Syphilis in the Brain – Clinics and Management of Neurosyphilis

Alexandra Geusau Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, Medical University of Vienna ESCMID eLibrary © by author Questions

Does neurosyphilis (NS) still exist ??

At which stage does NS manifest ??

How do you diagnose NS ?? ESCMIDHow can NS be eLibrarytreated ?? © by author 25 Incidence rates of Syphilis in Europe / USA Trend 1999-2014 20 Trends of the incidence of syphilis (cases / 100.000 inhab.); no comparison possible due to different case definitions and notification systems EU gesamt* USA all stages Deutschland* 15 Österreich*

Schweiz*

UK* 10 USA primär/sek. Switzer- and USA alle Stadien Austria

Germany

0 ESCMID1999 2000 2001 2002 2003 2004 2005 2006 2007eLibrary2008 2009 2010 2011 2012 2013 2014 © by author Rate of reported confirmed syphilis cases per 100 000 population, EU/EEA, 2014

Source: Country reports from Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, the Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, the United Kingdom.

European Centre for Disease Prevention and Control. Annual epidemiological report 2015. ESCMIDSyphilis. Stockholm: ECDC; 2016. © European Centre for Disease Prevention and Control, 2016.eLibrary Reproduction is authorised, provided the source is acknowledged © by author Neurosyphilis

• In the past decades, the incidence has been on the rise, largely because of an increasing pool of patients infected with syphilis and HIV at increased risk for neurosyphilis • Neurosyphilis is more commonly noted in patients infected with HIV, with a prevalence of 23.5% in HIV-positive patients with untreated late-latent syphilis ESCMID eLibraryChen XS, Lancet 2013 © by author Questions

Does neurosyphilis (NS) still exist ??

At which stage does NS manifest ??

How do you diagnose NS ?? ESCMIDHow can NS be eLibrarytreated ?? © by author Neurological involvement ‚natural progression‘ – no therapeutic intervention

Infection 30-?100% days

‚Neurological Invasion‘ ~ 80% ‚Clearance‘

Failure of the immune system to clear3,2 -the15% organism results5% in neurological complications

ESCMIDGhanem 2010 adapted eLibrary © by author Neurological involvement ‚natural progression‘ – no therapeutic intervention

Infection 30-?100% days ≤12 months ‚Neurological Invasion‘ ~ 80% ‚Clearance‘ 13,5-20%

Asymptomatic Neurosyphilis

The peak incidence of ANS occurs 12-18 months after infection and declines thereafter

ESCMIDGhanem 2010 adapted eLibrary © by author Neurological involvement ‚natural progression‘ – no therapeutic intervention

Infection 30-?100% days ≤12 months ‚Neurological Invasion‘ ~ 80% ‚Clearance‘ 13,5-20%

Asymptomatic Neurosyphilis

1,4-6%

‚Early‘ Meningeal Syphilis

infrequently diagnosed in the pre-HIV penicillin era; now eventually primary manifestation

ESCMIDGhanem 2010 adapted eLibrary © by author • 29- year old male patient

• had recently acquired Human Immunodeficiency virus (HIV) infection • for 6 months patchy hair loss and a history of a single self healing skin lesion in the anogenital area • For 1 week acute loss of vision on left eye

• Diagnosis: Ischemic papillitis → high dose systemic corticosteroids ESCMID eLibrary © by author MR Imaging

ESCMID eLibrary © by author • Syphilis serology 6 months prior: negative at time point of vision loss: positive VDRL reaktive 1:512 TPHA reaktive FTA-Abs reaktive IgM-test reaktive 1:128

• CSF: VDRL reaktive 1:2 TPHA reaktive 1:640, TPHA Index 96 FTA-Abs reaktive IgM-test negative

Diagnosis Neuritis n.optici ESCMIDin early infectious eLibrary syphilis © by author Perimetry left side right side

initially Corticosteroid treatment initiated →

12 days later AB treatment initiated →

10 days ESCMIDlater eLibrary © by author Neurological involvement ‚natural progression‘ – no therapeutic intervention

Infection 30-?100% days ≤12 5-12 months years ‚Neurological Invasion‘ ~ 80% ‚Clearance‘ 13,5-20%

Asymptomatic Neurosyphilis

1,4-6% 3,2-15% ‚Early‘ Meningeal Syphilis

Meningovascular Syphilis

endarteritis of vessels anywhere in the CNS resulting in ESCMIDGhanem 2010 adapted thrombosis and eLibraryinfarction © by author 38 year old patient with a stroke in his medical history

