Neurosyphilis and the prozone effect

INTRODUCTION: Neurosyphilis (NS) is an entity which still frequently presents to our Neurology Department. The prozone phenomenon occurs in approximately 2% of all cases of late primary syphilis or secondary syphilis; we have found no cases described of prozone and neurosyphilis occurring together. CLINICAL CASE: We present the unusual case of a 44 year old patient with NS and dementia PGP (progressive general paralysis). Initially serum VDRL was negative, but in CSF reacted at dilutions of 1:32. When serum VDRL was repeated using dilutions, it was reactive 1:128 and serum FTA was also reactive. The patient was treated with i.v. crystalline penicillin, after which his condition improved. CONCLUSIONS: We wish to draw attention to the possibility that patients with a dementia syndrome and negative serum VDRL may have the prozone phenomenon, and the laboratory should therefore be asked to do serial dilutions.     

Cerebrospinal fluid findings in asymptomatic patients with reactive serum fluorescent treponemal antibody absorption tests

It is common to examine the cerebrospinal fluid in untreated or inadequately treated asymptomatic patients with a reactive serum fluorescent treponemal antibody absorption (FTA-ABS) test before initiating antibiotic therapy for syphilis. This prospective study evaluated the usefulness of such examination. Four hundred thirty-two patients over 40 years old, reporting for annual physical examination, had a serum FTA-ABS test. Thirty-seven (8.6%) patients and 2 of 4 spouses were reactive repeatedly. Of the 39 patients with reactive tests, 7 had a history of penicillin therapy for syphilis, 5 had received heavy metal therapy, and 27 had no history of syphilis. These 39 patients had a neurological examination, serum VDRL, Treponema pallidum immobilization (TPI), and repeat FTA-ABS tests by two other laboratories. The TPI test was reactive in 30 (77%). Four had nonspecific neurological signs. Routine CSF examination (cells, total protein, VDRL, glucose, IgG%) on 30 patients with a history of inadequate treatment had a low diagnostic yield. Two patients had an unexplained total protein elevation (57 and 61 mg/dl) and 1 had a mildly increased IgG% (15%). All cell counts, VDRL tests, and glucose levels were normal. Agarose electrophoresis demonstrated one or more CSF immunoglobulin bands in 10 (36%) of 28 patients, possibly representing an immunological marker of past or latent central nervous system infection.     

Neurosyphilis. A comparative study of the effects of infection with human immunodeficiency virus

BACKGROUND: The course of neurosyphilis has been reported to be altered by human immunodeficiency virus (HIV) infection. Prior reports of neurosyphilis occurring in association with HIV infection have been largely anecdotal and have failed to compare neurosyphilis in patients with HIV infection with an uninfected control group. This study was performed to determine if the clinical presentation encountered is different in the presence of HIV infection. DESIGN: A retrospective, hospital-based, case series study based on chart review encompassing a 64-month period. SETTING: The study was performed in a large, university-affiliated, public health trust hospital in south Florida. PATIENTS: Forty-six hospitalized patients with neurosyphilis were identified; 13 patients fulfilled Centers for Disease Control and Prevention (Atlanta, Ga) criteria for acquired immunodeficiency syndrome (AIDS), 11 were HIV seropositive only, and 22 were HIV uninfected. Neurosyphilis was determined by a reactive cerebrospinal fluid VDRL slide test. RESULTS: The HIV-infected patients (both AIDS and HIV-seropositive groups) were younger and more frequently had features of secondary syphilis, such as rash, fever, adenopathy, headache, or meningismus. Significant differences were observed in cerebrospinal fluid measurements when the HIV-infected group was compared with the HIV-uninfected group, including a higher mean white blood cell count in patients with AIDS and a higher mean protein level and a lower mean glucose level in the HIV-infected group. Syphilitic meningitis was more common in HIV-seropositive patients, although the HIV-uninfected patients presented with a greater variety of types of neurosyphilis. Ophthalmic syphilis was observed more frequently in the HIV-infected group. CONCLUSIONS: Significant differences exist between neurosyphilis occurring in the presence and absence of HIV infection.     

