NeurosyphilisA52.1; A52.2; A52.3

Infection of the CNS through the spirochetes Treponema pallidum. Early syphilitic infection of the CNS can either heal spontaneously (in the majority of cases) or persist as asymptomatic or symptomatic syphilitic meningitis in the first weeks and months after infection. Tertiary central nervous syphilis is the most important form of late manifestation of syphilis. It is significantly more frequent than the cardiovascular form of late syphilis (Landry T et al. 2019). Untreated, the central nervous system infection can usually progress to meningovascular syphilis (endarteritis obliterans the small vessels of the meninges, brain and spinal cord) about 5-12 years after the primary stage, or to the parenchymatous form of neurosyphilis (tabes dorsalis, paralytic neurosyphilis) after 18-25 years. In about 30% of syphilis-infected patients, neurosyphilis as a manifestation of the tertiary stage is asymptomatic. It is then a pure liquor-serological diagnosis. In a few cases, ocular symptoms (syphilitic uveitis: unspecific anterior uveitis, acute syphilitic posterior placoid chorioretinitis, panuveitis, indications of neurosyphilis (Gutierrez B et al. 2019). In other cases the vascular involvement leads to an unusual apoplexy symptomatology occurring in middle-aged patients.

Asymptomatic neurosyphilis is often also observed in HIV-infected patients with low CD4 cell counts (Hobbs E et al. 2018). Thus, in HIV-positive patients with a positive syphilis serology, the "European Guidelines of Syphilis" recommend a lumbar puncture for clarification.

Neurosyphilis has various forms of manifestation:

• Syphilitic meningitis
• Meningovascular syphilis (involvement of the small vessels of the meninges, brain and spinal cord)
  • Rare: Isolated syphilitic meningomyelitis
  • Rare: Isolated spinal vascular neurosyphilis
• Asymptomatic syphilis: asymptomatic neurosyphilis is defined when there is positive syphilisserology, lymphocytic pleocytosis and CSF protein elevation and/or positive VDRL test in CSF, but no clinical symptoms (AWMF guidelines).
• Parenchymatous neurosyphilis
  • Tabes dorsalis
  • Progressive paralysis
• Syphilitic gummata

There are no current data on the actual incidence of neurosyphilis.

Before the introduction of antibiotic therapy, neurosyphilis(tertiary syphilis) was a common complication of syphilis. About 25 to 30% of infected persons developed neurosyphilis. Of these patients, about 30% each had asymptomatic neurosyphilis or tabes dorsalis; about 10% had progressive paralysis. However, the neurosyphilitic tertiary stage is still found in developing and emerging countries with inadequate health care (Elmouden H et al. 2019).

The clinical symptoms of syphilitic CNS infestation vary depending on the stage of the disease and the pattern of infestation. In the secondary stage, meningitis, polyradiculitis and rarely vascular brain stem syndromes are possible. Syphilitic meningitis is characterized by meningism, headache and cranial nerve lesions (optionally N. VIII, VII and III).

Meningovascular neurosyphilis: Meningovascular neurosyphilis is predominantly an endarteritis obliterans the small and medium-sized vessels of the meninges, brain and spinal cord. Furthermore, obliterating endarteritis may be present, affecting the medium-sized vessels at the base of the brain (A. cerebri media and branches of A. basilaris). Meningovascular neurosyphilis occurs 5-12 years after the primary stage. Since it can affect any part of the brain, the symptoms are varied. Involvement of cerebral vessels leads to arterial occlusion and a corresponding failure symptomatology (Shi M et al. 2019).

Note: The angiitic infestation of the A. cerebralis media can lead to its occlusion and to apoplectic insult (unusual apoplectic symptoms in medieval patients). Psychiatric changes may precede an occlusion symptomatology.

Parenchymatous neurosyphilis

In parenchymatous neurosyphilis there is a progressive breakdown of nerve tissue in the brain and/or spinal cord. Parenchymatous neurosyphilis appears 18-25 years after the primary stage as progressive paralysis or tabes dorsalis.

