Neurosyphilis¶
VERSION: 1.1 CREATED: January 30, 2026 REVISED: January 30, 2026 STATUS: Draft - Pending Review
DIAGNOSIS: Neurosyphilis
ICD-10: A52.2 (Asymptomatic neurosyphilis), A52.3 (Neurosyphilis, unspecified), A52.13 (Late syphilitic meningitis), A52.14 (Late syphilitic encephalitis)
SYNONYMS: Neurosyphilis, CNS syphilis, syphilitic meningitis, meningovascular syphilis, general paresis, general paralysis of the insane, GPI, tabes dorsalis, locomotor ataxia, Argyll Robertson pupil, syphilitic encephalitis, syphilitic myelopathy, ocular syphilis, otic syphilis, otosyphilis, tertiary syphilis with CNS involvement, Treponema pallidum CNS infection
SCOPE: Evaluation and management of neurosyphilis including early neurosyphilis (meningeal, meningovascular), late neurosyphilis (general paresis, tabes dorsalis), and ocular/otic syphilis. Includes diagnosis, treatment with IV penicillin G, management of Jarisch-Herxheimer reaction, penicillin desensitization for allergic patients, and post-treatment monitoring with serial CSF analysis. Excludes primary/secondary syphilis without CNS involvement, congenital syphilis, and HIV-specific antiretroviral management.
PRIORITY KEY: STAT = Immediate | URGENT = Within hours | ROUTINE = Standard | EXT = Extended/atypical cases | - = Not applicable to this setting
═══════════════════════════════════════════════════════════════ SECTION A: ACTION ITEMS ═══════════════════════════════════════════════════════════════
1. LABORATORY WORKUP¶
1A. Essential/Core Labs¶
| Test | Rationale | Target Finding | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|
| RPR (serum) (CPT 86592) | Non-treponemal screening test; quantitative titer used for treatment response monitoring; sensitivity ~70-80% in late syphilis (prozone effect possible) | Reactive with titer (document titer for follow-up comparison) | STAT | STAT | ROUTINE | STAT |
| VDRL (serum) (CPT 86592) | Alternative non-treponemal screening; quantitative titer; VDRL is the only validated non-treponemal test for CSF | Reactive with titer | STAT | STAT | ROUTINE | STAT |
| FTA-ABS (serum) (CPT 86780) | Treponemal confirmatory test; remains positive for life after infection; high sensitivity and specificity | Reactive (confirms treponemal exposure) | STAT | STAT | ROUTINE | STAT |
| TP-PA (serum) (CPT 86780) | Treponemal confirmatory test; alternative to FTA-ABS; high specificity | Reactive | STAT | STAT | ROUTINE | STAT |
| Treponemal IgG/IgM EIA or CIA (serum) | Many labs now use reverse screening algorithm (treponemal test first); automated, high throughput | Reactive | STAT | STAT | ROUTINE | STAT |
| HIV 1/2 antigen/antibody (4th generation) (CPT 87389) | High co-infection rate (syphilis-HIV co-infection in 25-70% in some populations); HIV affects neurosyphilis presentation, treatment response, and monitoring schedule | Document result; if positive, obtain CD4 and viral load | STAT | STAT | ROUTINE | STAT |
| CBC with differential (CPT 85025) | Baseline; infection markers; lymphocytosis may be present | Normal or mild lymphocytosis | STAT | STAT | ROUTINE | STAT |
| CMP (BMP + LFTs) (CPT 80053) | Renal function for penicillin dosing; hepatic function; electrolytes | Normal; document baseline Cr | STAT | STAT | ROUTINE | STAT |
| ESR (CPT 85651) | Elevated in active syphilis; non-specific inflammatory marker | Often elevated | URGENT | ROUTINE | ROUTINE | URGENT |
| CRP (CPT 86140) | Inflammatory marker; baseline | May be mildly elevated | URGENT | ROUTINE | ROUTINE | URGENT |
1B. Extended Workup (Second-line)¶
| Test | Rationale | Target Finding | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|
| CD4 count and HIV viral load (CPT 86360) | If HIV positive; CD4 <350 increases risk of neurosyphilis; affects monitoring frequency | Document baseline; CD4 <350 = higher risk | - | ROUTINE | ROUTINE | - |
| Hepatitis B surface antigen, surface antibody, core antibody (CPT 87340) | Co-infection screening (shared risk factors); hepatitis may complicate treatment | Negative | - | ROUTINE | ROUTINE | - |
