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

Syphilis in the Brain – Clinics

and Management of

Neurosyphilis

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Does neurosyphilis (NS) still exist ??

At which stage does NS manifest ??

How do you diagnose NS ??

How can NS be treated ??

Questions

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0

5

10

15

20

25

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

EU gesamt*

Deutschland*

Österreich*

Schweiz*

UK*

USA primär/sek.

USA alle Stadien

USA all stages

Austria

Switzer-

and

Germany

Trends of the incidence of syphilis (cases / 100.000 inhab.); no comparison

possible due to different case definitions and notification systems

Incidence rates of Syphilis in Europe / USA

Trend 1999-2014

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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.

Syphilis. Stockholm: ECDC; 2016. © European Centre for Disease Prevention and Control, 2016. Reproduction is authorised, provided the source is acknowledged ESCMID eLibrary

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• 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 syphilisChen XS, Lancet 2013

Neurosyphilis

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Questions

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Infection

‚Neurological Invasion‘

‚Clearance‘

3,2-15% 5%

~ 80%

30-?100%

Ghanem 2010 adapted

Failure of the immune system to

clear the organism results in

neurological complications

days

Neurological involvement‚natural progression‘ – no therapeutic intervention

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Infection


Asymptomatic Neurosyphilis

‚Clearance‘ 13,5-20%~ 80%

30-?100% days ≤12

months

Ghanem 2010 adapted

The peak incidence of ANS

occurs 12-18 months after

infection and declines thereafter


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Infection

‚Early‘ Meningeal

Syphilis



‚Clearance‘

1,4-6%

13,5-20%~ 80%

30-?100% days ≤12

months

Ghanem 2010 adapted

infrequently diagnosed in the

pre-HIV penicillin era; now

eventually primary manifestation


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• 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

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MR Imaging

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• 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.opticiin early infectious syphilis ESCMID eLibrary

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Perimetryleft side

initiallyCorticosteroid

treatment

initiated →

right side

12 days

later

10 days

later

AB treatment

initiated →

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Infection


Syphilis



‚Clearance‘

Meningovascular

Syphilis

1,4-6% 3,2-15%

13,5-20%~ 80%

30-?100% days ≤12

months

5-12

years

Ghanem 2010 adapted

endarteritis of vessels anywhere

in the CNS resulting in

thrombosis and infarction


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FLAIR, axial T2, coronal

L L

MRI Cerebrum Extensive non recent infarction in the territorium of

the left middle cerebral artery with associated cortical atrophy and

evacuo dilatation of the left lateral ventricle

38 year old patient with a stroke in his medical history

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L

MR- angiography Decreased vessel calibre of the left

middle cerebral artery of the circulosus arteriosus Willisi ESCMID eLibrary

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Infection


Syphilis



‚Clearance‘

Meningovascular

Syphilis

1,4-6% 3,2-15%

13,5-20%~ 80%

30-?100% days ≤12

months

5-12

years

Ghanem 2010 adapted

endarteritis of vessels anywhere

in the CNS resulting in

thrombosis and infarction

younger patients WITHOUT

cerebrovascular risk factors

> 75% sudden onset (‚syphilitic apoplexy‘)

mostly middle cerebral artery

spinal vascular syphilis less frequent


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Infection


Syphilis



‚Clearance‘

Meningovascular

Syphilis

General Paresis

Tabes

Dorsalis

1,4-6% 3,2-15% 5% 3-9%

13,5-20%~ 80%

30-?100% days ≤12

months

5-12

years

15-25

years

Ghanem 2010 adapted

Parenchymatous

Syphilis


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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

© Prof. Höftberger, Dept. Neuropathology, Medical University Vienna ESCMID eLibrary

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Infection


Syphilis



‚Clearance‘

Meningovascular

Syphilis

General Paresis

Tabes

Dorsalis

1,4-6% 3,2-15% 5% 3-9%

13,5-20%~ 80%

30-?100% days ≤12

months

5-12

years

15-25

years

Ghanem 2010 adapted

Parenchymatous

Syphilis


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Argyll-Robertson-pupils

42-year old patient (HIV-negative)

syphilis Serologie (serum)

