Didn't play the corresponding interactive case or want to try it again? Click here to do so.

Diagnosis and reasoning

The elderly individual who presents with alteration of behavior is not an uncommon presentation; the differential diagnosis is wide, including organic diseases and psychiatric conditions. However, a close assessment of this person's symptoms reveals features suggestive of dementia; this is supported by the psychiatric evaluation, and confirmed by the low score in the mini-mental state examination (MMSE). Note that certain conditions can give rise to cognitive impairment and thus, mimic dementia - these include hypothyroidism, liver or renal dysfunction, metabolic disturbances, and certain hematologic conditions. However, there are no clinical features suggestive of the above, while all investigations in this regard are normal. In the majority of patients, dementia is irreversible; however, there are a few reversible causes which should always be considered, as prompt identification and treatment may vastly improve the resultant prognosis. Important reversible causes include certain drugs and medications, alcohol abuse, depression, infections of the central nervous system (including lyme disease, neurosyphilis and AIDS-dementia complex), space occupying lesions (SOL), normal pressure hydrocephalus (NPH), and vitamin B12 deficiency. Medications, drugs and alcohol can be excluded via the history; nor are there clinical findings suggestive of depression. Structural abnormalities such as SOLs are excluded by the magnetic resonance imaging (MRI) scans of the brain; this also makes NPH less likely, as there is no evidence of ventricular enlargement. While there are no clinical features suggestive of Vitamin B12 deficiency (such as a vegan diet or associated neurological deficits), this still remains a possibility and requires further evaluation. Note also that assessment for lyme disease is generally only warranted in the presence of suggestive risk factors. Given the history of sexual promiscuity, a sexually transmitted disease (STD) panel seems to be the next most opportune investigation; this reveals a positive rapid plasma regain (RPR) with a titer of 1:64, suggesting a syphilis infection. The highly sensitive and specific fluorescent treponemal antibody absorption (FTA-Abs) is also positive, confirming that the infection is present; thus, neurosyphilis is a very real possibility. A cerebrospinal fluid analysis is an essential next step; this reveals a positive VDRL test with a titer of 1:4 and a positive Fluorescent Treponemal Antibody (FTA) Absorption Test, thus confirming the diagnosis of neurosyphilis. Parenterally administered penicillin-G is the drug of choice in the treatment of neurosyphilis; while doxycycline is an alternative in other forms of syphilis, it is not used in the treatment of these patients. Individuals who are allergic to penicillin should be considered for treatment with ceftriaxone, or for attempts at penicillin desensitization. Note that levodopa is used in the management of dementia due to Lewy body disease and Parkinson's disease; neither does electroconvulsive therapy (ECT) have a role in his treatment.