Progressive par alysis (paralytic neurosyphilis; dementia paralytica; general paresis): Progressive paralysis has become rare due to the current diagnosis and therapy of syphilis. It represents a chronic progressive encephalitis and is characterized by progressive dementia. Typical are psychotic symptoms such as delusions (especially megalomania) and personality disorders. Further severe depression, tongue tremor, speech disorders, headache and dizziness, abnormal pupil reaction (Argyll-Robertson sign with reflex pupil rigidity and often exuberant convergence reaction), "mimic tremor", epileptic seizures, reflex anomalies, urinary and fecal incontinence, marasmus.

Tabes dorsalis: The tabes dorsalis (tabes = putrefaction, decay) describes a syphilitic demyelination of the posterior spinal cord strands and the dorsal roots with chronic leptomeningitis. Untreated, tabes dorsalis occurred in about 30% of all patients with neurosyphilis. Today, this advanced form of parenchymatous syphilis is rare in industrialised countries, but should be considered for differential diagnosis in developing countries (Elmouden H et al. 2019). The symptoms appear 25-30 years after the primary infection. Lancing pain of the lower extremity and abdomen, cramps, ataxias, paresthesias, loss of depth and vibration sensitivity, loss of muscle reflexes, optic nerve damage are essential symptoms of this disease. Due to the sensitivity disorders, there is an incorrect loading of joints and plantar surfaces with consecutive mutilations (Charcot joints). The Argyll-Robertson phenomenon (a reflex pupil rigidity) is detectable in 60-70% of infected patients.

Syphilitic gums: Gums as circumscribed, space-occupying granulomas are very rare today. They develop from the meninges at the brain convexity (Soares-Fernandes et al. 2007). Depending on their location, they are clinically silent or cause focal symptoms. A polytopic appearance of the gums is called "gummy neurosyphilis".

The suspicion of neurosyphilis results either from anamnestic information about a previous syphilitic sexually transmitted disease or from a reactive treponemenserology with concomitant neurological and/or psychiatric symptoms. Note: Clinically decisive is to know that a negative treponema-specific syphilis screening test (e.g. TPPA or FTA-abs test) in serum definitely excludes neurosyphilis! Furthermore, it is important that all patients who have been serologically diagnosed with active, late-manifest syphilis must be examined for the presence of neurosyphilis. A lumbar puncture (LP) is indicated to clarify this.

Furthermore, LP is indicated in the following constellations: VDRL titre>1:32 in late latency, in HIV-positive patients in late latency, in serologically positive patients with neurological or psychiatric symptoms independent of the stage of syphilis. Note: in HIV infected patients, in rare cases, the TPPA, FTA-Abs and VDRL tests may be false negative, making the diagnosis of neurosyphilis more difficult. CSF testing is not indicated for early syphilis unless neurological, ocular or psychiatric symptoms are present.

The following diagnostic measures and examination steps are necessary to confirm the diagnosis of neurosyphilis:

• Imaging procedure (cMRI)
• Lumbar puncture with determination of cell count, total protein, cerebrospinal fluid lactate
• CSF serology: Synchronous analysis of CSF and serum to calculate the L/S ratios for albumin, IgG, IgA, IgM and an antibody index for treponema antibodies (e.g. ITpA index). Once the diagnosis of a confirmed syphilitic CNS infection has been established, the clinical activity of the process is checked.
• VDRL test: positivity in CSF is considered diagnostic evidence of neurosyphilis. The sensitivity of the VDRL test in CSF is 70% with a high specificity of 99%.
• Treponema-specific antibody tests (TPPA; FTA-abs test): CSF positivity is not diagnostic evidence. However, CSF negativity speaks against the presence of neurosyphilis.
• Liquor chemistry: Pleocytosis (cell count >5-10 leukocytes / μl) as well as an elevated cerebrospinal fluid protein (>0.4g/l) are regarded as markers for an inflammation of the cerebrospinal fluid space.
• ITpA index (iTpA=intrathecal produced T. pallidum antibodies): The iTpA index is calculated as the quotient of T. pallidum specific antibody titer in serum and CSF. ITpA>2.0 - neurosyphilis probable, ITpA>3.0 - indicating neurosyphilis.
• Other CSF indices are:
• IgG Index: IgG (CSF)/IgG(Serum)x Albumin(Serum)/Album (CSF): IgG Index >0.7 =increased
• IgM index: IgM(CSF)/IgM(serum)x Albumin(serum)/Album (CSF): IgM index >0.1 =increased
• The following signs indicate the activity of the infection:
• Treponemia-specific IgM detectable in serum (and no therapy performed in the last 12 months)
• Mononuclear pleocytosis in cerebrospinal fluid
• Very high pathogen-unspecific antibody titers in serum and CSF, e.g. VDRL test (Veneral Disease Research Laboratory) positive in CSF
• ITpA index>2.0 - neurosyphilis probable, ITpA>3.0 - proving neurosyphilis.
• Progression of neurosyphilis-typical symptoms (increase in cognitive deficits, increase in lanzinating pain or posterior strand ataxia)

