Neurosyphilis Current Drug Treatment Recommendations

CNS Drugs 3 (5) 328-336, 1995 PRACTICAL THERAPEUTICS 1172-7047/95/=5-0328/$04.50/0

David Goldmeier1 and Celia Skinner2 1 Department of Genitourinary Medicine, St Mary' s Hospital, London, England 2 Department of Genitourinary Medicine, Royal London Hospital, London, England

Contents Summary ...... 328 1. Definition, Clinical Features and Diagnosis 329 1.1 Definition. 329 1.2 Clinical Features 329 1.3 Diagnosis . 329 2, Epidemiology , 330 3. Neuropathology 330 4. Treatment of Symptomatic Neurosyphilis 331 4.1 Minimum Bactericidal Concentrations 331 4.2 Relevance of Cerebrospinal Fluid Antibiotic Concentrations . 331 4.3 Choice of Antibiotics . . . . 331 4.4 Patients with Penicillin Allergy . . . . . 333 5. Treatment of Asymptomatic Neurosyphilis 333 6. HIV and Neurosyphilis ...... 333 7. Treatment Outcome ...... 334 8. Jarisch-Herxheimer and Procaine Reactions 334 9. Other Treatment Issues ...... 335 9.1 ContactTracing ...... 335 9.2 Psychological Sequelae of the Diagnosis of Neurosyphilis 335 10. Conclusions ...... 335

Summary Neurosyphilis is a symptom of the tertiary stages of syphilis (a chronic sys• temic infection of Treponema pallidum subspecies pallidum), Classical neuro• syphilis has become a rare condition in Western countries because of the use of penicillin far the treatment of early or latent syphilis, Although textbook neuro syphilis is now uncommon, modified neuro syphilis as a consequence of intercurrent antibiotic use for other conditions may be more common. This latter condition is harder to diagnose than classical neurosyphilis because of atypical clinical and cerebrospinal fluid (CSF) findings. The coexistence of HIV infection and syphilis has further complicated the picture, There have been no weil controlled trials of treatments for neurosyphilis, Nevertheless, the treatment of choice for established neurosyphilis has been shown to be benzylpenicillin (penicillin G), The drug is administered as an inten• sive therapy offrequent intravenous high doses or high doses of an intramuscular repository formulation with probenecid. Other agents that can be used include Neurosyphilis 329

high dose amoxicillin (amoxycillin) with probenecid (but compliance cannot be monitored), tetracyclines, macrolides or ceftriaxone. If the individual is HIV• positive or of unknown serostatus, benzylpenicillin should be used to prevent or treat neurosyphilis. In patients who are allergie to penicillin, rush desensitisation can be used to allow administration of benzylpenicillin. Alternatively, non• penicillin antibiotics can be used. Much work has been performed to establish the bactericidal concentrations of penicillin and other antibiotics in serum and CSF. However, the significance of these values is uncertain because the causative pathology of neurosyphilis may lie in the perivascular space. Follow-up and counselling of patients with neuro syphilis, and repeat lumbar puncture for analysis of CSF where initially abnormal, are recommended.