| Hepatitis C antibody (CPT 86803) | Co-infection screening | Negative | - | ROUTINE | ROUTINE | - |
| Gonorrhea/Chlamydia NAAT (CPT 87591) | STI co-infection screening; shared risk factors | Negative | - | ROUTINE | ROUTINE | - |
| Coagulation panel (PT/INR, aPTT) (CPT 85610+85730) | Before lumbar puncture; coagulopathy workup | Normal | STAT | STAT | ROUTINE | STAT |
| Blood glucose (paired with CSF) (CPT 82947) | CSF:serum glucose ratio interpretation | Document paired with LP | STAT | STAT | - | STAT |
| Serum B12 level (CPT 82607) | Subacute combined degeneration in differential (posterior column dysfunction like tabes dorsalis) | Normal | - | ROUTINE | ROUTINE | - |
| TSH (CPT 84443) | Thyroid dysfunction in differential of cognitive decline | Normal | - | ROUTINE | ROUTINE | - |
| ANA, dsDNA (CPT 86235) | SLE meningitis/cerebritis in differential; biological false-positive RPR seen in SLE | Negative | - | ROUTINE | ROUTINE | - |
1C. Rare/Specialized (Refractory or Atypical)¶
| Test | Rationale | Target Finding | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|
| Treponemal PCR (CSF) (CPT 87798) | Limited availability; lower sensitivity than serology; may be useful in early infection before antibody response | Negative (positive confirms T. pallidum DNA) | - | EXT | EXT | - |
| Antiphospholipid antibodies (CPT 86146) | Syphilis can cause biological false-positive; meningovascular syphilis with stroke differential includes antiphospholipid syndrome | Negative | - | EXT | EXT | - |
| Autoimmune encephalitis panel (serum + CSF) (CPT 86255) | General paresis may mimic autoimmune encephalitis (psychiatric symptoms, cognitive decline) | Negative | - | EXT | EXT | - |
| Paraneoplastic panel (serum) (CPT 86255) | Rapidly progressive dementia differential | Negative | - | EXT | EXT | - |
| ACE level (serum) (CPT 82164) | Neurosarcoidosis in differential (cranial neuropathies, meningitis) | Normal | - | EXT | ROUTINE | - |
| Whipple PCR (CSF or tissue) | Whipple disease in differential (dementia, ophthalmoplegia, ataxia) | Negative | - | EXT | EXT | - |
2. DIAGNOSTIC IMAGING & STUDIES¶
2A. Essential/First-line¶
| Study | Timing | Target Finding | Contraindications | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|
| MRI brain with and without contrast (CPT 70553) | Within 24-48h; STAT if acute stroke symptoms or altered consciousness | Meningovascular: cerebral infarction (especially MCA territory in young patient), meningeal enhancement, gummatous lesions. General paresis: frontotemporal atrophy, mesial temporal T2 hyperintensity. Tabes dorsalis: spinal cord atrophy. May be NORMAL in early/asymptomatic neurosyphilis | Pacemaker, metallic implants | STAT | STAT | ROUTINE | STAT |
| CT head without contrast (CPT 70450) | Immediate in ED if acute presentation (stroke, altered consciousness, seizure) | Infarction (meningovascular), hydrocephalus, calcified gumma; may be normal | Pregnancy (relative) | STAT | STAT | - | STAT |
| ECG (12-lead) (CPT 93000) | On admission; before penicillin infusion | Baseline; syphilitic aortitis (conduction abnormalities); QTc for concurrent medications | None | URGENT | ROUTINE | ROUTINE | URGENT |
2B. Extended¶
| Study | Timing | Target Finding | Contraindications | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|
| MRI spine (cervical/thoracic) with contrast (CPT 72156) | If myelopathy symptoms (tabes dorsalis, syphilitic myelitis) | Spinal cord atrophy (tabes dorsalis: posterior columns), meningeal enhancement, myelitis signal change | Same as MRI | - | ROUTINE | ROUTINE | - |
| MRA head and neck (CPT 70544+70547) | If meningovascular syphilis with stroke suspected | Arteritis; vessel wall enhancement; stenosis (medium and large vessels); aneurysm | Same as MRI | URGENT | URGENT | - | URGENT |
| CT angiography head and neck (CPT 70496) | If MRA not available and stroke suspected | Same as MRA | Contrast allergy; renal impairment | STAT | URGENT | - | STAT |