L L

FLAIR, axial T2, coronal

MRI Cerebrum Extensive non recent infarction in the territorium of the left middle cerebral artery with associated cortical atrophy and ESCMIDevacuo dilatation of the left lateral ventricle eLibrary © by author L

MR- angiography Decreased vessel calibre of the left ESCMIDmiddle cerebral artery of the circulosus eLibrary arteriosus Willisi © by author Neurological involvement ‚natural progression‘ – no therapeutic intervention

Infection 30-?100% days ≤12 5-12 months years ‚Neurological Invasion‘ ~ 80% ‚Clearance‘ 13,5-20%

Asymptomatic Neurosyphilis

1,4-6% 3,2-15% ‚Early‘ Meningeal Syphilis younger patients WITHOUT cerebrovascular risk factors Meningovascular > 75% sudden onset (‚syphilitic apoplexy‘) Syphilis mostly middle cerebral artery spinal vascular syphilis less frequent

endarteritis of vessels anywhere in the CNS resulting in ESCMIDGhanem 2010 adapted thrombosis and eLibraryinfarction © by author Neurological involvement ‚natural progression‘ – no therapeutic intervention

Infection 30-?100% days ≤12 5-12 15-25 months years years ‚Neurological Invasion‘ ~ 80% ‚Clearance‘ 13,5-20%

Asymptomatic Neurosyphilis

1,4-6% 3,2-15% 5% 3-9% ‚Early‘ Meningeal Syphilis Parenchymatous Syphilis Meningovascular Syphilis

General Paresis

Tabes ESCMIDGhanem 2010 adapted eLibraryDorsalis © by author 48-year old man; increasing dementia for one year MRI: cortical atrophy of the temporal lobe CSF: 621/3 cells, protein , syphilis serology positive rapid progression of his dementia despite AB therapy, death ► General paresis, Invasion of cerebrum with T.pallidum ► autopsy specimens harbour T.pallidum

ESCMID© Prof. Höftberger, Dept.eLibrary Neuropathology, Medical University Vienna © by author Neurological involvement ‚natural progression‘ – no therapeutic intervention

Infection 30-?100% days ≤12 5-12 15-25 months years years ‚Neurological Invasion‘ ~ 80% ‚Clearance‘ 13,5-20%

Asymptomatic Neurosyphilis

1,4-6% 3,2-15% 5% 3-9% ‚Early‘ Meningeal Syphilis Parenchymatous Syphilis Meningovascular Syphilis

General Paresis

Tabes ESCMIDGhanem 2010 adapted eLibraryDorsalis © by author 42-year old patient (HIV-negative) syphilis Serologie (serum) VDRL 1:8 TPHA pos FTA-Abs pos ESCMIDArgyll-Robertson-pupils eLibraryIgM-test pos 1:16 © by author Tabes dorsalis: Pathologically degeration of the posterior roots and the column of the spinal cord Charcot joints due to diminished reflexes, impaired vibratory sense and proprioreception

ESCMID eLibrary © by author Neurological involvement ‚natural progression‘ – no therapeutic intervention

Infection 30-?100% days ≤12 5-12 15-25 months years years ‚Neurological Invasion‘ ~ 80% ‚Clearance‘ 13,5-20% Neurological symptoms can occur at any stage of infection Asymptomatictherefore Neurosyphilis ONLY LATE MANIFESTATIONS OF NEUROSYPHILIS SHOULD 1,4-6% BE3,2 -ADDRESSED15% 5% AS ‚TERTIARY3-9% SYPHILIS‘ ‚Early‘ Meningeal Syphilis Parenchymatous Syphilis Meningovascular Syphilis

General Paresis

Tabes ESCMIDGhanem 2010 adapted eLibraryDorsalis © by author Frequency of signs and symptoms of neurosyphilis without HIV infection

Sign or symptom Frequency % Asymptomatic < 37 Personality changes / depression, dementia or cognitive 33-86 changes, mania, paranoia Pupillary changes or ophthalmologic symptoms < 43 Hearing impairment, cochlearvestibular dysfunction 3-10 Sensory impairment 24-48 Painful polyradiculopathy, lightning pains rare Myelopathy 9 Parkinsonism, movement disorders rare

Headache 1-25 Hyporeflexia, hypotonia 10-50 Stroke 7-24 Seizures 1-25 Bladder dyfunction rare Gastric or visceral crises rare ESCMID eLibraryCostiniuk CMAJ 2013 © by author Questions

Does neurosyphilis (NS) still exist ??

