Early neurosyphilis with serofast state

Keywords:

• neurosyphilis
• meningitis
• serofast
• nontreponemal antibodies

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Dear Editor,

Early and late neurosyphilis differ by duration since symptoms onset; which occurs in patients within one or two years from primary infection in the case of early neurosyphilis (1). A variety of neurological symptoms may be observed, such as headaches, cranial nerve palsies, confusion or meningism. Cerebrospinal fluid (CSF) reveals pleocytosis and mildly elevated protein level concentration but asymptomatic meningitis is the most common presentation (1).

Response to treatment is monitored by nontreponemal antibody titer decrease 6 to 12 months after antimicrobial drugs for early neurosyphilis, with serological cure defined as more than a four-fold decline (2). Despite clinical recovery from neurosyphilis, some patients continue to have a persistently positive nontreponemal antibody titer without achievement of a four-fold decline at 6 to 12 months; this serological non-response defines a mismatch called “serofast status” (2–5). This condition has been referred to as “serological failure,” “serological non-response,” “seroresistance,” “reagin-fast.” The median proportion of patients (in all clinical features of syphilis or stages) who had serological non-response was 12.1% overall (interquartile range, 4.9–25.6), but varied depending on the time points after therapy (3). There are few data in the medical literature describing this status in neurosyphilis, with one new case in a recent Turkish cohort of 103 patients living with human immunodeficiency virus (HIV) (6). In, a Chinese systemic review of 7486 confirmed neurosyphilis cases; only 4% presented a serofast status with CSF serological evidence (7).

We report herein a rare case of confirmed early serofast neurosyphilis in HIV-negative patient initially presented with syphilitic meningitis (1) and diagnosed on serology and CSF analysis.

A 67-year-old man presented with a three-day history of generalized motor seizures, drowsiness and became unconscious. He had a past history of hypertension and uncontrolled type 2 diabetes mellitus, with Glycated hemoglobin A1c (HbA1c) at 8%. The patient had not sought antibiotics in the weeks prior to admission. On examination, pulse was 76/min regular, blood pressure was 130/80 mmHg, and Glasgow Coma Scale was 6/15 (Eye opening =4, Verbal response =1, Motor response =1). He was afebrile with normal cardiac and pulmonary auscultation. The patient was admitted in intensive care unit (ICU) for mechanical ventilation.

Electromyography and brain magnetic resonance imaging (MRI) with angio-MRI sequences were normal. COVID-19 real-time polymerase chain reaction (RT-PCR) on nasopharyngeal was negative. Lumbar puncture (LP) showed clear CSF with elevated white blood cell (WBC) count (16/mm³; normal range <5), slightly high total protein level concentration (0.85  g/l; normal range <0.4) and normal CSF glucose concentration (3.6 mmol/L; normal range 2.22–3.89 mmol/L); RT-PCR herpes simplex virus, varicella-zoster virus, Enterovirus spp. and Mycobacterium tuberculosis and Toxoplasma gondii were negative. Serology for Hepatitis B, C and HIV were negative. Treponema pallidum serology was positive with reactive nontreponemal (rapid plasma regain-RPR) and treponemal tests (Table). A reactive venereal disease research laboratory (VDRL) in CSF was positive. A verified neurosyphilis was diagnosed in our patient according to the 2018 CDC criteria’s (8). All samples were analyzed at the National Reference Center for sexually transmitted infections (STIs) at Cochin Hospital in Paris (9,10). The patient completely recovered after receiving a daily intravenous infusion of aqueous crystalline penicillin G 20 million units daily for 14 days (as first line treatment recommended by CDC guidelines) with successful extubation. The patient was also given levetiracetam to control seizures and was discharged from the hospital. One year after, LP follow-up conclude to a normal WBC count with decreased CSF protein concentration (0.74 g/L), decreased CSF albumin level (253 g/L; normal range <350 g/L) and a CSF VDRL negative result. The study of the CSF protein profile by isoelectrofocusing revealed an intrathecal synthesis of total IgG, with a prominent oligoclonal aspect and a high albumin quotient (1.06%; normal range < 0.65%). The patients reported that he had no sexual partner or contact. RPR was performed 3, 6, 12, 24 and 36 months after treatment with no declination of titers which persisted at 16 confirming the serofast state in our patient with no clinical evidence of relapse or affecting any symptoms of hypertension and diabetes afterwards during 3 years’ follow-up.

