Reference Work Entry

Encyclopedia of Molecular Mechanisms of Disease

pp 2011-2012

Syphilis of the Central Nervous System

  • Hilmar PrangeAffiliated withDepartment of Neurology, Georg-August-University Goettingen

Synonyms

Neurosyphilis; Neurolues; Tabetic, paretic, and meningovascular neurosyphilis; Syphilitic meningitis (primosecondary stage); Syphilis cerebrospinalis

Definition and Characteristics

Infection by Treponema pallidum (T.p.) induces syphilis – a multistage complaint with varying organ manifestations und courses. Syphilitic involvement of central nervous structures may occur in all stages after infection. Syphilitic meningitis in the primosecondary stage results in headache, nausea, vomiting, and stiff neck, at times combined with cranial nerve alterations (predominantly nerves II, VII, and VIII). Patients are usually afebrile. Laboratory indicators of inflammation such as increased sedimentation rate or C-reactive protein are mostly absent as are intrathecally synthesized antibodies against T.p.

CNS manifestations of tertiary syphilis are meningovascular neurosyphilis (syphilis cerebrospinalis), general paresis, and tabes dosalis. Meningovascular neurosyphilis usually occurs 4–7 years after infection. The inflammatory process subacutely takes place on meningeal and vascular tissues of the CNS, in some cases mainly cerebral while in others mainly spinal. Meningovascular neurosyphilis is extraordinarily variable. Early symptoms are vision impairment, vertigo, mono- or hemipareses (with stroke-like onset), headache, hearing loss, gait disturbances, and behavioral deviations. In progressed stages, syndromes of brain stem/cranial nerves (e.g., eighth cranial nerve), hemisyndromes, syndrome of chronic meningitis, spinal syndromes, epilepsy, and dementia may exist.

Tabetic neurosyphilis (tabes dorsalis) presents with a well-defined syndrome, characterized by episodic lightning pains, absent ankle and knee jerks, abnormal pupils (up to 66%), hyperflexibility of the hip joints, pallhypesthesia, gait disturbances, atonic bladder, and optic nerve atrophy. Most frequent initial symptoms are lightning pains, impairment of the vision, “locomotor” ataxia, gastric and visceral crises, paraesthesias, and vertigo.

Paretic neurosyphilis (general paresis, dementia paralytica) develops as a result of a chronic progressive meningoencephalitis about 10–20 years after T.p. infection. Initially, there are slight behavioral changes, subtle deterioration in cognitive functions, dysarthria, complaints of headache, and vertigo. Progressed complaint presents with organic brain syndrome, psychotic episodes, abnormal pupils, tremor of the tongue and hands, epileptic fits, eventually speech destruction, tetraparesis as well as loss of bowel, and bladder control. If untreated, general paresis is fatal in 3–5 years.

Prevalence

According to the WHO global estimates, over 12 million cases of syphilis exist worldwide. For Germany, the Robert Koch Institute reported in July 2005 an incidence of syphilis infections with 3,450 cases annually (4.1 per 100,000); 5–9% of untreated patients develop CNS involvement. Because most of the infected are treated with antibiotics during the early stage, at present the prevalence of neurosyphilis is low. However, male homosexuals represent a group at increased risk. With them, co-infection of syphilis and HIV are not infrequent, resulting in a special disposition to treponemal CNS infections.

Genes

A genetic disposition to syphilitic CNS involvement is not known so far. Yet, the genome of T.p. was clarified. The organism contains a single circular chromosome with 113,806 bp, an average G + C content of 52.8%, and no extrachromosomal elements. Lipoprotein genes comprise 2.1% of the open reading frames. There are observations suggesting that lipoproteins are involved in the host–pathogen interactions. Interestingly, in the genome of T.p., a gene family with 12 members, termed tpr, has been discovered. Although a consensus lipoprotein sequence is missing, three members (tprF, tprI, and tprK) may be associated with the outer membrane of T.p. Some findings suggest that tprK has the capacity to undergo recombination with generation of new alleles or gene variants [1]. This could provide an explanation for the ability of T.p. to evade the host defense system, surviving in the host, and inducing multistage protean clinical manifestations.