Syphilis, historically known as "the great imitator" is a sexually transmitted, highly contagious infectious disease caused by the spirochete treponema pallidum. While involvement of the central nervous system can occur during any stage of the disease, neurosyphilis is usually a manifestation of tertiary syphilis, and develops years after the initial infection (if left untreated). With the advent of penicillin, neurosyphilis became rare, and was at the verge of being proclaimed as uncommon in the developed world, except for the few cases where the condition coexisted with human immunodeficiency virus (HIV) infection. However, since the start of the new millenium, there has been a resurgence of neurosyphilis cases - particularly those unrelated to HIV. Unfortunately, neurosyphilis is a challenging enough diagnosis to make, even when one is familiar with the myriad presentations of the disease; this is compounded by the limited exposure most modern clinicians have to the disease (as compared to their forebears several decades ago). The 'classical' manifestations of neurosyphilis described in textbooks include general paresis of insane and tabes dorsalis; both of these are late manifestations of syphilis occurring as late as 20 to 30 years after the initial infection. The hallmark feature of the former is personality changes, paranoid ideations, emotional lability and eventually progression to dementia; this is due to syphilitic involvement of the cerebral cortex and meninges. Tabes dorsalis is characterized by loss of bladder and bowel control, failure of muscle coordination, lancinating pain in the limbs and abdomen and sensory ataxia; this is due to spinal cord involvement with subsequent demyelination of the posterior column, dorsal roots, and dorsal root ganglia. Less commonly known manifestations include asymptomatic neurosyphilis, meningovascular syphilis, meningeal syphilis, and acute syphilitic meningitis. Asymptomatic neurosyphilis is seen in 15% to 40% of patients during the early stages of the disease; while the majority are presumed to attain spontaneous recovery, several studies suggest that the majority of these patients are likely to have symptomatic neurosyphilis later in the life. Approximately 10% of patients with syphilis experience meningovascular syphilis and may present with a variety of symptoms ranging from headache, stiff neck, nausea, vomiting to hemiparesis, aphasia and seizures. A milder form known as meningeal syphilis also results in similar manifestations, but in contrast to patients with meningovascular syphilis, meningeal syphilis has a very low risk of cerebrovascular accidents. Acute syphilitic meningitis is typically the earliest manifestation of neurosyphilis and may occur in about 6% of affected patients. These patients have features of meningism and cranial nerve involvement with the VII, VIII, VI and II nerves affected in descending order of frequency. Note that a retrospective study that reviewed the clinical features of neurosyphilis within a four decade period (from 1965 to 2005) reported that atypical and masked clinical patterns were more common than the typical forms of the disease. A VDRL assay of the cerebrospinal fluid (CSF) is the current investigation of choice, and confirms the diagnosis if positive; unfortunately, a negative test does not necessarily rule out the diagnosis as this is known to be non-reactive in over 40% of patients. To aid the diagnosis, the centers for disease control and prevention (CDC) state that a positive CSF VDRL test indicates a 'definite' case of neurosyphilis; a 'probable' case is defined as the presence of CSF pleocytosis (> 5 WBC/mm3) or elevated protein in the context of syphilis exposure (evidenced by a positive serum treponemal antibody response) without a better explanation. While neuroimaging studies in patients with neurosyphilis have demonstrated generalized cerebral atrophy and foci of increased signal intensity, none of these findings are pathognomonic of the condition. Penicillin is the drug of choice in the treatment of neurosyphilis. Due to poor penetration of the central nervous system by penicillin-G, the CDC endorses two regimens - intravenous (IV) aqueous crystalline penicillin G for 10 to 14 days, followed by intramuscular (IM) penicillin-G procaine plus probenecid for another 10 to 14 days. Note that the response to parenteral penicillin is variable; meningovascular syphilis is known to have a better response than other forms of neurosyphilis. While the CSF white cell count and protein level change in response to therapy, these changes occur slowly. Thus, patients who initially demonstrate CSF pleocytosis should be followed up every six months until their CSF white cell counts normalize. The prognosis of neurosyphilis depends on the form of the disease, as well as the stage at which the treatment is initiated. As might be expected, the earlier the commencement of treatment, the better the prognosis; patients with asymptomatic or meningeal neurosyphilis are more likely to have a complete recovery than others. Preventive measures for neurosyphilis are the same as those for syphilis, including, screening all pregnant women, regular screening of men who have sex with men (among whom the disease has a higher incidence), treating diagnosed patients and screening their sexual partners, and notifying public health authorities.

Take home messages

  1. Neurosyphilis, once an extremely rare clinical entity, has become increasingly more common in recent times.
  2. A VDRL assay of the cerebrospinal fluid (CSF) is the diagnostic investigation of choice for neurosyphilis.
  3. Penicillin is considered the only effective treatment for neurosyphilis, but should be administered in a prolonged regimen, due to poor CSF penetration.
  4. The prognosis depends on the form of neurosyphilis and the time of initiation of therapy.

Insightful, fun cases to improve your diagnostic skills

Use your detective skills, strengthen fundamentals faster, and access a wealth of knowledge.

