A Clinical Study of New Cases of Parenchymal Neurosyphilis: Has Tabes Dorsalis Disappeared or Been Missed?

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1 ARTICLES A Clinical Study of New Cases of Parenchymal Neurosyphilis: Has Tabes Dorsalis Disappeared or Been Missed? Yong-Qing Zhang, M.D., M.Sc., Ming Huang, M.D., Xiao-Yan Jia, M.D., M.Sc., Ya-Fen Zou, M.D., M.Sc., Dan Chen, M.D. Tabes dorsalis (TD) was documented as the most common parenchymal neurosyphilis, but its incidence dramatically declined in the antibiotic era. Syphilis has resurged on the China mainland since the 1980s. In recent years, physicians have been reporting parenchymal neurosyphilis, and the overwhelming majority was general paresis, but this was not the case in the authors hospital. To make clear the real situation of parenchymal neurosyphilis in the authors hospital, a retrospective review was carried out of the records of patients during Overrepresented clinical new cases of tabetic and paretic parenchymal neurosyphilis were collected. Clinical characteristics, neuroimaging, laboratory data, and s to penicillin were analyzed in two groups. The efficiency of two current criteria based on CSF antibodies tests was inspected. In the 43 cases with positive serum rapid plasma reagin (RPR) and TPPA tests, 18 patients met the criteria of this study: 11 presented with symptoms of general paresis, and seven had typical presentations of TD. There were statistical differences in serum RPR titers, CSF RPR, white blood cell count, and TP between the paretic and tabetic groups. The to penicillin was relatively poor in TD. The efficiency of two current criteria was lower in the diagnosis of TD. TD was not uncommon in our area. Its clinical features remained typical, but underdiagnosis with CSF-based criteria and a decreased to penicillin were prominent issues. J Neuropsychiatry Clin Neurosci 2015; 27:e17 e21; doi: /appi.neuropsych Parenchymal neurosyphilis is a landmark in the evolution of modern neurology since its emergence at the end of the 19th century. In the early 20th century, neurosyphilis was a leading cause of neurologic. 1 Following the organized public health measures and introduction of penicillin in the 1950s, the incidence of syphilis dramatically declined, and as a result, neurosyphilis is uncommon. It was written in a textbook that if a patient presents no relevant symptoms and signs on neurologic examination, testing for nontreponemal antibodies is no longer recommended in the evaluation of dementia, sensory, and gait disturbance. 2 However, it is an incontrovertible fact that syphilis has resurged all over the world, 3 and there is a more prominent trend in China since the 1980s. 4 In the last 10 years, the occurrence of parenchymal neurosyphilis has increased significantly; mostly general paresis. 5 However, clinical syndromes of neurosyphilis have become nontypical. 6,7 There are some problems with the diagnosis, because current tests use two categories of antibodies: nontreponemal and treponemal specific. When used as serologic tests, the sensitivities and specificities of these tests are ideal. However, this is not the case in CSF, where the estimated specificity of nontreponemal tests is high but the sensitivity is lower (about 30%275% in different studies according to a variable definition of cases) Traditionally, treponemal-specific tests are not suitable to be used in CSF because of transudation of immunoglobulin from the serum. This means that we are not familiar with these disorders and lack a powerful diagnostic modality. Therefore, we have reason to question the present opinions about parenchymal neurosyphilis, especially tabes dorsalis (TD), which was the most common form in the preantibiotic era, but the reverse is true today. In our hospital, a medical center locating in southern China, general paresis and TD are not uncommon disorders. In this article, parenchymal neurosyphilis is reviewed. Clinical characteristics, neuroimaging, and laboratory data were analyzed in the paretic and tabetic groups. The efficiency of the two current criteria based on CSF antibodies tests was studied. METHODS Study Participants We retrospectively reviewed the medical records of all patients discharged from our hospital from January 2009 to December We first retrieved all cases with positive serum rapid plasma reagin (RPR) and TPPA. All participants underwent a structured history and neurologic examination that included assessment of cranial nerves, motor strength, sensation, coordination, reflexes, and gait. According to their symptoms and J Neuropsychiatry Clin Neurosci 27:1, Winter 2015 neuro.psychiatryonline.org e17