Recombinant antigen-based enzyme immunoassay for screening of Treponema pallidum antibodies in blood bank routine

This work reports a comparison of an enzyme immunoassay (EIA) using two major Treponema pallidum recombinant antigens with a T. pallidum hemagglutination (TPHA) assay and a nontreponemal Venereal Disease Reference Laboratory (VDRL) test. A total of 1,822 normal donor serum samples was tested for cardiolipin and T. pallidum antibodies, respectively, by the VDRL assay and EIA. Among these samples, 440 were further tested by TPHA technology. Four samples were found positive by EIA, while all were reported to be negative by both TPHA and VDRL routine assays. Subsequent testing of EIA-positive samples confirmed 100% (four of four samples) and 25% (one of four samples) positive results, respectively, by immunofluorescence assay and a Western blot (immunoblot) syphilis kit. The sensitivity of the recombinant EIA was estimated at virtually 100% with a reference panel of 50 syphilitic samples. According to this study, the newly developed EIA kit shows 100% sensitivity combined to a specificity greater than 99.8% for detecting treponemal immunoglobulin G antibodies in blood bank syphilis screening.     

Decreased interleukin-6 level in the cerebrospinal fluid of patients with Alzheimer-type dementia

We examined IL-6 levels in the cerebrospinal fluid (CSF) of patients clinically diagnosed with Alzheimer-type dementia (ATD) and with vascular dementia (VD) and of age-matched normal subjects. The IL-6 levels in the CSF of ATD, but not VD patients, were significantly decreased. In the early onset ATD patients (disease onset < 65 years), IL-6 levels were reduced to 21% of the control level. The IL-6 levels in the CSF were not associated with the severity of the dementia or the duration of the disease since the identification of the first symptoms.     

De novo status epilepticus as the presenting sign of neurosyphilis

Although the incidence of seizures in neurosyphilis ranges from 14 to 60%, status epilepticus (SE) as a presenting complaint of neurosyphilis is definitely rare. A 44-year-old human immunodeficiency virus (HIV)-negative man with no history of epilepsy suddenly presented with acute mental confusion and was diagnosed as having a de novo complex partial nonconvulsive SE. Cerebrospinal fluid (CSF) findings, neuroimaging, and clinical course indicated that SE was the presenting symptom of an undiagnosed syphilitic meningovasculitis. The case is presented with a review of previous reports to emphasize the differential features and to underscore the importance of considering neurosyphilis among the possible causes of de novo SE.     

A new look at the serology of treponemal disease

The serology of treponemal disease has become simpler and more rational in recent years, mainly as a result of the widespread adoption of specific antibody tests and the use of monospecific fluorescent antibody procedures which give information about the immunoglobulin class of antibodies. A set of tests which has proved particularly useful in routine diagnosis is the following: quantitative TPHA test, quantitative VDRL test, and monospecific (IgG and IgM) FTA-ABS tests. This combination is especially valuable in the assessment of new patients with positive results to serological tests and in the management of patients with treated syphilis.     

Dementia paralytica in a fifteen-year-old boy

A 15-year-old boy, whose history revealed an unremarkable pregnancy, birth and neonatal period and who had shown a normal motor and mental development, presented at the hospital with deterioration of cognitive functions since the age of 7. He was bedridden with manifest ataxia involving all limbs, anisocoria and a sluggish to absent pupil reaction to light. Syphilis serology was positive with a Venereal Disease Research Laboratory (VDRL) titer of 1:256 and a Treponema pallidum Haemagglutination Assay (TPHA) titer of 1:163840. Cerebrospinal fluid (CSF) protein concentration was 55 mg/dl and CSF-leucocyte count was 14/mm3 (85% mononuclear cells). CSF-VDRL-titer was 1:16. A diagnosis of congenitally acquired dementia paralytica was made, since the boy's parents' clinical exam and serology results were suggestive for latent syphilis. Although cognition was still very much deteriorated five months following penicillin treatment, clinical examination revealed partial recuperation. Screening for syphilis should be part of routine testing in every subject presenting with cognitive deterioration, regardless of age.     

Tuberculous meningitis: a clinical and laboratory study of 20 patients in Qatar

Twenty cases of tuberculous meningitis were diagnosed at the Hamad Medical Corporation between 1990 and 1995. Most of the patients (90%) were expatriates. The most common presenting features were fever, headache, neck stiffness and altered mental status. Five patients were in stage 1 disease at the time of presentation, 11 in stage 2, and four in stage 3. Examination of cerebrospinal fluid showed at least one abnormal finding in all patients, and culture grew Mycobacterium tuberculosis in 50%. A positive tuberculin skin test in 50% of patients, abnormal chest X-ray in 35%, abnormal CT scan or MRI showing tuberculoma or hydrocephalus in 55%, and positive sputum culture for M. tuberculosis in 15% helped establish the diagnosis. All the patients were treated with antituberculous drugs and steroids. Seventeen (85%) survived, three with severe neurological sequelae; three (15%) died. Poor outcome was associated with advanced stage of disease at presentation and high CSF protein. Tuberculous meningitis continues to be an important disease in Qatar, especially in expatriates, and should be considered in the differential diagnosis in any patient presenting with fever and change in sensorium.     