1. Definition, Clinical Features teHect and speech) and tabes dorsalis. Classical and Diagnosis neuro syphilis develops in up to 10% of patients with untreated syphilis. The c1inical picture of c1as• 1.1 Definition sical neurosyphilis has been weH described else• where.[21 Syphilis is a chronic systemic infection caused In the pre-antibiotic era, symptomatic neuro• by the spirochaete Treponema pallidum subspecies syphilis predominately presented as general paresis pallidum. The bacterium is usuaHy transmitted via and/or tabes dorsalis. In more recent years, some sexual contact with infectious lesions. In utero in• fection can also occur (congenital syphilis).[ll authors describe the incidence of these modes of presentation as unchanged,[31 but others describe a 1.2 Clinical Features greater preponderance of meningovascular and vascu• lar syphilis, which may represent partially treated Syphilis is characterised by 4 stages: syphilis, with symptoms such as hyporeflexia, ab• • An incubation period of approximately 3 weeks, sent ankle jerks and pupillary abnormalities.l4,51 followed by a primary phase associated with lesions (chancres) and regionallymphadenopathy. 1.3 Diagnosis • A secondary bacteraemic stage commonly asso• ciated with generalised mucocutaneous lesions With the intercurrent use of treponemacidal anti• and generalised lymphadenopathy. biotics for other conditions and, more recently, the • A latent period of subc1inical infection lasting coexistence of HIV infection and syphilis, neuro• many years [divided into early (the first year of syphilis may not present with a c1assical c1inical infection) and late (beginning 1 year after infec• picture.[6-81 Diagnosis and treatment may, there• tion) latent stages] or with a high reagin titre. fore, be difficult and complex. • A tertiary (or late) stage characterised by pro• Diagnostic confirmation of neuro syphilis is gressive destructive mucocutaneous musculo• based on abnormal cerebrospinal fluid (CSF) find• skeletal or parenchymallesions, aortitis or CNS ings in patients with positive serological tests for disease (i.e. neurosyphilis).lll T. pallidum and suggestive or obvious c1inical find• Late syphilis can present as either asymptomatic ings (see table I). CSF abnormalities inc1ude pleo• or symptomatic. Neurosyphilis is one manifesta• cytosis, raised protein levels and a positive reagin tion of late symptomatic syphilis, and can inc1ude antibody test. meningovascular and parenchymatous forms. The Serological tests used inc1ude reagin tests such latter category inc1udes general paresis (disorders as the Venereal Disease Reference Laboratory of personality, affect, reflexes, eye, sensorium, in- (VDRL) test, and treponemal tests ofthe CSF such

Table I. Criteria lor the diagnosis 01 neurosyphilis CSF changes Classical neurological signs Atypical neurological signs VORL positive, IwBC, Iprotein N N VORL positive only N N IwBC and/or Iprotein only N Na FTA-ABS N Na TPHA index and/or CSF TPHA IgG/total IgG: serum TPHA N Na IgG/total IgG a In the absence 01 other causes 01 neurological disease. Abbreviations and symbol: CSF =cerebrospinal Iluid; FTA-ABS =Iluorescenttreponemal antibody-absorption test; IgG =immunoglobulin G; N = diagnosis 01 neurosyphilis; TPHA = Treponema pallidum haemagglutination assay; VORL = Venereal Oisease Research Laboratory test; WBC = white blood cell; 1= increase. as the fluorescent treponemal antibody-absorption ilis, 3850 cases of congenital syphilis and 33 973 test (FTA-ABS) and the T. pallidum haemag• cases of primary and secondary syphilis. This com• glutination assay (TPHA). The VDRL has a sensi• pares with a total of 50 000 cases in 1990. The in• tivity of 30 to 70% in diagnosing neurosyphilis. cidence of the disease in the UK has not shown Interpretation can be difficult because blood• such an increase: 1307 cases of syphilis were re• stained specimens cause false-positive results, and ported in 1992, of which 343 were infectious. a non-reactive VDRL test does not exclude neuro• syphilis. Treponemal