2 NEW CASES OF PARENCHYMAL NEUROSYPHILIS FIGURE 1. Results of Recruitment of Cases a 43 cases with positive RPR and TPPA in blood considered. Definite neurosyphilis is defined according to published criteria. If CSF RPR was positive, the case was considered fulfilling criteria A. Criteria B was defined as having positive CSF TPPA with either an increased white blood cell count or total protein. 2,7,11 13 cases, no clinical features of neurosyphilis 2 cases, no data of CSF 3 cases of vascular and meningeal form 17 paretic 6 cases excluded: previously treated in 5 cases; 1 case of VD 27 cases of parenchymal form 9 tabetic 2 cases excluded: previously treated in 1 case; 1 case of DPN 1 taboparetic Definition of Response to Penicillin In this study, all patients received regular therapy of 4 million units of penicillin intravenously every 4 hours for 14 days. At 3 months after treatment, doctors, according to the following definitions as their literal meaning, appraised s to therapy: progressive, stable, partial, and complete. We define progressive and stable as noneffective and partial and complete s as an effective to penicillin. 11 cases of latent syphilis or asymptomatic neurosyphilis 17 paretic 9 tabetic a Forty-three patients with positive rapid plasma reagin (RPR) and TPPA were documented. In the 30 cases of diverse syndromes of neurosyphilis, three cases are consistent with the vascular and meningeal form; 17, nine, and one cases have syndromes of the paretic, tabetic, and taboparetic type, respectively. Five of the paretic form and one of the tabetic form were excluded because of previous treatment as neurosyphilis. Two cases, one each in the two groups, were excluded because of possible vascular dementia and diabetic polyneuropathy according to related criteria. Therefore, 18 new cases of parenchymal neurosyphilis were recruited in this study. signs, patients were classified. In this study, those patients with encephalopathy including cognitive impairment, personality change, convulsion, and/or psychiatric symptoms were classified to the paretic type and those with spinal cord symptoms including lancinating pain, ataxia, bladder disturbance, and paresthesia were classified as tabetic neurosyphilis. Past and family history, neuroimaging, and electrophysiological data of these patients were fully reviewed; patients with other s that can induce similar syndromes were excluded, such as Alzheimer s, vascular dementia, and major depression in the paretic form and diabetic neuropathy, subacute combined degeneration, and chronic inflammatory demyelinating polyneuropathy in the tabetic form. Patients who had been diagnosed and treated with neurosyphilis were also ruled out. Participants included in this study represent a convenience sample selected to overrepresent newly diagnosed paretic and tabetic neurosyphilis cases based on these clinical features. The study protocol was reviewed and approved by the Xiamen ChangGung Hospital Review Board, and human experimentation guidelines were followed in the conduct of this research. Written inform consent was obtained from all participants. Laboratory Data and Diagnostic Criteria Serum RPR and TPPA, CSF white blood cell count, total protein, RPR, and TPPA were analyzed. The titers of antibodies in serum were collected; in CSF, only qualitative data were Statistical Methods Patients were classified as paretic or tabetic. Their age, titers of serum RPR and TPPA, CSF white blood cell count, and total protein, we performed using Mann-Whitney U test, and comparison of proportions was performed using 32 or Fisher exact tests. A two-sided p value,0.05 was considered statistically significant. RESULTS Participant Characteristics Forty-three patients with positive RPR and TPPA were documented, and none of them had a positive HIV reaction. In the 30 cases of diverse syndromes of neurosyphilis, three cases were consistent with the vascular and meningeal form; 17, nine, and one cases had syndromes of the paretic, tabetic, and taboparetic type, respectively. Five with the paretic form and one with the tabetic form were excluded because of previous treatment for neurosyphilis. Two cases, one each in two groups, were excluded because