Presence of matrix metalloproteinase-9 activity in the cerebrospinal fluid of human immunodeficiency virus-infected patients

To determine whether matrix metalloproteinase (MMP)-9 is a potential mediator involved in the frequently detected blood-brain barrier leakage in human immunodeficiency virus (HIV)-infected patients, zymography was used to detect MMP-9 activity in cerebrospinal fluid (CSF) samples of 80 HIV-infected patients and of 10 control patients. CSF MMP-9 activity was detected in 40% of HIV-infected patients (but not in controls) and was significantly more frequent in HIV-infected patients than in those without neurologic deficits (50% vs. 13.6%). The frequency of CSF MMP-9 activity did not significantly differ between neurologically symptomatic HIV-infected patients with or without opportunistic central nervous system disease (51.6% vs. 48.1%). Additionally, the presence of CSF MMP-9 activity in HIV-infected patients was associated with an increased CSF white blood cell count and an elevated CSF-to-serum albumin ratio, suggesting that it may play a role in blood-brain/CSF barrier leakage in HIV-infected patients.     

Plasma levels of clonidine following epidural bolus injection in children

PURPOSE: To describe dense vitritis as the primary manifestation of ocular syphilis in three human immunodeficiency virus (HIV)-positive patients and to determine the response of these patients to the established regimen for neurosyphilis. METHODS: Anti-Toxoplasma gondii IgM and IgG antibody titers, tuberculin skin test, chest radiograph, and serum angiotensin-converting enzyme level were obtained because tuberculosis, sarcoidosis, and toxoplasmosis were in the differential diagnosis. Two of the three patients were not known to have HIV infection at the time of initial examination and consented to HIV testing. Treponemal and nontreponemal tests were performed on serum and cerebrospinal fluid to establish a definitive diagnosis. Treatment for neurosyphilis was initiated, and daily ophthalmic examinations were performed, with careful attention to signs commonly associated with syphilitic eye disease. RESULTS: All three patients exhibited improvement in visual acuity and resolution of vitreous haze. There was no evidence of other signs of posterior uveitis. The one patient for whom there has been a 6-month follow-up showed no sequelae of his eye disease. CONCLUSIONS: Human immunodeficiency virus-positive patients with syphilis may present atypically dense vitritis. In these patients, vitritis may be the first manifestation of syphilis. The regimen for neurosyphilis provides effective therapy. Moreover, in some patients, syphilitic vitritis may be the initial manifestation of HIV disease.     

Human cytomegalovirus (HCMV) encephalitis in an immunocompetent young person and diagnostic reliability of HCMV DNA PCR using cerebrospinal fluid of nonimmunosuppressed patients

Human cytomegalovirus (HCMV) encephalitis in adult nonimmunosuppressed patients has rarely been reported. We have diagnosed HCMV encephalitis in an anti-HCMV immunoglobulin G-negative, nonimmunosuppressed young woman by HCMV DNA PCR and virus isolation from cerebrospinal fluid (CSF). At the same time, HCMV antigen and HCMV DNA could be demonstrated in peripheral blood leukocytes, and the virus was isolated in fibroblast cultures. After 22 days of acute illness, the virus disappeared from the CSF. Remarkably, the patient did not generate detectable anti-HCMV antibodies within 5 months after the beginning of illness. To investigate the significance of HCMV DNA detection in CSF, samples of CSF, blood cells, and serum from 35 nonimmunosuppressed patients with various neurological disorders (but no herpes simplex virus central nervous system [CNS] disease) were tested for HCMV DNA, antigen, and antibodies. Eleven of these patients were found to be positive for virus DNA and/or antigen in peripheral blood leukocytes. Additionally, HCMV DNA was detected in the CSF of two patients with noninflammatory CNS diseases. A causative role of HCMV in the CNS diseases of these two patients was not evident. In summary, HCMV DNA amplification from CSF samples is a very suitable method to verify HCMV-associated encephalitis, but it should be taken into consideration that there are few cases of positive PCR with DNA from CSF without any known clinical correlative.     