  1. 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 [online] 2008, 22(4):257-61 [viewed 05 June 2014] Available from: doi:10.1002/jcla.20254
  2. CONWAY JH. Recognizing and reducing the global burden of congenital syphilis: the time is now. Sex Transm Dis [online] 2007 Jul, 34(7 Suppl):S2-4 [viewed 05 June 2014] Available from: doi:10.1097/OLQ.0b013e31805c752f
  3. CORDATO DJ, DJEKIC S, TANEJA SR, MALEY M, BERAN RG, CAPPELEN-SMITH C, GRIFFITH NC, HANNA IY, HODGKINSON SJ, WORTHINGTON JM, MCDOUGALL AJ. Prevalence of positive syphilis serology and meningovascular neurosyphilis in patients admitted with stroke and TIA from a culturally diverse population (2005-09). J Clin Neurosci [online] 2013 Jul, 20(7):943-7 [viewed 05 June 2014] Available from: doi:10.1016/j.jocn.2012.08.011
  4. HARDING AS, GHANEM KG. The performance of cerebrospinal fluid treponemal-specific antibody tests in neurosyphilis: a systematic review. Sex Transm Dis [online] 2012 Apr, 39(4):291-7 [viewed 05 June 2014] Available from: doi:10.1097/OLQ.0b013e31824c0e62
  5. JAY CA. Treatment of neurosyphilis. Curr Treat Options Neurol [online] 2006 May, 8(3):185-92 [viewed 05 June 2014] Available from:
  6. KAMB ML, NEWMAN LM, RILEY PL, MARK J, HAWKES SJ, MALIK T, BROUTET N. A road map for the global elimination of congenital syphilis. Obstet Gynecol Int [online] 2010 [viewed 05 June 2014] Available from: doi:10.1155/2010/312798
  7. MITSONIS CH, KARARIZOU E, DIMOPOULOS N, TRIANTAFYLLOU N, KAPAKI E, MITROPOULOS P, SFAGOS K, VASSILOPOULOS D. Incidence and clinical presentation of neurosyphilis: a retrospective study of 81 cases. Int J Neurosci [online] 2008 Sep, 118(9):1251-7 [viewed 05 June 2014] Available from: doi:10.1080/00207450701239426
  8. NEWMAN LORI, KAMB MARY, HAWKES SARAH, GOMEZ GABRIELA, SAY LALE, SEUC ARMANDO, BROUTET NATHALIE, MENENDEZ CLARA. Global Estimates of Syphilis in Pregnancy and Associated Adverse Outcomes: Analysis of Multinational Antenatal Surveillance Data. PLoS Med [online] 2013 February [viewed 05 June 2014] Available from: doi:10.1371/journal.pmed.1001396
  9. PACELLA F, DE GIUSTI M, LOMBARDI AM, TURCHETTI P, SMALDONE G, BRILLANTE C, PACELLA E. [Epidemiology of syphilis: new cases of neurosyphilis]. Ann Ig [online] 2012 Jul-Aug, 24(4):319-24 [viewed 05 June 2014] Available from:
  10. SAIK S, KRAUS JE, MCDONALD A, MANN SG, SHEITMAN BB. Neurosyphilis in newly admitted psychiatric patients: three case reports. J Clin Psychiatry [online] 2004 Jul, 65(7):919-21 [viewed 05 June 2014] Available from:
  11. SANCHEZ FM, ZISSELMAN MH. Treatment of psychiatric symptoms associated with neurosyphilis. Psychosomatics [online] 2007 Sep-Oct, 48(5):440-5 [viewed 05 June 2014] Available from: doi:10.1176/appi.psy.48.5.440
  12. TIMMERMANS M. Neurosyphilis in the modern era. Journal of Neurology, Neurosurgery & Psychiatry [online] 2004 December, 75(12):1727-1730 [viewed 05 June 2014] Available from: doi:10.1136/jnnp.2004.031922
  13. ZHANG HL, LIN LR, LIU GL, ZENG YL, WU JY, ZHENG WH, TONG ML, DONG J, SU YH, LIU LL, YANG TC. Clinical spectrum of neurosyphilis among HIV-negative patients in the modern era. Dermatology [online] 2013, 226(2):148-56 [viewed 05 June 2014] Available from: doi:10.1159/000347109