At which stage does NS manifest ??

How do you diagnose NS ?? ESCMIDHow can NS be eLibrarytreated ?? © by author Diagnostic criteria for neurosyphilis

There is no ‚gold standard‘ test to diagnose neurosyphilis

BUT: a negative treponemal serological screening test rules out neurosyphilis

CDC 2015 ‚confirmed‘ ‚presumptive‘

► any stage of syphilis ► any stage of syphilis with and without clinical symptoms with and without clinical symptoms ► CSF-VDRL reactive ► CSF-VDRL negative (Specificity 99%, Sensitivity max 70%) ► pleocytosis / protein  (CSF) ESCMID ►eLibrarycorresponding symptoms © by author Diagnostic criteria for neurosyphilis

CDC ► pos TPPA test / FTA-Abs test (CSF): not diagnostic BUT: neurosyphilis highly unlikely with negative tests ► pleocytosis: > 5 WBC/mm3 in HIV+ patients higher cutoff >20 WBC/mm3 (under ART) ► protein (CSF): cutoff?; dependent on type of neurosyphilis; >0,4g/l European guidelines

►  intrathecal Ab production: IgG index  0,7, IgM Index  0,10 ► TPHA-index Goh BT Int J STD AIDS 2001;12:S3: 14-26; French P, Int J STD AIDS 2009

► specific intrathecal Ab production: ITpA Index (= intrathecal-produced T.pallidum amtibodies) Schöfer, Hautarzt 2005 ESCMID0,5-2,0 (NS ruled out), > 2,0 (NS possible), >eLibrary 3,0 (NS confirmed) © by author Diagnostic criteria for neurosyphilis

►  intrathecal Ab production: IgG index  0,7, IgM Index  0,10 ► TPHA-index Goh BT Int J STD AIDS 2001;12:S3: 14-26; French P, Int J STD AIDS 2009

► spezifische intrathekale Ak Produktion: ITpA Index (= intrathekal-produzierte T.pallidum Antikörper) ESCMID0,5-2,0 (keine NS), > 2,0 (NS wahrscheinlich), eLibrary > 3,0 (beweisend) © by author Diagnostic criteria for neurosyphilis

►  intrathecal Ab production: IgG index  0,7, IgM Index  0,10 ► TPHA-index Goh BT Int J STD AIDS 2001;12:S3: 14-26; French P, Int J STD AIDS 2009

ITpA-Index Tp.spec. IgG-tire (CSF) x total-IgG (serum)____ total IgG (CSFr) Tp.spec. IgG-titre (serum) intrathecal unspecific IgG- and IgM-antibody-production

IgG-Index IgG (mg/l) (CSF) x Albumin (mg/l) (serum) = IgG (mg/l) (serum) Albumin (mg/l) (CSF)

IgM-Index IgM (mg/l) (Liquor) x Albumin (mg/l) (serum) = IgM (mg/l) (serum) Albumin (mg/l) (Liquor) ‚TPHA-Index‘

= CSF-TPHA-titre albumin quotient Luger, A. F., B. L. Schmidt, et al. (2000). Significance of laboratory findings ESCMIDfor the diagnosis of neurosyphilis.eLibrary Int J STD AIDS 11(4): 224-34. © by author CSF examination is indicated I

• In patients who have syphilis and symptoms or signs suggesting neurologic / psychiatric, or ophthalmic or tertiary disease • In patients who have treatment failure

• NOT in patients who have primary or secondary syphilis as invasion of CSF by T. pallidum accompanied by CSF laboratory abnormalities is common in these stages, unless clinical signs or symptoms of neurologic or ophthalmic involvement • In patients with syphilis of > 1 year duration? ESCMID• In HIV+ patients? eLibrary © by author 265 patients with late latent syphilis at the Medical University Vienna +/- neurological symptoms

Neurosyphilis + - S Sex female [n] 5 (11.6%) 74 (33.3%) 79 (29.8%) male [n] 38 (88.4%) 148 (66.7%) 186 (70.2%) Mean age [y] ± SD 46.7 ± 14.8 48.5 ± 17.2 48.2 ± 16.8 HIV positive [n] 7 65 72 S 43 (16%) 222 265 ESCMID eLibrary © by author Serology (serum)