of possible vascular dementia and diabetic polyneuropathy according to related criteria. Therefore, 18 new cases of parenchymal neurosyphilis were recruited in this study (Figure 1). The characteristics of the study participants are shown in Table 1. The sex ratio and age were similar in the two groups for statistical analysis. For clinical symptoms and signs, dementia and/or personality change were recorded in all patients with general paresis, and lancinating pain was found in six of seven cases of TD; another one case was recruited in this study because of visual loss. At neurological examination, no consistent signs were recorded in general paresis cases. The most common signs were dysarthria in five of 11 cases and and myoclonic jerk in two and one cases, respectively. However, in patients with TD, decreased DTR or DTR loss were found in seven of seven cases, and was found in five of seven cases, in which two cases had A-R pupils. Neuroimaging Two types of changes were identified using brain MRI in paretic cases, which were hypertense in T 2 -weighted and e18 neuro.psychiatryonline.org J Neuropsychiatry Clin Neurosci 27:1, Winter 2015

3 ZHANG ET AL. TABLE 1. Characteristics of Study Participants a General information Clinical Features Serum CSF Criterion N Gender Age (years) Symptoms and Signs Form Neuroimaging RPR TPPA RPR TPPA WBC (/ml) TP (mg/dl) A B Response to Penicillin 1 M 53 Personality change, dysarthria, myoclonic jerk 2 M 58 Dementia, personality change, dysarthria Paretic Right frontal lobe and periventricular, brain atrophy 1:16 1:5120 1:16 1: Yes Yes Partial Paretic Brain atrophy 1:8 1:2560 1:4 1: Yes Yes Partial 3 M 53 Dementia, personality change Paretic Subcortical and periventricular 1:32 1:1280 1:8 1: Yes Yes Partial 4 M 50 Dementia, dysarthria Paretic Subcortical and periventricular 1:32 1:2560 1:16 1: Yes Yes Complete 5 M 40 Personality change, Paretic Subcortical and periventricular 1:32 1:2560 1:1 1: Yes Yes Stable 6 M 57 Dementia, dysarthria Paretic Brain atrophy 1:32 1:2560 1:8 1: Yes Yes Complete 7 M 47 Dementia Paretic Brain atrophy 1:64 1:2560 1:2 1: Yes Yes Partial 8 F 55 Dementia, personality change, Paretic Subcortical and periventricular, brain atrophy 9 F 54 Dementia, personality change Paretic Subcortical and periventricular 1:128 1:2560 1:4 1: Yes Yes Partial 1:8 1:2560 1: No Yes Stable 10 M 52 Dementia, dysarthria Paretic Brain atrophy 1:64 1:2560 1:4 1: Yes Yes Complete 11 F 64 Dementia, personality change Paretic Subcortical, brain atrophy 12 F 52 Lancinating pain, decreased DTR, abnormal (A-R) pupil 13 M 58 Lancinating pain, ataxia, loss of proprioception, impotence, decreased DTR, 14 F 48 Lancinating pain, decreased DTR, (A-R), impaired deep sensation 15 M 66 Lancinating pain, decreased DTR, 16 F 58 Lancinating pain, loss of proprioception, ataxia, decreased DTR 17 M 49 Visual loss, ataxia, DTR loss, 18 M 48 Lancinating pain, decreased DTR, 1:16 1:2560 1:2 1: Yes Yes Partial Tabetic Normal 1:8 1:2560 1: No Yes Stable Tabetic Normal 1:2 1:2560 1: Yes No Partial Tabetic Normal 1:2 1: No No Stable Tabetic Normal 1:2 1:2560 1: No No Progressive Tabetic No data 1:2 1:64 1: No Yes Partial Tabetic Normal 1:16 1:2560 1:2 1: Yes Yes Stable Tabetic Normal 1:16 1:2560 1: No No Stable a DTR= ; RPR=rapid plasma regain; TPPA= ; WBC=white blood cell count. J Neuropsychiatry Clin Neurosci 27:1, Winter 2015 neuro.psychiatryonline.org e19

4 NEW CASES OF PARENCHYMAL NEUROSYPHILIS TABLE 2. Laboratory and Clinical Characteristics of Paretic and Tabetic Patients Characteristic/Value Paretic (N=11) Tabetic (N=7) p Male 8 (72.7%) 3 (42.9%) Age (years) 53 (50 57) 52 (48 58) Time from onset (months) 7 (5 10) 24 (18 60) Serum RPR (1/titer) 32 (16 64) 2 (2 16) Serum TPPA (1/titer) 2560 ( ) 2560 ( ) CSF WBC (/ml) 16 (1 64) 1 (0 2) CSF TP (mg/dl) 82 (61 89) 431 ( ) CSF RPR (percentage) 10 (90.9%) 2 (28.6%) CSF TPPA (percentage) 11 (100%) 5 (71.4%) Rate of criterion A (percentage) 10 (90.9%) 2 (28.6%) Rate of criterion B (percentage) 11 (100%) 3 (42.9%) 0.02 Response to penicillin 9 (81.8%) 2 (28.6%) (percentage) brain atrophy. Neuroimaging of the spinal cord was available in six of seven cases of TD, and no significant lesions were found (Table 1). Laboratory Tests In serum antibodies tests, serum RPR and TPPA tests were reactive in all cases according to our inclusion criteria. RPR titers in the paretic group [median (interquartile), 1:32 (1:16 1: 64)] were significantly