahave encephalitis Box 1:Diagnosticcriteriaforpossibleautoimmune encephalitis andneurosyphilis encephalitis, centralnervoussystemWhipple’sdisease,HIV causes suchasherpessimplexvirusencephalitis,HHV-6 Reasonable exclusionofalternativecauses,includinginfectious • • • • At leastoneofthefollowing: status orpsychiatricsymptoms Subacute onsetofworkingmemorydeficits,alteredmental restricted tooneorbothmedialtemporallobes attenuated inversionrecovery(FLAIR)hyperintensityhighly MRI featuressuggestiveofencephalitis,includingT Cerebrospinal fluidpleocytosis Seizures notexplainedbypreviouslyknownseizuredisorder New focalcentralnervoussystemfindings 1 3 Acompetentimmunesystemmaytherefore 3 of patientstreatedwithantimi - 1 Cliniciansshouldkeep CMAJ 4 andisthereforea | JULY 24,2017 1,5 isolatedlow 2 /fluid- | VOLUME 189 reviews thestagesofdisease. simplex virusencephalitis. by thediscoveryofanti-NMDARencephalitistriggeredherpes reached theforefrontofneurologyinrecentyears,asevidenced The interfaceofinfectiousandautoimmuneencephalitishas show neuroinvasivedisease(leukocyte count≥5×10 lumbar punctureisessentialto assessforCSFabnormalitiesthat logic testingispositiveinapatientwithsuspectedneurosyphilis, to aJarisch–Herxheimer-likereactioninthecerebrospinalfluid. from 2.9per100 000in2003to5.82012. The rateofreportedinfectioussyphiliscasesinCanadadoubled Diagnosing andmanagingneurosyphilis date complexmechanismsofdiseaseinpatientssuchasours. this relationship. Itisthereforepossiblethe patienthadcon- seronegative forsyphilis,andhe deniedsexualactivityoutsideof second treponemalassaytominimizefalse-positives. by confirmatorytestingwithanontreponemalassayaswell a chemiluminescent immunoassaystoscreenforsyphilis,followed with most laboratories using treponemal automated enzyme/ infection. Recently, this approach has been reversed in Canada, fluorescent treponemalantibody absorptionassay)toconfirm treponemal assay(Treponema pallidum reagin) havebeenusedtoscreenforsyphilis,followedby a rosyphilis classicallycausesdementiaortabesdorsalis. presents asmeningitisormeningovasculardisease,andlateneu- time duringthecourseofinfection;earlyneurosyphilis typically CSF-VDRL). • • • Box 2:Clinicalstagesofsyphilis Our patient’sexclusivepartner ofmorethan30yearstested Traditionally, non-treponemalassays(VDRL,rapidplasma • • Neurosyphilis (canoccurduringanystageofinfection) • • Late syphilis • • • Early syphilis (causing tabesdorsalis) typically affectingthebrain(causingdementia)orspinalcord Late neurosyphilis:Occursyearstodecadesafterinfection, meningovascular disease after infection,mostcommonlypresentingasmeningitisor Early neurosyphilis:Occurswithinmonthstoafewyears after infection serologic testingwithoutsymptoms,morethanoneyear Late latentsyphilis:Referstodiagnosedby cardiovascular system,orgummatousdisease 1 tomorethan30yearsafterinfection,whichinvolvethe Tertiary syphilis:Referstodiseasemanifestationsoccurring testing withoutsymptoms,withinoneyearofinfection Early latentsyphilis:Referstodiagnosedbyserologic weeks tomonthsafterinfection other symptoms,suchaspharyngitisandmucouspatches, classically involvesthepalmsandsoles,fevermalaise, Secondary syphilis:Referstosystemicillnesswithrashthat of inoculation,afteranincubationperiodaboutthreeweeks Primary syphilis:Typicallyconsistsofpainlesschancreatsite 2 | ISSUE 29 6 Futurestudyinthisfieldmayeluci- 2 Neurosyphilis can occuratany 2 particleagglutination, 6 /L, positive 2 8 Ifsero- 7