tests can give a positive result 3_ Neuropathology because of active neuro syphilis, asymptomatic neurosyphilisor-treated neurosyphilis, and false• Although predominantly a symptom of late positive reactions where serum leaks into the CSF. syphilis, meningovascular syphilis may complicate These tests are, therefore, oversensitive and tend to secondary syphilis; however, there are no neuro• overdiagnose neurosyphilis. pathological studies in patients with early syphilis The TPHA index[91 and CSF TPHA immuno• (i.e. the primary and secondary phases of the dis• globulin G (IgG)/total IgG : serum TPHA IgG/total ease). Classical work demonstrates changes in the IgG[IOJ ratio are 2 methods of estimating true intra• CSF, such as pleocytosis and an increase in the pro• thecal treponemal antibody production. Rabbit in• tein level, in up to 70% of patients with this early oculation and polymerase chain reaction (PCR) of stage of syphilis.[l] However, positive reagin anti• the CSF can be used to detect the presence of T. body tests (e.g. VDRL) from sampies of CSF are pallidum, but are not used for routine clinical di• more common as the duration of the infection in• agnosis at present.[6] creases. In both classical and recent studies, T. pallidum 2. Epidemiology has been found in the CSF in up to 40% of patients with uncomplicated early syphilis.[8] The more ab• Syphilis is much more common in certain areas normal the CSF in early or latent syphilis, the more of the world than others. It is more common in likely it is that classical neuro syphilis will ensue if Africa and the US than in the UK. Worldwide fig• the infection is not treated. The high frequency of ures are difficult to obtain, but there has been a CNS involvement in early syphilis is an interesting down ward trend in the incidence of the disease in finding. The conventionally accepted treatment for Western countries since 1960. This trend has re• eady and latent syphilis does not consistently pro• cently been reversed in the US with an increase in duce treponemacidal concentrations of penicillin the incidence of primary and secondary syphilis in the CSF (see section 4.3) and yet the subsequent and the re-emergence of congenital syphilis. In occurrence of neurosyphilis is almost nonexistent, 1992, there were 112581 cases of all types of syph- except in HIV seropositive patients,lI,6]

The basic neuropathology ofneurosyphilis is an concentrations have also been estimated for a num• endarteritis with perivascular inflammation of ber of other antibiotics.[6] plasma cells and lymphocytes. It is this effect that results in the pathology oftabes dorsalis, meningo• 4.2 Relevance of Cerebrospinal Fluid vascular syphilis, gummata and paretic dementia, Antibiotic Concentrations rather than a direct action of T. pallidum on the In order to effectively treat neurosyphilis, anti• brain parenchyma. In this situation, it would be the biotics must penetrate the diseased sites. Much has serum or perivascular antibiotic concentration that been written about CSF antibiotic concentrations, would have to be treponemacidal, not the CSF or the implication being that treponemacidal concen• brain concentrations. In spite of this, it is known trations of agents in the CSF are necessary to ensure that a high, but not a low, level of T. pallidum in• clinical cureP] However, we believe that the main fection disrupts sensory (dorsal root) nerve func• pathology in neurosyphilis is at or near the menin• tion. In the past when paretic dementia was com• geal blood vessels (i.e. the perivascular space), mon, T. pallidum was found in brain parenchyma with some treponemes being present within brain in up to 40% of patients. These conflicting data are tissue itself. Infection of the perivascular space re• hard to reconcile. sults in ischaemia and infarction of neuronal tissue, although T. pallidum can directly produce patho• 4. Treatment of Symptomatic logical change when in contact with such tissue. It Neurosyphilis may not, therefore, be necessary to attain trepon• Fortunately, T. pallidum is still exquisitely sen• emacidal concentrations in the CSF or brain for sitive to penicillin. This is despite the recent dis• treatment to be successful. The perivascular con• covery of a plasmid that suggests that penicillin centration may be of greater importance. resistance may OCCUr.