Blood-VDRL Blood-TPHA Cut off titre ≥ 1:0 > 1:80 Neurosyphilis pos [n] 43 36 neg [n] 0 0 No neurosyphilis pos [n] 116 132 neg [n] 106 4 Sensitivity 100,0% 100,0% Specificity 47,7% 2,9% ESCMIDWöhrl S, GeusaueLibrary A, Acta Derm Venereol 2006 © by author without neurosyphilis neurosyphilis patients

HIV-negative HIV-positive

Blood VDRL Blood VDRL Distribution of VDRL titres in neurospyhilis negative (a) and positive (b) patients. The median VDRL test titre was higher in neurosyphilis patients. The difference was ESCMIDhighly significant (1:32 vs 1:0) eLibrary p<0,001 © by author CSF examination is indicated II

• In patients with syphilis of > 1 year duration? RPR  1:32 in late latent syphilis Marra et al; JID 2004 • In HIV+ patients?? (according to CDC 2015) same criteria as in HIV-neg patients; exception: CD4<350/ul; RPR32) Marra Clin Infect Dis 2004 ESCMID eLibrary © by author …..and in HIV+ patients??

Risk factors for neurosyphilis: ≤350 CD4/ul cell count , RPR>128 - use of ART before syphilis infection reduces odds ratio of neurosyphilis by 65% and the risk of serological ‚failure‘ - most of them (>60%) early manifestations within 9 months - 66% symptomatic (33% Uveitis), 34% ANS Ghanem AIDS 2008 (231 co-infected patients) • Current guidelines for the treatment of syphilis among HIV-infected subjects are based on limited objective data. The optimal antimicrobial regimen to treat syphilis in HIV-infected subjects is unknown ESCMIDBlank et al,eLibrary Sex Transm Infect 2011 © by author Questions

Does neurosyphilis (NS) still exist ??

At which stage does NS manifest ??

CNS involvement can occur during any stage of syphilis

1. Neurological manifestations due to syphilis should always be managed according to the treatment recommendations for neurosyphilis, independent from the stage of syphilis

2. Patients with early infectious syphilis, with CSF laboratory abnormalities in the absence of clinical neurologican findings, should be managed according to ESCMIDthe respective stage eLibrary © by author Treatment of neurosyphilis II

1. CSF examination should be repeated avery 6 months until the cell count is normal. If this is not the case after 2 years retreatment should be considered. CDC 2015

2. A 4-fold decline in serologic RPR titers correlates with resolution of CSF parameters in HIV negative neurosyphilis patients. Marra et al; Clin Infect Dis 2008

3. Response to therapy depends on the stage of infection. Quick resolution in patients with early meningeal neurosyphilis. For late disease, resolution may not occur Simon RP, Neurosyphilis Arch Neurol 1985 ESCMIDHahn et al,eLibrary Arch Neurol Psychiatr 1959 © by author ….what else?

ESCMID eLibrary © by author . 35 year old male patient, HIV + (2007),CD4-cells: 351/ul, HIV RNA (Plasma): 3,80 log c/ml, HIV RNA (CSF): 2,44 log c/ml . Atripla 600 mg/200 mg/245 mg . forgetful, disoriented, amnestic syndrome . dermatologically without path. findings

cMRT: . Swelling, FLAIR hyperintense signal alteration of the der temporal lobe . Hippocampus and insula bilat. affected ESCMID. Diffusion restricted (left > right) eLibrary © by author Syphilis-Serology / Serum: VDRL reaktive, titer 1:64 TPPA positive (titer 1:524.880) IgM-ELISA positive Syphilis Serology /CSF): TPPA positive (titer 1:2621440) FTA-Abs-Test positive VDRL reaktive, titer 1:8 ITpA 13,6 (pos > 3)

- The clinical picture of NS often non-specific and may develop at any time - also in immunocompetent patients - In HIV+ patients NS - more fulminant course - Change in the interval early syphilis and NS manifestations

- ? Standard BPG inefficient ? - existence of ‚particularly‘ neuroinvasive T.pallidum strains ESCMID eLibraryDrago et al, JEADV 2016 © by author Thank you for your attention ESCMID eLibrary © by author