| Echocardiogram (TTE) (CPT 93306) | If cardiovascular syphilis suspected (aortitis); concurrent evaluation | Aortic regurgitation; ascending aortic aneurysm; aortitis | None significant | - | ROUTINE | ROUTINE | - |
| Chest X-ray (CPT 71046) | Admission; cardiovascular syphilis screening | Ascending aortic calcification (eggshell pattern); aortic dilatation | None significant | URGENT | ROUTINE | - | URGENT |
2C. Rare/Specialized¶
| Study | Timing | Target Finding | Contraindications | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|
| Vessel wall MRI (high-resolution) | If meningovascular syphilis with negative standard MRA | Concentric vessel wall enhancement (vasculitis pattern); distinguishes from atherosclerotic disease | Same as MRI | - | EXT | EXT | - |
| FDG-PET brain (CPT 78816) | Atypical cognitive decline; general paresis with unclear diagnosis | Frontotemporal hypometabolism (general paresis pattern) | Pregnancy | - | - | EXT | - |
| EEG (routine or continuous) (CPT 95816) | If seizures or altered mental status | Focal slowing; generalized slowing (general paresis); epileptiform discharges | None significant | URGENT | URGENT | - | STAT |
| CT/MRI aorta with contrast | If cardiovascular syphilis suspected (aortitis, aneurysm) | Ascending aortic aneurysm; aortitis | Contrast allergy; renal impairment | - | ROUTINE | ROUTINE | - |
| Nerve conduction studies / EMG (CPT 95907+95861) | Peripheral neuropathy evaluation; tabes dorsalis differential | Sensory neuropathy pattern; dorsal root ganglionopathy | Anticoagulation (relative for EMG) | - | ROUTINE | ROUTINE | - |
LUMBAR PUNCTURE¶
Indication: ALL patients with suspected neurosyphilis, confirmed syphilis with neurologic/ophthalmologic/otologic symptoms, HIV-positive with syphilis (especially CD4 <350 or RPR >=1:32), or syphilis with treatment failure. CSF examination is ESSENTIAL for diagnosis and monitoring.
Timing: URGENT. Perform before treatment if possible, but do NOT delay IV penicillin if LP will be significantly delayed.
Volume Required: 10-15 mL (standard diagnostic)
| Study | Rationale | Target Finding | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|
| Opening pressure | Elevated in syphilitic meningitis | Normal or mildly elevated (10-20 cm H2O); elevated in acute meningitis | URGENT | ROUTINE | ROUTINE | - |
| Cell count with differential (tubes 1 and 4) (CPT 89051) | CSF pleocytosis is the hallmark of active neurosyphilis; lymphocytic predominant; most sensitive CSF marker | WBC >5 cells/uL (lymphocyte predominant); typically 10-400 cells/uL; elevated WBC is the most sensitive indicator of active CNS infection | STAT | ROUTINE | ROUTINE | - |
| Protein (CPT 84157) | Elevated in neurosyphilis (45-200 mg/dL) | Elevated (>45 mg/dL); typically 50-200 mg/dL | STAT | ROUTINE | ROUTINE | - |
| Glucose with paired serum glucose (CPT 82945) | May be mildly decreased; helps distinguish from other causes of meningitis | Normal or mildly low (>60% serum glucose ratio); markedly low glucose suggests bacterial or TB meningitis | STAT | ROUTINE | ROUTINE | - |
| CSF VDRL (CPT 86592) | GOLD STANDARD for neurosyphilis diagnosis; highly SPECIFIC (99%) but sensitivity only 30-70%. A REACTIVE CSF VDRL confirms neurosyphilis. A NON-REACTIVE CSF VDRL does NOT exclude neurosyphilis | Reactive = diagnostic of neurosyphilis. Non-reactive does NOT rule out neurosyphilis | STAT | ROUTINE | ROUTINE | - |
| CSF FTA-ABS (CPT 86780) | More SENSITIVE than CSF VDRL (>95%) but LESS SPECIFIC (false positives from blood contamination). A NEGATIVE CSF FTA-ABS essentially rules out neurosyphilis. Used mainly to EXCLUDE the diagnosis | Non-reactive = neurosyphilis unlikely. Reactive = possible neurosyphilis (but not confirmatory due to lower specificity) | STAT | ROUTINE | ROUTINE | - |
| CSF RPR | NOT validated for CSF; some labs offer it but CSF VDRL is the standard non-treponemal test for CSF | CSF VDRL preferred; CSF RPR has uncertain performance characteristics | - | - | ROUTINE | - |