[lI] The treatment of neuro• Nevertheless, at present, convention dictates syphilis involves different regimens than those that treponemacidal CSF concentrations are a nec• used in non-neurological disease. essary aim of treatment. It should be noted that meningeal inflammation markedly increases anti• 4.1 Minimum Bactericidal Concentrations biotic penetration into the CSF.[6] In rabbit inoculation studies, the division time 4.3 Choice of Antibiotics for T. pallidum has been found to be approximately 33 hoursp,6] Such studies simulate primary syphil• There have been no controlled trials of treat• itic lesions. In spite of successful treatment of early ments for neurosyphilis. Therefore, treatment rec• syphilis, treponeme-like forms persist, suggesting ommendations are based on case series of particu• that for some organisms the division time must be lar regimens. Table 11 provides a summary of the much longer and treatment should be prolonged. dosage, route of administration and duration of treat• Even high dose penicillin does not appear to affect ment with antibiotics that can be used in patients T. pallidum where the organism is not dividing or with neurosyphilis (regardless of HlV status). is 'indifferent' .[6] Penicillin has an affinity for enzymes such as 4.3. 1 Penicillins transpeptidases that are vital for the construction Benzylpenicillin (Penicillin G) of the bacterial cell wall. Minimal bactericidal con• Benzylpenicillin (penicillin G) is the drug of centrations in rabbits and cell culture are 0.005 to choice for neurosyphilis. It has a short serum elim• 0.01 mg/Land 0.0025 mg/L, respectively.[2.6-8] The ination half-life. This means that treponemacidal World Health Organization (WHO) recommend concentrations in the brain and CSF either have to that 0.018 mg/L be accepted as a minimal trep• be obtained by high frequency intravenous admin• onemacidal concentrationp,6-8] Treponemacidal istration or by lower doses given by the intramus-

Table 11. Treatment recommendations for patients with neurosyphilis regardless 01 HIV status Drug Dosage Route of administration Duration (days) Procaine penicillina 2.4 MU/day Intramuscular 14-21 Benzylpenicillin (penicillin G)a 500 OOOU 6-hourly Intramuscular 14-21 Benzylpenicillin 2-4MU 4-hourly Intravenous 14-21 Amoxicillin (amoxycillin)a 2g 8-hourly Oral 14-21 Doxycyclineb 1OOmg 8-hourly Oral 21 Ceftriaxoneb 1 g/day Intramuscular 14-21 a Plus probenecid 1 9 6-hourly orally. b Used in patients with penicillin allergy. cular route with probenecid (table II). 500 OOOU of older patients than in younger patients. The usual benzylpenicillin intrarnuscularly 6-hourly plus pro• dosage is 2.4MU given weekly. However, trepon• benecid orally 1.0g 6-hourly consistently yields emacidal concentrations of penicillin are not con• treponemacidal eSF concentrations. sistently achieved in either serum or eSF with this When 3.2MU of benzylpenicillin is given intra• regimen and so it should not be used for the treat• muscularly just prior to neurosurgery, treponema• ment of neurosyphilis.[17] cidal concentrations are only inconsistently ob• tained in brain tissueJl2] eSF concentrations of Amoxicillin Amoxicillin given in high dosages with proben• benzylpenicillin are increased when the patient is ecid consistently produces treponemacidal drug con• febrile. centrations (>0.42 mg/L) in the eSF.