Early syphilis

Given the transmission of Treponema pallidum during human sexual contact, syphilis now occurs in France only in sexually high-risk, disadvantaged populations. The English-language terminology of "early syphilis" has progressively replaced that of "primary" and "secondary" in French usage. Induration of the chancre and the papular nature of secondary skin rashes remain the best criteria for clinical diagnosis. Serological tests associate test specific for treponematoses (Treponema pallidum haemagglutination assay, TPHA) and a nonspecific screening test (Venereal diseases research laboratory, VDRL) to confirm clinically suspected disease. Routine use of long-acting penicillin (benzathine penicillin) is consistently effective. The continuing risk of active syphilis in a pregnant woman and the possibility of severe syphilis in HIV patients require vigilance.     

Spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension

Spinal cerebrospinal fluid (CSF) leaks are often implicated as the cause of the syndrome of spontaneous intracranial hypotension, but they have rarely been demonstrated radiographically or surgically. The authors reviewed their experience with documented cases of spinal CSF leaks of spontaneous onset in 11 patients including their surgical observations in four of the patients. The mean age of the six women and five men included in the study was 38 years (range 22-51 years). All patients presented with a postural headache; however, most had additional symptoms, including nausea, emesis, sixth cranial-nerve paresis, or local back pain at the level of the CSF leak. All patients underwent indium-111 radionucleotide cisternography or computerized tomographic (CT) myelography. The location of the spontaneous CSF leak was in the cervical spine in two patients, the cervicothoracic junction in three patients, the thoracic spine in five patients, and the lumbar spine in one patient. The false negative rate for radionucleotide cisternography was high (30%). Subdural fluid collections, meningeal enhancement, and downward displacement of the cerebellum, resembling a Chiari I malformation, were commonly found on cranial imaging studies. In most patients, the symptoms resolved in response to supportive measures or an epidural blood patch. Leaking meningeal diverticula were found to be the cause of the CSF leak in four patients who underwent surgery. In three patients these diverticula could be ligated with good result but in one patient an extensive complex of meningeal diverticula was found to be inoperable. Two patients had an unusual body habitus and joint hypermobility, and two other patients had suffered a spontaneous retinal detachment at a young age. In conclusion, spontaneous spinal CSF leaks are uncommon, but they are increasingly recognized as a cause of spontaneous intracranial hypotension. Most spinal CSF leaks are located at the cervicothoracic junction or in the thoracic spine, and they may be associated with meningeal diverticula. The radiographic study of choice is CT myelography. The disease is usually self-limiting, but in selected cases our experience with surgical ligation of leaking meningeal diverticula has been satisfactory. An underlying connective tissue disorder may be present in some patients with a spontaneous spinal CSF leak.     

Neurosyphilis and penicillin levels in cerebrospinal fluid

Because neurosyphilis may progress despite therapy with the recommended penicillin regimens, 15 subjects with positive tests for syphilis in the serum and cerebrospinal fluid (CSF) were studied. All of these patients had CSF pleocytosis. Two received penicillin G (5 and 10 million units per day intravenously, respectively) and 13 received benzathine penicillin G, 3.6 million units per week intramuscularly; treatment lasted four weeks. During intravenous and after intramuscular penicillin therapy, a spinal tap was performed on all subjects; later, assays were done. Of two patients who received intravenous penicillin G, one had 0.3 mug/ml and the other had 2.4 mug/ml penicillin in the CSF. Twelve of 13 patients who received benzathine penicillin G had no detectable penicillin in the CSF; one patient had 0.1 mug/ml penicillin in the CSF.     

Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is characterized by selective upper and lower motor neuron degeneration, the pathogenesis of which is unknown. About 60%-70% of sporadic ALS patients have a 30%-95% loss of the astroglial glutamate transporter EAAT2 (excitatory amino acid transporter 2) protein in motor cortex and spinal cord. Loss of EAAT2 leads to increased extracellular glutamate and excitotoxic neuronal degeneration. Multiple abnormal EAAT2 mRNAs, including intron-retention and exon-skipping, have now been identified from the affected areas of ALS patients. The aberrant mRNAs were highly abundant and were found only in neuropathologically affected areas of ALS patients but not in other brain regions. They were found in 65% of sporadic ALS patients but were not found in nonneurologic disease or other disease controls. They were also detectable in the cerebrospinal fluid (CSF) of living ALS patients, early in the disease. In vitro expression studies suggest that proteins translated from these aberrant mRNAs may undergo rapid degradation and/ or produce a dominant negative effect on normal EAAT2 resulting in loss of protein and activity. These findings suggest that the loss of EAAT2 in ALS is due to aberrant mRNA and that these aberrant mRNAs could result from RNA processing errors. Aberrant RNA processing could be important in the pathophysiology of neurodegenerative disease and in excitotoxicity. The presence of these mRNA species in ALS CSF may have diagnostic utility.     