| Gram stain and bacterial culture (CPT 87205+87070) | Exclude bacterial meningitis if acute presentation | No organisms | STAT | ROUTINE | - | - |
| BioFire FilmArray ME Panel (CPT 87483) | Rapid multiplex PCR to exclude bacterial/viral meningitis if acute presentation | Negative (no bacterial or viral pathogen identified) | STAT | ROUTINE | - | - |
| Oligoclonal bands, IgG index (CPT 83916) | Intrathecal antibody production; elevated in neurosyphilis; also elevated in MS (differential) | Often positive (intrathecal IgG synthesis); not specific to syphilis | - | ROUTINE | ROUTINE | - |
| AFB smear and culture (CPT 87116) | TB meningitis in differential (chronic lymphocytic meningitis) | Negative | - | ROUTINE | - | - |
| Cytology (CPT 88104) | Leptomeningeal malignancy in differential | Negative | - | ROUTINE | - | - |
| Cryptococcal antigen (CSF) (CPT 87327) | HIV co-infection; chronic meningitis differential | Negative | - | ROUTINE | - | - |
Special Handling: CSF VDRL must be performed on CSF, NOT serum. Ensure lab receives sample labeled for CSF testing. Avoid bloody taps as blood contamination can cause false-positive CSF FTA-ABS.
Contraindications to LP: Coagulopathy (INR >1.5, platelets <50K) -- correct first if possible. Mass lesion with midline shift (CT first). Signs of impending herniation.
Diagnostic Interpretation Guide:
| CSF VDRL | CSF FTA-ABS | CSF WBC | Interpretation |
|---|---|---|---|
| Reactive | Reactive | Elevated (>5) | Confirmed neurosyphilis |
| Non-reactive | Reactive | Elevated (>5) | Probable neurosyphilis (treat as neurosyphilis) |
| Non-reactive | Non-reactive | Normal | Neurosyphilis essentially excluded |
| Non-reactive | Reactive | Normal | Possible prior treated neurosyphilis or false positive FTA-ABS; clinical correlation required |
| Reactive | Reactive | Normal | Possible neurosyphilis; monitor closely; consider treatment |
3. TREATMENT¶
3A. Acute/Emergent¶
| Treatment | Route | Indication | Dosing | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|
| Penicillin G (aqueous crystalline) (CPT 96365) | IV | First-line treatment for ALL forms of neurosyphilis (meningeal, meningovascular, general paresis, tabes dorsalis, ocular syphilis, otic syphilis) | 3-4 million units q4h :: IV :: q4h :: 18-24 million units/day IV, given as 3-4 million units IV q4h continuously for 10-14 days. Infuse each dose over 30-60 min. Alternative: continuous IV infusion 18-24 million units/day. Duration: minimum 10-14 days | Penicillin anaphylaxis (perform desensitization -- see below); dose adjust for severe renal impairment (CrCl <10: 2-3 million units q4h) | Renal function (BUN, Cr) daily; serum potassium (high-dose penicillin contains potassium); CBC; monitor for Jarisch-Herxheimer reaction in first 24h; monitor for seizures at very high doses | STAT | STAT | - | STAT |
| IV normal saline (hydration) | IV | Maintain hydration during IV penicillin therapy; prevent volume depletion | 75-125 mL/h :: IV :: continuous :: 75-125 mL/h IV maintenance; bolus 500-1000 mL if dehydrated | Volume overload, CHF | I/O; electrolytes daily | STAT | STAT | - | STAT |
| Acetaminophen (Jarisch-Herxheimer prophylaxis/treatment) | PO/IV | Prophylaxis and treatment of Jarisch-Herxheimer reaction (fever, rigors, headache, myalgia occurring 2-8h after first penicillin dose; occurs in up to 50% of neurosyphilis patients) | 650-1000 mg q6h :: PO :: q6h :: 650-1000 mg PO/IV q6h for first 24-48h of treatment; premedicate before first penicillin dose | Severe hepatic disease | Temperature; LFTs | STAT | STAT | - | STAT |
| Methylprednisolone (severe Jarisch-Herxheimer prevention) | IV | Prevention of severe Jarisch-Herxheimer reaction in patients at high risk (high RPR titer, HIV co-infection, ocular/otic syphilis with risk of permanent vision/hearing loss, meningovascular syphilis with stroke risk) | 60-125 mg :: IV :: once :: 60-125 mg IV 30 min before first penicillin dose to attenuate Jarisch-Herxheimer reaction | Active untreated infection (relative); uncontrolled diabetes | Glucose; blood pressure | STAT | STAT | - | STAT |