[18] It is thus a Although benzylpenicillin is the most effective very useful oral alternative to benzylpenicillin. agent, the usefulness of this drug is limited by the However, it should be mentioned that probenecid fact that it has to be administered 6-hourly and may hin der the accumulation of amoxicillin in intramuscularly or intravenously. This route of ad• brain tissue. ministration is not ideal for outpatients. Therefore, alternative agents that can be administered orally 4.3.2 Tetracyclines have been used [e.g. amoxicillin (amoxycillin)]. Doxycycline has several advantages over tetra• cycline. It has a long elimination half-life (20 Procaine Penicillin hours) and, therefore, can be administered once or After 2 doses of 600 OOOU of procaine penicillin, twice daily. It is weil absorbed and its good lipid a regimen generally accepted as successful in clin• solubility leads to high eSF concentrations. eSF ically curing early syphilis, a treponemacidal con• concentrations have been reported to be 26% of centration of penicillin is not consistently achieved serum concentrations. [19] in brain tissue or eSF,[13] even if probenecid is With the other tetracyclines, oxytetracycline addedJI4.1S] Procaine penicillin 2.4 MU/day ad• and chlortetracycline, brain concentrations have ministered intramuscularly plus probenecid 1.0g been shown to be significantly higher than eSF 6-hourly is generally accepted as achieving tre• concentrations.16.19] ponemacidal concentrations in eSF, but even this finding is inconsistent.[16] 4.3.3 Macrolides

Benzathine Benzylpenicillin Erythromycin Benzathine benzylpenicillin was launched in Erythromycin is treponemastatic and only be• 1952. The drug ensures bactericidal penicillin con• comes treponemacidal at high dosages. The mini• centrations in the serum for long periods. However, mal bactericidal concentration is 0.005 mglL. A its use is associated with pain at the site of injec• street strain of T. pallidum has been found to be tion. Higher serum concentrations are achieved in resistant in vitra to erythromycin.[II] eSF and brain

penetration of the drug is poor, and is only im• 5. Treatment of Asymptomatic proved by meningeal inflammation. Erythromycin Neurosyphilis is, therefore, not a drug that can be reliably used in the treatment of neurosyphilis. About 30% of patients with early latent syphilis will have CSF changes indicating neurosyphilis. Azithromyein and Clarithromyein Approximately 30% of these patients will eventu• Azithromycin inhibits T. pallidum pro tein syn• ally develop c1inical neurosyphilis ifleft untreated. thesis in vitro as efficiently as erythromycin.[6] Thus, of the 40% of patients with T. pallidum in the However, azithromycin takes longer than benza• CSF in early syphilis about 30% will eradicate the thine benzylpenicillin to cure rabbit syphilis.l6] infection without treatment. This finding shows Tissue penetration of azithromycin is very high. that of every 100 patients with untreated early syph• Clarithromycin seems to have a similar spectrum ilis up to 10% may develop neurosyphilis.l2] of activity to azithromycin. Does conventional treatment cure patients who are in the asymptomatic stage? One study in sympto• 4.3.4 Ceffriaxone matic patients demonstrated that a single dose of 50% of T. pallidum are immobilised by a con• benzathine benzylpenicillin 2.4MU produced almost centration of ceftriaxone of 0.01 mg/L. The mini• no detectable penicillin in the CSF, but T. pallidum mum inhibitory concentration of the drug for were no longer found in the CSF after 6 to 7 days T. pallidum is 0.006 mg/L. In a rabbit model com• (during wh ich time low concentrations of penicil• paring ceftriaxone and benzylpenicillin, the equiv• lin were found in the blood).[8] In 2 combined stud• alent of ceftriaxone 1 g/day intramuscularly erad• ies,[22·231 standard low doses of repository penicil• icated inoculated T. pallidum in the brains of 6 of lins for 1 to 2 weeks resulted in the CSF returning 7 rabbits. However, the mean serum VDRL titre to normal in 994 of 996 treated patients with asymptomatic neurosyphilis. The 2 patients who and CSF pleocytosis were significantly reduced af• failed to respond to treatment showed only minor ter treatment in the aqueous benzylpenicillin com• CSF changes after treatment completion. pared with the ceftriaxone group.