The differential diagnosis must be adapted to the different stages of the disease:

• In the secondary stage "aseptic" meningitis of other aetiology must be excluded. Co-infections of syphilis and HIV are of increasing importance because of overlapping risk groups.
• Herpes virus infections (herpes simplex, varicella zoster, cytomegaly, Epstein Barr) must be excluded in the case of cranial nerve lesions (diagnosis: CSF PCR, intrathecal antibody synthesis).
• In case of meningovascular neurosyphilis, a septic-embolic herd encephalitis must be excluded!
• Furthermore a zoster vasculitis, a Borrelia vasculitis, vasculitides in mycoplasmas and others, vasculitides in autoimmune diseases, a tuberculous meningitis.
• In progressive paralysis: all chronic encephalitis courses including multiple sclerosis, progressive multifocal leukoencephalopathy, CMV encephalitis and Whipple's disease.)
• In tabes dorsalis: funicular spinal disease in B12 avitaminosis, "pseudotabes" diabetica, uremica, porphyrica and alcoholica (AWMF Guidelines 2010).

The first-line therapy for neurosyphilis is penicillin G in crystalloid solution, administered intravenously at 18- 24 million IU/d (4 x 6 million, 5 x 5 million or 3 x 10 million IU per day, corresponding to 3-4 million IU every 4 hours) for 14 days (minimum 10)(AWMF Guideline 2020).

Assessment of treatment success by:

• clinical (improvement of symptoms if present)

• decrease of CSF parameters (pleocytosis, CSF protein), repetition approx. 6 months after therapy.

• VDRL test (in serum and CSF) quarterly, in this case usually a drop of 3 - 4 titer levels (with successful therapy) within one year.

(from S1 Guideline - Neurosyphilis, 2020)

Alternative: 2g Ceftriaxon/day(initial dose 4 g) for 10-14 days

Alternative: doxycycline 2 × 200mg for 28 days. However, tetracyclines are contraindicated in pregnancy and children up to 8 years of age.

Adjunctive therapy: Epileptic seizures are treated according to anticonvulsant therapy guidelines.

Lancinating pain (it is mostly refractory to usual analgesics): carbamazepine, gabapentin, pregabalin, amitryptiline or flupirtine.

Hydrocephalus (very rare late complication): shunt implantation.

Psychotic episodes and confusion syndromes: anxiolytics and/or neuroleptics.

Note a Jarisch-Herxheimer reaction which, however, occurs in neurosyphilis in only 1-2% of cases. The Jarisch-Herxheimer reaction occurs 12-24 hours after the start of antibiotic treatment (fever, headache or muscle pain, fatigue, tachycardia, leukocytosis and relative lymphopenia). Furthermore, seizures and/or worsening of neurological deficits may occur.

See also p.11 of the current guidelines of the STI Society.

In the tertiary stage, even high doses of antibiotics are usually only able to heal defects, because on the one hand, the inflammatory process, which has developed over a long period of time, only subsides slowly.

Course: a successful treatment is recognizable by:

• Decrease in cerebrospinal fluid pleocytosis (if present) within several weeks Normalisation of the blood-cerebrospinal fluid barrier within a few months
• Decreasing IgM antibody kinetics in serum within 6-12 months (negative results are usually observed within 18 months) However, in case of reinfection or if there is a long time interval between infection and therapy start, treponeme-specific IgM antibodies may remain detectable in the serum for a longer time.
• Decreasing lipoid antibody kinetics (VDRL, cardiolipin-KBR); within the first year a decrease in titer by 3-4 dilution levels is often observed. However, in the case of reinfections or a long time interval between infection and the start of therapy, lipoid antibodies may remain detectable for longer.

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