| Probenecid (with IM penicillin alternative) | PO | Used ONLY with procaine penicillin G IM regimen (alternative to IV penicillin when IV access impossible); blocks renal excretion of penicillin to maintain treponemicidal CSF levels | 500 mg QID :: PO :: QID :: 500 mg PO QID for 10-14 days (must be given with each IM penicillin dose); ensure adequate hydration | Uric acid nephrolithiasis; blood dyscrasias; sulfonamide allergy | Uric acid; renal function; ensure compliance (QID dosing) | - | ROUTINE | ROUTINE | - |
| Procaine penicillin G IM (alternative ONLY if IV not feasible) | IM | Alternative to IV penicillin G ONLY when IV access is impossible. MUST be combined with probenecid. CDC considers this acceptable but less preferred than IV | 2.4 million units daily :: IM :: daily :: 2.4 million units IM daily for 10-14 days PLUS probenecid 500 mg PO QID. This regimen REQUIRES strict compliance with probenecid; any missed doses compromise CSF levels | Procaine allergy; injection site concerns | Injection sites; compliance with probenecid; clinical response | - | ROUTINE | ROUTINE | - |
3B. Symptomatic Treatments¶
| Treatment | Route | Indication | Dosing | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|
| Gabapentin | PO | Neuropathic pain (lightning pains of tabes dorsalis; lancinating pain) | 300 mg :: PO :: TID :: Start 300 mg qHS; titrate by 300 mg q1-3d to 300-900 mg TID; max 3600 mg/day | Severe renal impairment (dose adjust: CrCl <60) | Sedation; dizziness; edema; renal function | - | ROUTINE | ROUTINE | - |
| Pregabalin | PO | Neuropathic pain (tabes dorsalis; alternative to gabapentin) | 75 mg :: PO :: BID :: Start 75 mg BID; may increase to 150-300 mg BID q1wk; max 600 mg/day | Severe renal impairment (dose adjust); angioedema history | Sedation; weight gain; edema; renal function | - | ROUTINE | ROUTINE | - |
| Carbamazepine | PO | Lancinating/lightning pain of tabes dorsalis (particularly effective for paroxysmal neuropathic pain) | 100 mg :: PO :: BID :: Start 100 mg BID; titrate by 200 mg/day q1wk; target 400-800 mg/day; max 1200 mg/day | AV block; history of bone marrow suppression; concurrent MAOIs; HLA-B*1502 positive (Asian descent -- screen before starting) | CBC with differential q2wk x 2 months then q3 months; LFTs; sodium (SIADH); drug level (target 4-12 ug/mL) | - | ROUTINE | ROUTINE | - |
| Duloxetine | PO | Neuropathic pain (tabes dorsalis); concurrent depression | 30 mg :: PO :: daily :: Start 30 mg daily x 1 wk; increase to 60 mg daily; max 120 mg/day | Severe hepatic impairment; concurrent MAOIs; uncontrolled narrow-angle glaucoma | LFTs; blood pressure; serotonin syndrome symptoms | - | ROUTINE | ROUTINE | - |
| Levetiracetam | IV/PO | Seizures (neurosyphilis-related seizures; meningovascular with cortical involvement) | 1000-1500 mg BID :: IV :: BID :: 1000-1500 mg IV load; then 500-1000 mg IV/PO BID; max 3000 mg/day | Severe renal impairment (dose adjust) | Renal function; mood/behavioral changes | STAT | STAT | ROUTINE | STAT |
| Lorazepam | IV | Active seizure rescue | 0.1 mg/kg IV push :: IV :: PRN seizure :: 0.1 mg/kg IV (max 4 mg); may repeat x1 in 5 min | Respiratory depression; severe hepatic failure | RR, SpO2; airway equipment ready | STAT | STAT | - | STAT |
| Sertraline | PO | Depression (common with general paresis and chronic neurosyphilis) | 50 mg :: PO :: daily :: Start 50 mg daily; increase by 50 mg q2-4wk; max 200 mg/day | Concurrent MAOIs; QT prolongation | Suicidality monitoring (first 4 weeks); serotonin syndrome | - | ROUTINE | ROUTINE | - |
| Quetiapine | PO | Psychotic symptoms (general paresis with psychosis, paranoid delusions, grandiosity) | 25 mg :: PO :: BID :: Start 25 mg BID; titrate slowly to 50-100 mg BID; target 150-300 mg/day for psychosis | QT prolongation; dementia-related psychosis (black box) | Metabolic panel q3 months; fasting glucose; lipids; QTc; tardive dyskinesia monitoring | - | ROUTINE | ROUTINE | - |