VDRL 1:8

TPHA pos

FTA-Abs pos

IgM-test pos 1:16 ESCMID eLibrary

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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

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Infection


Syphilis



‚Clearance‘

Meningovascular

Syphilis

General Paresis

1,4-6% 3,2-15% 5%

13,5-20%~ 80%

30-?100% days ≤12

months

5-12

years

15-25

years

Ghanem 2010 adapted

Tabes

Dorsalis

Parenchymatous

Syphilis

3-9%

Neurological symptoms can occur at any stage of infection

therefore

ONLY LATE MANIFESTATIONS OF NEUROSYPHILIS SHOULD

BE ADDRESSED AS ‚TERTIARY SYPHILIS‘


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Sign or symptom Frequency %

Asymptomatic < 37

Personality changes / depression, dementia or cognitive

changes, mania, paranoia

33-86

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

Frequency of signs and symptoms of neurosyphilis without HIV infection

Costiniuk CMAJ 2013 ESCMID eLibrary

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Questions

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There is no ‚gold standard‘ test to diagnose neurosyphilis

CDC 2015

BUT: a negative treponemal serological screening test

rules out neurosyphilis

‚confirmed‘ ‚presumptive‘

► any stage of syphilis with and without clinical symptoms

► CSF-VDRL reactive(Specificity 99%, Sensitivity max 70%)

► any stage of syphilis with and without clinical symptoms

► CSF-VDRL negative

► pleocytosis / protein (CSF)

► corresponding symptoms

Diagnostic criteria for neurosyphilis

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► 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

CDC

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

0,5-2,0 (NS ruled out), > 2,0 (NS possible), > 3,0 (NS confirmed) ESCMID eLibrary

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CDC

European guidelines

► spezifische intrathekale Ak Produktion: ITpA Index(= intrathekal-produzierte T.pallidum Antikörper)

0,5-2,0 (keine NS), > 2,0 (NS wahrscheinlich), > 3,0 (beweisend)


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CDC

European guidelines

► specific intrathecal Ab production: ITpA Index(= intrathecal-produced T.pallidum amtibodies) Schöfer, Hautarzt 2005

0,5-2,0 (NS ruled out), > 2,0 (NS possible), > 3,0 (NS confirmed)








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Tp.spec. IgG-tire (CSF) x total-IgG (serum)____

total IgG (CSFr) Tp.spec. IgG-titre (serum)

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)

intrathecal unspecific

IgG- and IgM-antibody-production

Luger, A. F., B. L. Schmidt, et al. (2000). Significance of laboratory findings

for the diagnosis of neurosyphilis. Int J STD AIDS 11(4): 224-34.

‚TPHA-Index‘

ITpA-Index

= CSF-TPHA-titre

albumin quotient


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• 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?

• In HIV+ patients?

CSF examination is indicated I

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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 43 222 265(16%)

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Serology (serum)

Cut off titre

Blood-VDRL

≥ 1:0

Blood-TPHA

> 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%

Wöhrl S, Geusau A, Acta Derm Venereol 2006 ESCMID eLibrary

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without neurosyphilis neurosyphilis patients

HIV-negative HIV-positive

negneg pos

Blood VDRL

pos

Blood VDRL ESCMID eLibrary

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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

highly significant (1:32 vs 1:0) p<0,001

Blood VDRL Blood VDRL

neurosyphilis patientswithout neurosyphilis

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• 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; RPR32) Marra Clin Infect Dis 2004

CSF examination is indicated II

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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

Blank et al, Sex Transm Infect 2011

…..and in

HIV+ patients??

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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

the respective stage

CNS involvement can occur during any stage of syphilis

Treatment of neurosyphilis I

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Follow-up of patients with

neurosyphilis

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

Hahn et al, Arch Neurol Psychiatr 1959 ESCMID eLibrary

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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

Diffusion restricted (left > right) ESCMID eLibrary

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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)

Diagnosis

Syphilitic encephalitis ESCMID eLibrary

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- 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

Changes in neurosyphilis (NS)

Drago et al, JEADV 2016 ESCMID eLibrary

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Syphilis in the Brain – Clinics and Management of Neurosyphilis

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