Syphilitic Gummata in the Central Nervous System: A Narrative Review and Case Report about a Noteworthy Clinical Manifestation

Infection with Treponema pallidum is on the rise. In this narrative literature review, we show that the incidence of rare manifestations of syphilis, such as intracerebral gummata, is increasing and should be considered in the differential diagnosis of intracerebral lesions. With the exemplary case that we present here, we aim to raise awareness of the resurgence of this disease, which should be considered in the differential diagnosis of intracerebral lesions, especially for patients who have a risk profile for syphilis, and serological testing for T. pallidum prior to surgery should be discussed in order to avoid an unnecessary operation.


Introduction
Treponema pallidum is a Gram-negative, spiral-shaped bacterium (spirochete) of the family Spirochaetaceae that causes syphilis in humans [1,2]. The clinical manifestations of syphilis are diverse and depend on the stage of the disease, which can cause difficulty in distinguishing syphilis from other pathologies. After the Second World War, the worldwide incidence of syphilis decreased because of the efforts of the World Health Organization's global health programs and the central health policies of the former Soviet Union [3,4]. However, the incidence has been increasing in Eastern European and Western countries, particularly among men who have sex with men (MSM) [3,5]. Neurosyphilis can occur at any time after an initial infection [6,7]. On the basis of clinical examination and laboratory findings, its manifestations can be classified according to disease phase as early, early or late, and late [7]. Early-stage neurosyphilis can be asymptomatic, although the meninges are usually involved. Meningovascular involvement can be present in the early or late phase [7]. The late phase is characterized by general paresis or tabes dorsalis. Syphilitic gummata usually occur in tertiary syphilis, a stage in which blood vessels, the heart, and the nervous system are affected. However, syphilitic gummata are rare and therefore not integrated into the aforementioned neurosyphilis classification scheme. Although the incidence of syphilitic gummata is low, an increased number of patients with intracerebral gummata should be expected in the future due to the recent increase in the incidence of syphilis. To the best of our knowledge, there are no reliable data regarding the prevalence or incidence of neurosyphilitic gummata. We therefore conducted a literature review of articles concerning syphilitic gummata in the central nervous system that were published

Review
We have identified and extracted data from 49 neurosyphilitic gumma cases in addition to our case since 1990. An additional report describes six cases from the U.S. However, no conclusions can be drawn from the patient-specific information (report from 1992) [8].
In total, 8 of the 50 cases were women (mean age, 49.6 years; range, 37-65) and 42 were men (information about age was given in 39 cases: mean age, 45.5 years; range, 20-75). For two men, no age was reported; the age of one man was described as "in his 30s." Among the 42 men, 5 were reported to be heterosexual (mean age, 46.6 years; range, [41][42][43][44][45][46][47][48][49][50][51][52][53][54]. MSM was reported for four cases (mean age, 50 years; range, [42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61], and two of them were human immunodeficiency virus (HIV)-positive aged 42 and 46 years. Otherwise, 33 had no sexual preference reported. Overall, 14 of the men were HIV-positive (33.3%), and 2 of the 5 heterosexual reported men were HIV-positive. Among the men whose sexual preference was not reported, 14 were HIV-positive (42.42%). None of the women were reported to be HIV-positive, although HIV status was not reported for one case. Surgery was performed in 28 patients (56%), and 21 received conservative treatment only (42%). Information about surgery was not reported in one patient. In Table 1 are all 50 cases listed by location of the gumma, sex, MSM, age, HIV status, and country of the report. Many cerebral syphilitic gummata were reported in North America at the beginning of the 1990s. Since 2000, cases have been reported in Europe, and an increase in the overall number of reported cases began in 2016, predominately in China and Japan. In Table 2, it is shown how the patients clinically presented, whether the patients underwent an operation, which drug treatment was carried out, and the clinical outcome of the patients. As is typical of syphilis, the clinical symptoms varied widely, are difficult to divide into individual categories, and depend on the gumma's localization. In most cases, the therapy regimen was carried out with IV penicillin, with differences in dosage and therapy duration (details in Table 2). Table 3 lists the diagnostic results (histological, CSF, and neuroimaging) for the corresponding cases. In the multitude of histological findings, inflammatory processes were demonstrated, often accompanied by increased vascularization. Strain analyzes for T. pallidum were not always positive. White blood cells were often present and increased or reactivated VDRL or a positive T. pallidum antibody index. Increased protein levels and pleocytosis were also often present. On imaging, syphilitic gummata presented mostly solid and contrasted medium, with perifocal edema and signs of inflammatory processes (details in Table 3).