| Haloperidol | IV/IM | Acute agitation with psychosis (general paresis with severe agitation) | 2-5 mg q4-6h PRN :: IV :: PRN agitation :: 2-5 mg IV/IM q4-6h PRN; max 20 mg/day | QT prolongation; Parkinson disease; dementia (black box) | QTc monitoring; EPS; vital signs | STAT | STAT | - | STAT |
| Metoclopramide | PO | Gastroparesis (visceral autonomic neuropathy in tabes dorsalis) | 10 mg TID :: PO :: TID :: 10 mg PO 30 min before meals and at bedtime; max 40 mg/day; limit to 12 weeks | Parkinson disease; tardive dyskinesia; bowel obstruction | Tardive dyskinesia; EPS (limit duration) | - | ROUTINE | ROUTINE | - |
| Oxybutynin | PO | Bladder dysfunction (neurogenic bladder in tabes dorsalis; urgency/incontinence) | 5 mg :: PO :: BID :: Start 5 mg BID; may increase to 5 mg TID; max 15 mg/day | Urinary retention; uncontrolled narrow-angle glaucoma; GI obstruction | Post-void residual; anticholinergic effects (cognition in elderly) | - | ROUTINE | ROUTINE | - |
3C. Second-line/Refractory¶
| Treatment | Route | Indication | Dosing | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|
| Ceftriaxone IV (alternative to penicillin G) | IV | Alternative for neurosyphilis when penicillin desensitization is not feasible; CDC-recommended alternative. Evidence supports adequate CSF penetration and treponemicidal activity | 2 g daily :: IV :: daily :: 2 g IV daily for 10-14 days. Some experts recommend 14 days. Limited clinical trial data but supported by observational studies and CDC guidelines | Cephalosporin anaphylaxis; severe penicillin allergy with cephalosporin cross-reactivity (low risk, ~1-2%) | Renal function; CBC; LFTs; biliary sludge with prolonged use | STAT | STAT | - | STAT |
| Penicillin desensitization protocol (for penicillin-allergic patients) | PO then IV | Penicillin allergy with no acceptable alternative; allows safe IV penicillin G administration. Desensitization takes 4-6 hours and must be done in monitored setting (ICU or equivalent) | See Appendix A :: PO then IV :: :: Oral desensitization protocol over 4-6h (see Appendix A); begin IV penicillin G immediately after desensitization complete; patient must remain on continuous penicillin (no gaps >8h or desensitization is lost) | Anaphylaxis to penicillin (proceed with extreme caution in ICU); unstable cardiac/respiratory status | Continuous cardiac monitoring; SpO2; BP q15min during protocol; epinephrine at bedside; IV access x2; crash cart available | - | STAT | - | STAT |
| Doxycycline (third-line alternative) | PO | Third-line alternative ONLY when both IV penicillin and ceftriaxone are contraindicated; limited evidence for neurosyphilis; better studied for early syphilis | 200 mg BID :: PO :: BID :: 200 mg PO BID for 28 days. Some experts recommend 30 days. LOWER confidence in CNS penetration; use only if no other option. Close CSF monitoring mandatory | Pregnancy; children <8 years; concurrent retinoids | LFTs; sun protection counseling; GI tolerance; photosensitivity | - | ROUTINE | ROUTINE | - |
| Corticosteroids (adjunctive for ocular/otic syphilis) | PO/IV | Adjunctive anti-inflammatory therapy for ocular syphilis (uveitis, optic neuritis, retinal vasculitis) or otic syphilis to prevent permanent vision/hearing loss; used in addition to IV penicillin, not as standalone | 1 mg/kg daily :: PO :: daily :: Prednisone 1 mg/kg/day PO (max 60 mg) with IV penicillin; taper over 2-4 weeks based on ophthalmology/ENT guidance; or IV methylprednisolone 250 mg q6h x 3 days then oral taper for severe cases | Uncontrolled diabetes; active GI bleed; psychosis (relative) | Glucose; BP; GI prophylaxis; ophtho/ENT follow-up | - | STAT | ROUTINE | STAT |
4. OTHER RECOMMENDATIONS¶
4A. Referrals & Consults¶
| Recommendation | ED | HOSP | OPD | ICU |
|---|---|---|---|---|