[7] The use of We believe that when the patient has syphilis as ceftriaxone I g/day for 14 days resulted in the cure determined by serological tests, but there are no of a single patient with asymptomatic neuro• neurological signs, the CSF need not be examined syphilisP] and conventional treatment may be used. Wiesel et aU24] agree and feel that lumbar punctures only 4.4 Patients with Penicillin Allergy increase morbidity in this situation and confer no c1inical benefit. Where there is a suggestive or c1earcut history of penicillin allergy in the presence of serious neuro• 6. HIV and Neurosyphilis syphilis, one option is to skin test patients to con• firm or refute the diagnosis. Patients are then 'rush Syphilis may be difficult to diagnose in HIV desensitised' by giving increasing oral dosages of seropositive patients because there may be no CSF penicillin over a number of hours in order to stabi• treponemal or reagin antibody response, particu• li se mast cells. High dose penicillin is then imme• larl y if the CD4 count is low. If these tests are pos• diately given. In aseries of 44 patients treated in itive they may react slowly and only be weakly this way, there were no serious allergic phenom• positive. Conversely, serum reagin titres may be ena.l20.21 ] Other nonpenicillin drug options that can higher than expected in the presence of HIY. [6] be used in patients with penicillin allergy are pre• Therefore, in the presence of HIV where neuro• sen ted in table 11. syphilis is suspected, some reliance may have to be

placed on histopathology, dark-field microscopy reflexes, abnormal pupillary reflexes, lightening and even the PCR.l25] pains, sensory ataxia, optic atrophy and hearing loss, The significance of finding a positive VDRL The symptoms or signs that may progress are Char• and pleocytosis in the CSF of a patient with HIV cot's joints, lightening pains and optic atrophy. and unexplained neurological disease can only be U nfortunately, studies detailing neurological decided by c1inical judgement. Both HIV and ac• progression have not controlled for neurological tive syphilis can cause a similar c1inical picture be• change, i.e. a nonsyphilitic group of matched patients cause of biological false-positive reagin tests. The has not been inc1uded. Wilner and Brody[30] fol• TPHA index has been used to diagnose neuro• lowed patients with general paresis after treatment syphilis,[26J and PCR, for T. pallidum, is more often for 30 years and found that 30% developed new positive in patients with neurological signs rather neurological signs, The significance of these are than those without. The significance of this is un• unc1ear and the post-mortem studies available sug• clearJ25] gest that there is no active neuro syphilis in such This differentiation is almost academic because patients.[30] high dose antibiotic treatment (see table II) is In the case of neuro syphilis in the presence of needed for all patients with syphilis and concurrent HIV, CSF abnormalities such as raised protein HIV infection. However, benzathine benzyl• level and pleocytosis may suggest active neuro• penicillin 2.4MU does not eradicate T. pallidum syphilis or HIV disease, Clinical judgement is from the CSF in HIV-positive patients with early needed as to when to retreat such patients. The syphilis[8] and may lead to severe meningovascular TPHA index may be useful in this case, being less disease. [27 ,28] than 100 in inactive or non-neurological syphilis in the presence of HIV, probably indicating that pa• 7. Treatment Outcome tients do not need treatmentJ26] PCR on the CSF to detect T. pallidum DNA may be oversensitive and Rothenberg[29] determined the status of patients remain positive in the absence of active infection. who had been treated for neuro syphilis (treatment ranged from a total of 600 OOOU to 36MU of benzylpenicillin) at a follow-up point of 6 months 8. Jarisch-Herxheimer and to 15 years after treatment from 24 studies. About Procaine Reactions 75% ofpatients were cured, improved or stabilised. The conditions treated were general paresis or ta• The