In this current report, we describe herein a HIV-negative patient who had persistently raised non-treponemal titers following treatment for severe syphilitic meningitis and stated the importance of not misinterpreting the serofast state.

Due to impossible culture in vitro of T. pallidum and poor sensitivity of PCR assay, serological techniques are crucial for the diagnosis and follow-up of syphilitic infections to assess recovery, especially nontreponemal antibodies (5). Serofast status is an uncommon serological event in which nontreponemal antibodies persist after treatment. It is more often reported in elderly patients, with female predominance (2), and immunocompromised patients, especially among people living with HIV (3,11), and patients treated before the secondary stage of syphilis (5). Ren et al. reported that 84/171 (49%) of patients living with HIV achieved seroreversion with a median (95% confidence interval) time of 2 (1.44, 2.68) years. However, Sena concluded that among 333 HIV-negative patients with early syphilis who demonstrated an initial serological response, only 17.1% had seroreversion at 12 months after therapy (12).

After syphilitic infection, treponemal antibodies persist, reflecting the production of specific antibodies by memory B lymphocytes, despite pathogen clearance after treatment (1). Nontreponemal antibodies target cardiolipin, which is one of the main mitochondrial membrane components released by tissue damage caused by infection. These antibodies are autoreactive. Down-regulation is therefore required and expected after treatment, resulting in a decrease in nontreponemal antibody levels. Thus, serofast status or persisting nontreponemal antibodies after effective therapy may thus represent failure of immune tolerance rather than lack of pathogen clearance (3). Liu et al. indicates that anti-neurosyphilis therapy can partially change the serofast status in a study comparing asymptomatic neurosyphilis and serofast control patients. However, the cumulative rates of serological cure in the asymptomatic neurosyphilis group were 9.6, 22.1, 25.9, and 30.2% in 3, 6, 9, and 12 month after treatment, which were statistically higher than those of the serofast control group (13). Another suggested hypothesis in our patient, the serofast state may be persisted by the uncontrolled type 2 diabetes mellitus. It is known that HbA1c is an indicator of diabetes and neurosyphilis, playing an unclear role in blood-brain barrier (BBB) disruption, an essential step in the progression of both diseases (14).

In such situations, several studies suggested that there is no impact on serological response after retreatment (3). Only a small proportion of patients showed seroreversion after retreatment, without being able to conclude whether this was a delayed effect of the initial treatment or a result of retreatment (3). We must be aware of serofast status to correctly inform patients of the absence of contagiousness and not to misinterpret it, given the lack of demonstrated benefit of retreatment.

Conflicts of Interest:

The authors declare no conflicts of interest.

Ethics Statement:

The patient in this manuscript has given written informed consent to publication of his case details.

Table 1. Serologic test results and cerebrospinal fluid analysis in early neurosyphilis patient with seraofast status

		Last 2 years*	At admission	One year follow-up
CSF analysis	WBC count (normal range <5)		16	2
	Protein concentration (normal range < 0.45 g/L)		0.85	0.74
	Glucose concentration (normal range : 2.22–3.89 mmol/L)		5	3.7
	qPCR tpp47/ploA **		Negative	Negative
	VDRL**		Positive	Negative
	CSF albumin (mg/L) (normal range <350 g/L)		488	253
	CSF IgG ((normal range :10-50 mg/L)		151	106
	CSF/serum albumin quotient (Q.alb) (normal range <0.65%)		-	1.06
	CSF/serum IgG quotient (Q.IgG) (normal range <0.7%)		-	0.83
Serum	Treponemal test***	Negative	Positive (>45)	-
	Nontreponemal test (RPR)****	Negative	16	16

Abbreviations: CSF; cerebrospinal fluid; RT-PCR: real-time polymerase chain reaction; RPR: rapid plasma regain; VDRL: venereal disease research laboratory; WBC: white blood cell

*Previous Treponema pallidum serologies were negative in this patient from any time within the last 2 years prior to diagnosis.

**Real-time polymerase chain reaction on QuantStudio™ 5 Real-Time PCR System (ThermoFisher). polA and Tpp47 genes were amplified in LCS using PCR assays.

***Using immunoenzymatic assays for the detection of anti-Treponema pallidum antibodies.

****NADAL® VDRL: Agglutination tests providing a qualitative and semi-quantitative determination of plasma regains (antibodies ‘anti-cardiolipin’ (aCL) against some components of damaged tissue from patients infected with Treponema pallidum).

Funding Information:

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data Availability Statement:

Data available on request due to privacy restrictions. The data presented in this case study are available on request from the corresponding author.