Burkitt-type lymphoma in France among non-Hodgkin malignant lymphomas in Caucasian children

In a retrospective analysis of 87 cases of Caucasian childhood non-Hodgkin malignant lymphoma (NHML) from Lyon, France, all the case were diffuse lymphomas, but 47 were diagnosed as monomorphic small non-cleaved NHML, pathologically indistinguishable from Burkitt's lymphoma (BL). BL could then be the most frequent childhood lymphoma in France. This homogeneous series allows better definition of the characteristics of BL within NHML. Age distribution is similar to that of endemic BL, with a sex ratio of 3.7/1. Abdominal masses are initially present in 68% of the cases, whereas jaw is involved in only 4%. The disease is characterized by its overwhelming evolution in the absence of therapy. However, complete remission (CR) is usually obtained after the first chemtherapy regimen. Most relapses occur at 3-8 months. Death could be related to cerebrospinal fluid (CSF) involvement, local recurrence or secondary marrow involvement. Ninety per cent of the patients alive with no evidence of disease (NED) 8 months after CR can be considered as definitely cured. Our study on Caucasian children with NHML indicates that, from histological and clinical criteria, nearly half the cases are very similar to African BL. Even though EBV rarely associated with our cases, BL could be a worldwide lymphoma.     

Diagnosis of Creutzfeldt-Jakob disease by two-dimensional gel electrophoresis of cerebrospinal fluid

BACKGROUND: The diagnosis of Creutzfeldt-Jakob disease (CJD) is based on clinical and electroencephalographic criteria which do not allow a reliable diagnosis to be made during life. METHODS: Serum and cerebrospinal fluid (CSF) samples were obtained after informed consent from relatives of suspected cases of CJD referred to the German CJD surveillance unit. CSF samples from 58 definite (neuropathologically verified), 46 probable, and 34 possible CJD cases, and from 44 patients without CJD were analysed by two-dimensional gel electrophoresis (2-DE). Two investigators blinded to clinical findings recorded the presence of two proteins, p130/131. The kappa value for the level of agreement between these investigators was calculated. Results obtained were compared with the determination of neuron-specific enolase (NSE) in CSF. NSE concentrations of more than 35 ng/mL were considered indicative of CJD. FINDINGS: p130/131 was detected in 81% of definite (47/58), 80% of probable (37/46), 68% of possible (23/34) CJD cases, and in none of the other 44 cases. NSE concentrations of more than 35 ng/mL were seen in 79% of definite (46/58), 80% of probable (37/46), 59% of possible (20/34) CJD cases, and 9% of other cases (4/43). The positive predictive value for 2-DE of CSF is 100% and the negative predictive value is 69%. The level of agreement for the detection of p130/131 by two evaluators in a subset of 141 2-DE gels was a kappa of 0.93 (95% CI 0.86-0.99). Of 13 cases initially classified as possible and later reclassified as definite, ten cases were identified correctly by the 2-DE analysis, indicating a better diagnostic accuracy of this test compared with the current clinical classification. None of nine cases classified as other by neuropathology had p130/131 in 2-DE. INTERPRETATION: 2-DE for p130/131 is a specific test for the diagnosis of CJD. These data suggest including detection of p130/131 as a criterion for the diagnosis of probable CJD in addition to the currently accepted criteria of a rapidly progressive dementia of less than 2 years duration, typical neurological signs, and periodic sharp-wave complexes in the EEG.     

Resolution of serum and cerebrospinal fluid abnormalities after treatment of neurosyphilis. Influence of concomitant human immunodeficiency virus infection

BACKGROUND AND OBJECTIVES: Little is known about resolution of serum and cerebrospinal fluid abnormalities after neurosyphilis treatment, especially in patients infected with human immunodeficiency virus (HIV). GOAL: To examine the time course of resolution of these abnormalities. STUDY DESIGN: Case series of 22 patients with neurosyphilis (13 infected with HIV) with reactive cerebrospinal fluid Venereal Disease Research Laboratory test who underwent at least one lumbar puncture after treatment. RESULTS: Resolution of all serum and cerebrospinal fluid measures was slower in patients infected with HIV. Serum and cerebrospinal fluid abnormalities resolved in most patients not infected with HIV by 30 weeks, and all met Centers for Disease Control and Prevention criteria for cure. One patient infected with HIV failed therapy by Centers for Disease Control and Prevention criteria, and three others had persistent pleocytosis. CONCLUSIONS: HIV-infected patients with neurosyphilis have slower resolution of serum and cerebrospinal fluid abnormalities after therapy. This observation may suggest impaired clearance of Treponema pallidum from the central nervous system.