larisch-Herxheimer reaction can occur boparesis 00 studies), tabes dorsalis (6 studies) within 12 hours of commencing treatment for neuro• and meningovascular meningitis (8 studies). There syphilis. This reaction is characterised by swelling was no correlation between dosage used and out• of inflammatory tissue associated with neuro• come, syphilis as weIl as shivering, an increase in body After treatment, CSF protein and pleocytosis temperature and pulse, and hyperventilation, fol• should revert to normal over a number of months or lowed by a hypotensive flush phase with subsquent 1 or 2 years, The VDRL titre should fall significantly, recovery. but may remain reactive even when the disease is no Systemic steroids (prednisolone 40 mg/day longer active. Relapse of CSF abnormalities have not starting 36 hours prior to treatment) have been been reported more than 2 years after reversion to advocated to control exacerbation of signs and normal. Luger and colleagues[9] consistently found symptoms of neuro syphilis associated with the that cured or 'bumt out' neurosyphilis yielded a reaction, e.g. psychotic symptoms in general pa• TPHA index of less than 100 (i.e. c1inical cure). resis. However, new cranial nerve lesions have ap• The fixed c1inical deficits that remain after pre• peared after giving systemic steroids before peni• sumed bacteriological cure inc1ude impaired cillin is started in patients with meningovascular

disease and, therefore, some authors do not recom• References mend steroid usage. I. Holmes KK, Lukehart SA. Syphilis. In: Braunwald E, Isselbacher Kl, PetersdorfRG, et al., editors. Harrison's prin• Meptazinol, a partial opiate agonist, has been used ciples of internal medicine. II th edition. New York: McGraw• successfully to diminish the larisch-Herxheimer Hill, 1987: 639-49 2. Holmes KK, Märdh P-A, Sparling PF, et al., editors. Sexually reaction in patients with relapsing fever. [31] In pa• transmitted diseases. New York: McGraw-Hill, 1984: tients in whom general paresis is associated with 291-384 the reaction, symptomatic control with phenothi• 3. Luxon L, Lees AJ, Greenwood Rl. Neurosyphilis today. Lancet 1979; 1: 90-3 azines or benzodiazepines may be used. 4. Burke 1M, Schaberg DR. Neurosyphilis in the antibiotic era. The procaine reaction is an almost instanta• Neurology 1985; 33: 1368-71 5. Hooshmand H, Escobar MR, Kopf SW. Neurosyphilis - a study neous short-lived psychotic reaction to the admin• of241 patients. JAMA 1972; 219: 726-9 istration of the drug, in wh ich the patient feels 6. Goldmeier D, Hay P. A review and update on adult syphilis, 'they are dying'. The patient needs to be restrained with particular reference to its treatment. Int 1 STD AIDS 1993; 4: 70-82 and reassured. 7. Marra CM, Slatter V, Tartaglione TA, et al. Evaluation of aque• ous penicillin G and ceftriaxone for experimental neuro• syphilis. 1 Infect Dis 1992; 165: 396-7 9. Other Treatment Issues 8. Lukehart SA, Hook III EW, Baker-Zander SA, et al. Invasion of the central nervous system by Treponema pallidum: impli• 9.1 Contact Tracing cations for diagnosis and treatment. Ann Intern Med 1988; 109: 855-62 9. Luger A, Schmidt BL, Steyrer K, et al. Diagnosis of neuro• Meningovascular neurosyphilis may be a char• syphilis by examination of the cerebrospinal fluid. Br 1 Vener acteristic of untreated secondary syphilis, and so Dis 1981; 57: 232-7 10. Muller F, Moskophidis M. Estimation of the local production sexual contacts of the patient over the previous 2- of antibodies to Treponema pallidum in the central nervous to 3-year period should be traced. Tertiary neuro• system of patients with neurosyphilis. Br 1 Vener Dis 1983; syphilis is noninfectious, and discretion and tact 59: 80-4 I!. Stamm LV, Stapleton JT, Bassford Pl. In vitra assay to dem• should be used so as not to cause family disruption onstrate high level erythromycin resistance of a clinical iso• and the accusation of recent infidelity. late of Treponema pallidum. Antimicrob Agents Chemother 1988; 32: 164-9 12. Kramer PW, Griffiths RS, Campbell RL. Antibiotic penetra• 9.2 Psychological Sequelae of the tion of the brain. A comparative study. 