Molecular and Systemic Pathophysiology

Treponemal lipoproteins may be involved in the initial inflammatory processes that occur in the primary lesion after infection. Signal transduction in host phagocytes is mediated by toll-like receptor-2, which reacts with the lipoproteins inducing an intracellular signal cascade. This process ends in the expression of genes designated for infection defense. Besides the activation of transcription factors NF-kappaB and AP-1 in the antigen presenting cells, co-stimulating molecules like B7 and MHC are upregulated and the pro-inflammatory cytokines Il-6, Il-12, and TNF-alpha are released. An additional role may play an initial signaling or binding event with the CD-14 receptor activating the production of Il-6, Il-8, and PAF.

In the dermal lesion of primary syphilis, the local defense of the host is characterized by predominating T cell infiltrates, preferentially T helper/inducer cells. In secondary syphilis lesions, the ratio of T helper/inducer and suppressor/cytotoxic cells is approximately equal with tendency in favor of the latter [2]. The increased count of T-suppressor cells in these lesions is thought to result in the natural shutdown of the early vigorous immune response following clearance of most of the organisms from the lesions, ushering in the latent stage of syphilis. In this stage, intermittent bacteremia occurs enabling T.p. to penetrate parenchymatous organs like the CNS. Additional virulence factors may be the bacterial phosphodiesterase neutralizing antibodies and the deposition of host`s MHC class I molecules onto surface of T.p., probably resulting in an impairment of regulation processes between immune cells [3]. Tertiary stage organ manifestations are characterized by plasma cell infiltrations and obliterative endarteritis reflecting an (hyperergic) immunological reaction.

Diagnostic Principles

Syphilis of the central nervous system is to be verified by serologic tests (TPPH-, FTA-, and VDRL-test) and CSF analysis. In the early stage of syphilis, T.p. can be demonstrated in CSF using fluorescent or darkfield microscopy. T.p. PCR is an alternative option with undefined sensitivity so far. Further CSF analysis, carried out in all stages of syphilis, includes cell counts, determination of total protein, albumin, and IgG (IgM and IgA) concentrations, and isoelectric focusing for oligoclonal IgG bands. Albumin and immunoglobulin determination as well as oligoclonal antibody detection should be performed simultaneously in serum and CSF samples to obtain CSF/serum quotients. CSF/serum quotients of IgG, IgM, and IgA as compared with the albumin quotient can give indications to intrathecal immunoglobulin synthesis. By this means, an IgG-index calculated >0.69 substantiates a local humoral immune response within the CNS. To verify the syphilitic cause of the latter, the local production of antitreponemal antibodies must be proven by calculating an antibody index (CSF/serum quotient of antibody concentrations divided by IgG quotient). Antibody index >2 points to syphilitic CNS involvement with probability; index >3 proves neurosyphilis with specificity of 100 and sensitivity of 84% [4].

The activity of the syphilitic CNS process can be ascertained by CSF pleocytosis, proof of antitreponemal IgM antibodies in serum (T.p. IgM-ELISA, 19S-(IgM)FTA-ABS test) and positive VDRL test. However, in later stages, pleocytosis is absent in about 1/3 of cases with untreated neurosyphilis.

Therapeutic Principles

Therapy of the first choice is penicillin G in high doses; ceftriaxone represents an equivalent alternative. These beta-lactam antibiotics inhibit the treponemal transpeptidase by irreversibly binding at the C7 atom of the beta lactam circle. Thus, the peptidoglycan structure of bacterial wall ruptures.

In vitro concentrations that immobilize 50% of the treponemes are 0.002 μg penicillin G/ml and 0.01 μg ceftriaxone/ml. These concentrations should be exceeded tenfold in vivo. Doses of penicillin G of 20 million IU/day and 2 g ceftriaxone/day (initial 4 g) are adequate to achieve corresponding CSF concentrations [5]. In patients allergic to beta-lactam antibiotics alternatively doxycyclin can be administrated (at least 200 mg daily for 28 days).

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© Springer-Verlag GmbH Berlin Heidelberg 2009
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