12
Hearing loss in right ear and right-side facial paralysis since two weeks ago. no "2015 U.K. national guidelines".
After two weeks: facial nerve palsy improved markedly; hearing loss improved gradually. [18] 13 Headache, right-sided hearing loss, tinnitus, and vertigo since three months ago. no IV penicillin G. [19] 14 Worsening pain and numbness in both lower legs for four weeks, started one year ago. yes [20] 15 Speech disturbance and a mild headache since 10 days ago. yes Penicillin G IV daily (24 million units for 14 days), followed by IM benzathine penicillin G (2.4 million units three-weekly).
"Improving gradually". [21] 16 Headache, swallowing difficulties, and dysarthria for four months, and vomiting for a month and a half; progressive right facial and neck numbness for two years; dysarthria; right Babinski sign positive.  Cranial nerves: After three weeks, full recovery in III, IV, V1, and V2, and partial recovery in cranial nerve VI. [32] 28 Eight-day history of right-sided vision loss, slurred speech, incoordination of his right arm and leg, and imbalance ad admission.
yes IV penicillin G 14 days, followed by three-weekly IM shots of benzathine penicillin G (2.4 million units).
One-month follow-up: gait and use of right hand improved dramatically; right-sided visual loss persisted. [33] 29 After two-month asymptomatic period, follow-up MRI: residual focal contrast enhancement, marked reduction of perilesional edema, and normal signal on diffusion weighted imaging (DWI).
[39]  48 Headache for three months; mild ataxia, intermittent low-grade fever, skin rashes, cervical lymph node enlargement, conjunctivitis, and progressively decreased libido Initial diagnosis sarcoidosis: prednisone; after second lumbar puncture and diagnosis of syphilis: IV penicillin G (24 million units per day) for 10 days.
Three months after therapy: Neurological examination was normal; left hemi-ataxia resolved [52] 49 Dorsal midbrain syndrome, cognitive dysfunction, and a left peripheral seventh nerve palsy no "Intravenous penicillin" [53] 50 Right eye vision suddenly became "totally black," cleared totally within 10-12 s; edema of the right optic nerve with dilated vessels on its surface and a bit of hemorrhage around the papilla; less than one month later: transient obscurations in the right eye, floaters in the left eye, photophobic, and persistent blurring left eye no IV penicillin G (20 million U/day) for 10 days Transient obscurations stopped completely during hospital stay; after five months: right optic disc appeared notably improved; blind spot sizes within normal limits in both eyes; iritis and vitritis of left eye improved [54]  Granulomatous inflammation with small areas of caseous necrosis, multinucleated giant cells infiltration, surrounded by large numbers of lymphocytes and small numbers of neutrophils; swelling and hyperplasia of some vascular endothelial cells with massive infiltration of lymphocytes and plasma cells around the blood vessels; immunohistochemistry: immunopositivity with glial fibrillary acidic protein, myelin basic protein, neurofilament protein, CD3, CD45RO, and CD68, but was negative for periodic acid-Schiff and CD56; acid-fast staining: negative; further Warthin-Starry staining confirmed spirochetes. MRI: irregular nodule at T8 level intradural-extramedullary and intramedullary, slightly hyperintense (T1), heterogeneously hyperintense signal (T2), significantly and homogeneously enhanced with contrast.
MRI: narrowing of the disc space at L4-5, mass behind vertebral body. CT: "Extensive wormy appearance". [20] 15 Severe inflammation and putrescence formation with a large quantity of inflammatory cell infiltration (mainly of the lymphocytes and plasma cells). RPR and Treponema pallidum particle agglutination test: positive; RPR titer: 1:8.
This case 23 Epithelioid cell macrophages and plasma cells without evidence of a pathogen. TPHA: CSF/serum index negative. MRI: mass lesion. [28] 24 Chronic inflammation; Warthin-Starry: no spirochetes; necrotic material infiltrated predominantly with plasma cells; peri-vascular region with fibrosis contained lymphocytes and plasma cells; parenchymal infiltration of lymphocytes and plasma cells in the gumma.    MRI: "abnormal signal" (T2); multifocal contrast enhancement. [46] 42 Necrotic center, surrounded by a layer of granulation tissue infiltrated with proliferating fibroblasts, variable numbers of lymphocytes, macrophages, and histiocytes, and many newly formed small blood vessels; perivascular lymphocytes and histiocytes.
CT: Small ring-like enhanced mass with a surrounding low-density area. MRI: low-signal-intensity basal ganglia (T1); small ring-like enhancement in the vicinity of the right optic nerve (contrast); high-signal intensity surrounding the lesion (T2). [47] 43 Epithelioid granuloma; central caseating necrosis, plasma cell infiltration; destruction of the tunica media of small arteries embedded in the lesion. TPHA: positive.
CT: ambiguous hypodense lesions; oval homogeneously contrast-enhanced mass lesion attached to the dura mater right temporal. MRI: low-intensity lesions in right cerebellar hemisphere, right middle cerebellar peduncle, and right temporal lobe (T1); and high intensity in T2, homogeneously enhanced (contrast). [48] 44 Postmortem: lesions with rubbery greenish core, surrounded by darker area; necrosis with marked inflammatory exudate (lymphocytes and plasma); multinucleated giant cells; silver staining with modified Steiner stain: spirochetal forms; PCR of coded specimens: syphilis (confirmed with DNA hybridization).
[49] MRI: contrast-enhancing lesions (T1); edema. One month later: CT: substantial resolution of the lesions while the patient was receiving only corticosteroid therapy (contrast). Nine months later: MRI: after treatment with both antibiotics and corticosteroids, demonstrated resolution of the lesions, except for a subtle abnormality in the left midbrain (Tl + contrast). [50] 46 Lymphoplasmacytic infiltrate with extensive perivascular inflammation.
MRI: dural thickening in the area of the lesion. CT: isolated, peripherally located, contrast-enhancing lesion of the brain. [51]

Discussion
Although reports of intracerebral gummata are rare [9], the increasing reports of syphilis suggest that healthcare professionals will encounter an increasing number of cerebral manifestations, as shown by our review. With this case report and review, we aim to raise awareness of the resurgence of this well-known, but mostly historical, disease that should be considered in the differential diagnosis of intracerebral lesions.