1 Neurosurg 1969; 31: Diagnosis of Neurosyphilis 295-302 13. Wellman WE, Dodge lr HW, Heilman FR, et al. Concentration of antibiotics in the brain. 1 Clin Lab Med 1954; 43: 275-9 In spite af syphilis na langer being the fearful 14. Goh BT, Smith GW, Samarasinghe L, et al. Penicillin concen• scourge it once was, it is not uncommon for pa• trations in serum and cerebrospinal fluid after intramuscular tients to be devastated when they learn they have injections of aqueous procaine penicillin 0.6 MV with and without probenecid. Br 1 Vener Dis 1984; 60: 371-3 syphilis. Counselling must be part of the treatment 15. Goldmeier D, Waterworth PM, Penetration of penicillin into the of neuro syphilis, to ensure that the patient has cerebrospinal fluid of patients with latent syphilis. Pharmo• therapeutica 1981; 1: 14-7 come to terms with the diagnosis, treatment and 16. Van Der Valk PFM, Kraai El, Von Voorster-Vader PL, et al. implications of the condition. Penicillin concentrations in cerebrospinal fluid (CSF) during repository treatment regime for syphilis. Genitourin Med 1988; 64: 223-5 10. Conclusions 17. Frentz G, Neilson PB, Esperson F, et al. Penicillin concentra• tions in blood and spinal fluid after a single intramuscular In the antibiotic and HIV era, syphilis that affects injection of penicillin G benzathine. Eur 1 Clin Microbiol 1984; 3: 147-9 the nervous system can cause a clinical picture that 18. Faber WR, Bos lD, Rietra P1GM, et al. Treponemacidallevels is not typical of those described in the classical of amoxycillin in cerebro spinal fluid after oral administration. texts. Keeping updated on the literature and a di• Sex Transm Dis 1983; 10: 148-50 19. Whiteside Yim C, Flynn NM, Fitzgerald FT. Penetration of oral vergent mi nd on therapeutic options are necessary doxycycline into the cerebro spinal fluid of patients with la• to ensure that patients with neurosyphilis are ade• tent or neurosyphilis. Antimicrob Agents Chemother 1985; 28: 347-8 quately followed up both physically and psycho• 20. Sullivan Tl. Antigen speeifie desensitisation ofpatients allergie logically. to penicillin. 1 Allergy Clin Immunol 1982; 69: 500-8

21. Wendel GD, Stark Bl, lamison RB, et al. Penicillin allergy and 27. lohns DR, Tierny M, Felsenstein D. Alterations in the natural desensitisation in serious infection in pregnancy. N Engl 1 history of neurosyphilis by concurrent infection with the human Med 1985; 312: 1229-32 immunodeficiency virus. N Engl 1 Med 1987; 316: 1569-72 22. Fernando WL, Cerebrospinal fluid findings after treatment of 28. Berry CD, Hooton TM, Collier AC, et al. Neurological relapse early syphilis with penicillin. A further series of 80 cases. Br after benzathine penicillin therapy for secondary syphilis in 1 Vener Dis 1968; 68: 134-5 HIV infection. N Engl 1 Med 1987; 316: 1587-9 23. Hahn RD, Cutler RC, Curtis AC, et al. Penicillin treatment of 29. Rothenburg R. Treatment of neurosyphilis. 1 Am Vener Dis asymptomatic central nervous system syphilis. Arch Dermatol Assoc 1976; 3: 153-8 1956; 74: 355-66 30. Wilner E, Brody lA. Prognosis of general paresis after treat• 24. Wiesel 1, Rose DN, Silver AL, et al. Lumbar puncture in asymp• ment. Lancet 1968; 11: 1370-1 tomatic late syphilis. An analysis of the benefits and risks. 31 . Teklu B, Habte-Michael A, Warrell D, et al. Meptazinol dimin• Arch Intern Med 1985; 145: 465-8 ishes the larisch-Herxheimer reaction of relapsing fever. Lan• 25. Hay PE, Clarke lR, Taylor-Robinson D, et al. Detection of tre• ce!: 1983; I: 835-9 ponemal DNA in the CSF of patients with syphilis and HIV infection using the polymerase chain reaction. Genitourin Med 1990; 66: 428-32 26. Tomberlin MG, Holtom PD, Owens lL, et al. Evaluation of neurosyphilis in human immunodeficiency virus - infected Correspondence and reprints: Dr David Goldmeier, St Mary's individuals. Clin Infect Dis 1994; 18: 288-94 Hospital, Praed Street, London W2 INY, England.