Box 2 2

PRACTICE ​ ​ . 9 - www. www. E965 1637- 81: 2013; Available: 32. 2017. Neurology 1129- Can J Infect Dis Med Microbiol 252: 2005; 2015 [updated 2016]. Available: Herpes simplex virus-1 encephalitis canHerpes simplex virus-1 encephalitis Canadian Public Health Laboratory Net- Canadian Public Health Laboratory Use of clinical and neuroimaging charac- Use of clinical and neuroimaging accessed 2017 May 18). www.phac-aspc.gc.ca/publicat/ccdr-rmtc - to diagnosis of autoim A clinical approach J Neurol et al. Spectrum of neurological syndromes associ- Spectrum of neurological syndromes et al. , E et al. - and paraneoplastic limbic encephali Neurosyphilis Infectious syphilis in Canada: 2003–2012. Can Com- Infectious syphilis in Canada: et al. RS, . H, et al. E R, Available: L, et al. , Aguilar www.phac-aspc.gc.ca/std-mts/sti-its/cgsti-ldcits​/section tors of the work. Richard Dr. thank We Acknowledgement: Chan for reviewing the manuscript. Correspondence to: Adrian Budhram, [email protected] content. All authors approved the final version guaran as act to agreed and published be to T Tsang Balu Sheriff Payne MJ, K, , 41-02. R MJ, CA, Sabater Vetter , Y, accessed 2017 May 18). R Available: 2015; Titulaer ; Waltham (MA): UpToDate Neurosyphilis. Fonseca ISSUE 29 ISSUE , Glaser | F MacLean Voltz Titulaer 2016. , , Blanco S R PN, CM. F, FC, A, mun Dis Rep 2015;26(Suppl A):6A-12A. Section 5 — ManagementCanadian guidelines on sexually transmitted infections. Public Health Agency ofand treatment of specific infections — Syphilis. Ottawa: Canada; ( /15vol41/dr-rm41-02/surv-3-eng.php Levett for the use of serological tests (excluding point-of- work laboratory guidelines of syphilis in Canada. care tests) for the diagnosis -5-10-eng.php ( - consider and recommendations Screening Guidelines: Treatment STD 2015 sources. Atlanta: Cen- ations referenced in treatment guidelines and original ters for Disease Control and Prevention; (accessed 2017 May 18). cdc.gov/std/tg2015/screening-recommendations.htm Totten teristics to distinguish temporal lobe herpes simplex encephalitis from its lobe herpes simplex encephalitis from its teristics to distinguish temporal ;60:1377-83. mimics. Clin Infect Dis 2015 Saiz trigger anti-NMDA receptor encephalitis: case report. trigger anti-NMDA receptor Graus Chow accessed 2017 May 18). (accessed 2017 uptodate.com/contents/neurosyphilis Scheid tis: important differential diagnoses. tis: important differential antibodies: diagnostic clues for this ated with glutamic acid decarboxylase :2553-63. association. Brain 2008;131 Leypoldt :391-404. Lancet Neurol 2016;15 mune encephalitis. Marra . . . . 8. 5. 1. 4. 2. 6 9 7 3

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References

VOLUME 189 VOLUME | JULY 24, 2017 JULY | The authors have obtained patient consent. Affiliation: Departments of Clinical Neurologi- cal Sciences (Budhram, Burneo) and Medicine (Silverman), Schulich School of Medicine, Western University, London, Ont., Canada Contributors: Adrian Budhram drafted the manuscript. Michael Silverman and Jorge G. Burneo edited the manuscript for intellectual Success of anti­ of Success 9 10 CMAJ - - Our patient had sustained Our patient had sustained 2 9 Jorge G. Burneo re Burneo G. Jorge In keeping with the Public Health Agency of Canada guideline, Agency of Canada with the Public Health In keeping In light of our experience, we suggest considering syphilis test- In light of our experience, Competing interests: Competing ports research funding and educational grants from UCB Canada, Ontario Brain Institute and Epilepsy Ontario outside the submitted work, and was on the advisory boards of Sunovion inter competing other No Canada. UCB and ests were declared. This article has been peer reviewed. our patient was treated with high-dose intravenous aqueous aqueous intravenous high-dose with treated was patient our neurosyphilis. for G penicillin crystalline clinical improvement after treatment, with both serologic and and after treatment, with both serologic clinical improvement Unfortunately, therapy. to response confirming analysis CSF - to per due possibly persisted, impairment some neurocognitive shown by atrophy of medial temporal manent neuronal injury, lobe structures on MRI. especiallyencephalitis, autoimmune possible with patients in ing on neuroimaging, to those with temporal lobe abnormalities as ours. The US Cen- avoid diagnostic delay in atypical cases such also recommends that ters for Disease Control and Prevention men who have sex withHIV-infected persons and sexually active men be screened for syphilis at least annually.

tracted syphilis more than 30 years ago, and would be classified be classified ago, and would 30 years more than syphilis tracted our in tracing contact rigorous More neurosyphilis. late having as of Canada Public Health Agency required per the case was not and is not is noninfectious because late neurosyphilis guideline, a reportable disease. designated - by clinical improvement or stabiliza microbial therapy is marked count at six months and resolution tion, decline in CSF leukocyte at two years. of all CSF abnormalities