| Infectious disease consultation for treatment optimization, duration guidance, penicillin desensitization planning, and HIV co-management | STAT | STAT | ROUTINE | STAT |
| Neurology consultation for diagnosis confirmation, CSF interpretation, differentiation of neurosyphilis subtypes, and management of neurologic complications | STAT | STAT | ROUTINE | STAT |
| Ophthalmology STAT evaluation for ALL patients with ocular symptoms (vision loss, floaters, photophobia) as ocular syphilis can cause permanent blindness without prompt treatment | STAT | STAT | ROUTINE | STAT |
| Audiology evaluation for ALL patients with hearing loss or tinnitus (otic syphilis) for baseline audiometry and monitoring | URGENT | URGENT | ROUTINE | URGENT |
| ENT consultation for otic syphilis evaluation and management of sensorineural hearing loss | URGENT | URGENT | ROUTINE | - |
| Psychiatry consultation for behavioral/psychiatric symptoms in general paresis (psychosis, personality change, cognitive decline, depression) | - | ROUTINE | ROUTINE | ROUTINE |
| Allergy/Immunology consultation for penicillin desensitization if patient reports penicillin allergy | URGENT | URGENT | ROUTINE | URGENT |
| Neuropsychology for formal cognitive testing in suspected general paresis (dementia evaluation, treatment response monitoring) | - | ROUTINE | ROUTINE | - |
| Physical therapy for gait training, balance rehabilitation, and fall prevention in tabes dorsalis (sensory ataxia, proprioceptive loss) | - | ROUTINE | ROUTINE | - |
| Occupational therapy for ADL assessment and adaptive strategies given proprioceptive and fine motor deficits | - | ROUTINE | ROUTINE | - |
| Social work for STI partner notification coordination, housing stability, substance use resources, and discharge planning | - | ROUTINE | ROUTINE | - |
| Public health department notification (syphilis is a reportable disease in all US states) | STAT | STAT | ROUTINE | - |
| Sexual health/STI clinic referral for partner notification, ongoing STI screening, and prevention counseling | - | ROUTINE | ROUTINE | - |
4B. Patient Instructions¶
| Recommendation | ED | HOSP | OPD | ICU |
|---|---|---|---|---|
| Return to ED if: new vision loss, worsening headache, new weakness, seizure, confusion, hearing loss, or high fever after starting treatment (Jarisch-Herxheimer reaction may worsen in first 24h) | STAT | STAT | ROUTINE | STAT |
| Complete the FULL course of IV penicillin (10-14 days); do NOT stop treatment early even if symptoms improve, as incomplete treatment leads to relapse and progressive CNS damage | - | ROUTINE | ROUTINE | ROUTINE |
| Expect possible fever, chills, headache, and muscle aches within 2-12 hours of first penicillin dose (Jarisch-Herxheimer reaction); this is a normal inflammatory response and NOT an allergic reaction; notify nursing staff but do NOT stop antibiotics | STAT | STAT | - | STAT |
| Abstain from sexual contact until treatment is complete and RPR titers decline to confirm cure; use condoms consistently after treatment | - | ROUTINE | ROUTINE | - |
| All sexual partners from the past 90 days (primary), 6 months (secondary), or 1 year (latent) must be notified and tested for syphilis | - | ROUTINE | ROUTINE | - |
| Follow-up blood tests (RPR titers) required at 3, 6, 12, and 24 months after treatment to confirm cure; failure of titers to decline by 4-fold at 6-12 months may indicate treatment failure | - | ROUTINE | ROUTINE | - |
| Follow-up lumbar puncture required at 6 months (and possibly 3, 12, and 24 months) after treatment to confirm CSF normalization | - | ROUTINE | ROUTINE | - |
| Report any new neurologic symptoms (vision changes, hearing changes, numbness, balance problems, cognitive changes) between follow-up visits as they may indicate treatment failure or reinfection | - | ROUTINE | ROUTINE | - |
| If HIV positive: ensure adherence to antiretroviral therapy as HIV co-infection increases risk of treatment failure and neurosyphilis relapse | - | ROUTINE | ROUTINE | - |