higher than that of the tabetic group [median (interquartile), 1:2 (1:2 1:16), p=0.003]. However, TPPA titers were not significantly different from each group (p=1.00). In CSF routine studies, the CSF white blood cell count of the paretic group [median (interquartile), 16 (1 64)] was higher than that of the tabetic group [median (interquartile), 1(0 2), p=0.027]. Total protein of the paretic group [median (interquartile), 82 (61 89)] was significantly higher than that of the tabetic group [median (interquartile), 43 (34 55), p=0.001]. In CSF antibodies tests, RPR was positive in 10 (90.9%) cases with the paretic form, but only two (28.6%) patients with the tabetic form, and there was a statistical difference between the two groups (p=0.013). TPPA was reactive in all patients with the paretic form and in five (71.4%) patients with the tabetic form; no statistical difference was recorded (p=0.137; Table 2). Efficiency of Criteria The statistical data for the efficiency of criteria A are the same as the CSF RPR according to the definition (p=0.013). Regarding criterion B, all cases of general paresis and three (42.9%) cases of TD met the criterion, and there was a statistical difference between the two groups (p=0.02; Table 2). Response to Penicillin Effective treatments were recorded in nine cases of general paresis and two cases of TD. There was a statistical difference between these two groups (p=0.049; Table 2). DISCUSSION Median (IQR) or number (percentage) a RPR=rapid plasma regain; TPPA= ; WBC=white blood cell count. First of all, we asked ourselves an essential question in this study: were the cases of TD correctly diagnosed. TD, or locomotor ataxia, was the most common form of neurosyphilis described in the preantibiotic era. 12 TD was typically seen in patients between 44 and 60 years of age, and onset ranged from 3 to 47 years after primary infection, with an average of 21 years. TD is manifested by lancinating or lightning-like pain, progressive ataxia, loss of proprioception, dysfunction of sphincters, and impaired sexual function in men. The chief signs are loss of tendon reflexes, impaired vibratory and position sense in the legs, and s. 2 In the antibiotic era, clinicians detected a shift in clinical patterns of neurosyphilis, with a dramatically decreasing rate of TD. 6,13 This change was interpreted as its susceptibility to antibiotics and an overestimation of the frequency because of being ill defined. 7 However, the reason remains obscure. In our seven cases of TD, the chief complaints of six cases were lancinating or lightning-like pain in legs, and another one case was progressive visual loss. Ataxia and loss of proprioception were recorded in three and two patients, respectively. At neurological examination, decreased or diminished DTR was recorded in all cases, with five cases having abnormal pupils, in which three cases were Argyll-Robertson pupils. Although tabes is an ill-defined syndrome, these unique combined symptoms and signs, with the exclusion of other possible s by PNS electrophysiological and spinal cord neuroimaging studies, gave us the confidence to ensure the clinical diagnosis of TD. General paresis, or general paresis of the insane, was the first cause of dementia and admission to a psychiatric hospital before the 1950s. Behavior changes may suggest a psychosis, but the most common problem is dementia, with loss of memory, poor judgment, and emotional liability. In the final stages, dementia and quadriparesis are severe. 2 Neuroimaging is not specific, but may aid in the diagnosis. 14 In the 11 patients with general paresis, the most common symptoms were subacute and chronic-onset dementia and personality change, with no consistent signs. Although the differential diagnoses are broad, we could confirm that the symptoms of these patients resulted from the pathological changes of syphilis with positive serum and CSF antibodies tests of all the 11 cases in this study. The presentations were not atypical in our 18 cases. This argues the general viewpoint. However, this result was also demonstrated in a study from the United Kingdom in 1979 that reported 17 cases of neurosyphilis. 15 On the basis of this observation, we believe that TD was not uncommon, at least in our area. However, one should pay attention to the special situation of our study. Syphilis, a well-known sexually transmitted, is severely discriminated against in Chinese culture. 16 Penicillin is so inexpensive that regular treatment of syphilis is not an attractive point for most of our current forprofit medical institutions. 17 All our 18 cases had negative HIV e20 neuro.psychiatryonline.org J Neuropsychiatry Clin Neurosci 27:1, Winter 2015

5 ZHANG ET AL. tests. This is also a key factor for different clinical spectrums that compared with many studies in the United States and Europe. In serologic and CSF tests, statistical differences were noted with the serum RPR titers, CSF white blood cell counts, CSF TP, and CSF RPR between the two groups. These differences perhaps resulted from the different pathological changes in these two distinct disorders caused by same pathogen. The paretic form is characterized by infiltration of lymphocytes and plasma cells into small cortical vessels and the cortex itself following an inflammatory meningeal reaction. Otherwise, in TD, such inflammation of meninges is followed by insidious degeneration of the posterior roots and posterior fiber columns of the spinal cord. 18 The pathogen, spirochetes, may be found in the paretic form, but only rarely in other forms. 2,19 That means that the tabetic form is a primarily degenerative with less inflammatory change. As a result, tests based on inflammatory changes were more prominent in general paresis than TD. These differences were also verified by the findings in neuroimaging. Hyperintense in T 2 -weighted and/or brain atrophy were found in all paretic cases, but in patients with the tabetic form, there were no significant findings with their spinal cord MRI. This is also a reasonable explanation of the to penicillin, whose target is spirochetes, but not the degenerative pathological change. Therefore, the treatment of TD still remains a challenge as it did in the 1940s and 1950s. 20 AUTHOR AND ARTICLE INFORMATION From the Dept. of Neurology, Xiamen ChangGung Hospital, Xiamen, China. Send correspondence to Yong-Qing Zhang, M.D., M.Sc.; yqzhmed@ gmail.com Received Oct. 20, 2013; revised Feb. 8, 2014; accepted Feb. 13, REFERENCES 1. Brandt AM: No Magic Bullet: A Social History of Venereal Disease in the United States Since New York, Oxford University Press, Stefanis L, Rowland LP: Infections of the nervous system: neurosyphilis, in Merritt s Neurology. Edited by Rowland LP. Philadelphia, Lippincott Williams and Wilkins, Tichonova L, Borisenko K, Ward H, et al: Epidemics of syphilis in the Russian Federation: trends, origins, and priorities for control. Lancet 1997; 350: Chen ZQ, Zhang GC, Gong XD, et al: Syphilis in China: results of a national surveillance programme. Lancet 2007; 369: Zhang HL, Lin LR, Liu GL, et al: Clinical spectrum of neurosyphilis among HIV-negative patients in the modern era. Dermatology 2013; 226: Hooshmand H, Escobar MR, Kopf SW: Neurosyphilis. A study of 241 patients. JAMA 1972; 219: Timmermans M, Carr J: Neurosyphilis in the modern era. J Neurol Neurosurg Psychiatry 2004; 75: Hart G: Syphilis tests in diagnostic and therapeutic decision making. Ann Intern Med 1986; 104: Ratnam S: The laboratory diagnosis of syphilis. Can J Infect Dis Med Microbiol 2005; 16: Castro R, Prieto ES, da Luz Martins Pereira F: Nontreponemal tests in the diagnosis of neurosyphilis: an evaluation of the Venereal Disease Research Laboratory (VDRL) and the Rapid Plasma Reagin (RPR) tests. J Clin Lab Anal 2008; 22: Workowski KA, Berman S; Centers for Disease Control and Prevention (CDC): Sexually transmitted s treatment guidelines, MMWR Recomm Rep 2010; 59(RR-12): Merritt HH, Adams RD, Solomon HC: Neurosyphilis. New York: Oxford, Wolters EC: Neurosyphilis: a changing diagnostic problem? Eur Neurol 1987; 26: Peng F, Hu X, Zhong X, et al: CT and MR findings in HIV-negative neurosyphilis. Eur J Radiol 2008; 66: Luxon L, Lees AJ, Greenwood RJ: Neurosyphilis today. Lancet 1979; 1: Xiao Z, Mehrotra P, Zimmerman R: Sexual revolution in China: implications for Chinese women and society. AIDS Care 2011; 23 (Suppl 1): Hu S, Tang S, Liu Y, et al: Reform of how health care is paid for in China: challenges and opportunities. Lancet 2008; 372: Adie WJ: Critical review: the pathogenesis of tabes dorsalis. J Neurol Psychopathol 1921; 2: Gager WE, Israel CW, Smith JL: Presence of spirochaetes in paresis despite penicillin therapy. Br J Vener Dis 1968; 44: Nicol CS: The treatment of neurosyphilis. Postgrad Med J 1953; 29: J Neuropsychiatry Clin Neurosci 27:1, Winter 2015 neuro.psychiatryonline.org e21