| Driving restrictions if cognitive impairment, seizures, or significant visual deficit until cleared by neurology | - | ROUTINE | ROUTINE | - |
4C. Lifestyle & Prevention¶
| Recommendation | ED | HOSP | OPD | ICU |
|---|---|---|---|---|
| Safer sex practices: consistent condom use reduces but does not eliminate syphilis transmission risk; regular STI screening for sexually active individuals | - | ROUTINE | ROUTINE | - |
| Alcohol cessation as alcohol worsens cognitive impairment and neuropathy, and complicates medication adherence and follow-up | - | ROUTINE | ROUTINE | - |
| HIV pre-exposure prophylaxis (PrEP) discussion for patients at ongoing risk who are HIV-negative | - | ROUTINE | ROUTINE | - |
| Fall prevention measures including assistive devices, home safety evaluation, and nightlight use for patients with sensory ataxia (tabes dorsalis), as proprioceptive loss worsens in darkness | - | ROUTINE | ROUTINE | - |
| Cognitive rehabilitation strategies including memory aids, structured routines, and supervised medication management for patients with general paresis | - | ROUTINE | ROUTINE | - |
| Regular exercise appropriate to functional level for cardiovascular health and prevention of deconditioning | - | ROUTINE | ROUTINE | - |
| Smoking cessation to reduce vascular risk (especially important in meningovascular syphilis with stroke risk) | - | ROUTINE | ROUTINE | - |
═══════════════════════════════════════════════════════════════ SECTION B: REFERENCE (Expand as Needed) ═══════════════════════════════════════════════════════════════
5. DIFFERENTIAL DIAGNOSIS¶
| Alternative Diagnosis | Key Distinguishing Features | Tests to Differentiate |
|---|---|---|
| HIV-associated neurocognitive disorder (HAND) | Progressive cognitive decline in HIV; may coexist with neurosyphilis; no CSF pleocytosis unless opportunistic infection | HIV viral load (CSF and serum); CD4 count; syphilis serologies negative; MRI: diffuse atrophy |
| Tuberculous meningitis | Subacute/chronic meningitis; basilar predominance; cranial neuropathies; CSF: lymphocytic, very low glucose, very high protein | AFB culture; TB PCR (GeneXpert); ADA; chest X-ray (miliary pattern); PPD/IGRA |
| Cryptococcal meningitis | HIV/immunocompromised; chronic headache; elevated opening pressure; minimal pleocytosis | CSF cryptococcal antigen; India ink; fungal culture; serum CrAg |
| CNS vasculitis (primary or secondary) | Multifocal strokes in young patient; headache; cognitive decline; CSF pleocytosis | Brain biopsy (gold standard); vessel wall MRI; CTA/MRA; ESR/CRP; ANA; ANCA; syphilis serologies to exclude |
| Multiple sclerosis | Relapsing-remitting neurologic deficits; optic neuritis; myelopathy; white matter lesions | MRI (periventricular/juxtacortical lesions; Dawson fingers); CSF oligoclonal bands; syphilis screen (should be done in all MS workups) |
| Autoimmune encephalitis (anti-NMDAR, LGI1) | Psychiatric symptoms; seizures; movement disorders; subacute onset | Autoimmune encephalitis antibody panel (serum + CSF); MRI; EEG |
| Neurosarcoidosis | Cranial neuropathies (especially CN VII); chronic meningitis; granulomatous inflammation | Chest CT (hilar adenopathy); serum/CSF ACE; biopsy; CSF lymphocytic; syphilis serologies negative |
| CNS lymphoma | Progressive cognitive decline in immunocompromised; periventricular enhancing lesion | MRI with contrast; CSF cytology; EBV PCR (CSF); stereotactic biopsy |
| Normal pressure hydrocephalus | Triad: gait apraxia, urinary incontinence, dementia; ventriculomegaly out of proportion to atrophy | Large volume LP (improvement after 30-40 mL removal); MRI (ventriculomegaly, DESH); gait assessment pre/post LP |
| Vitamin B12 deficiency myelopathy | Posterior column dysfunction (like tabes dorsalis); peripheral neuropathy; megaloblastic anemia | Serum B12; methylmalonic acid; homocysteine; MRI spine (dorsal column signal) |
| Lyme neuroborreliosis | Cranial neuropathies (CN VII); radiculopathy; meningitis; endemic area exposure; erythema migrans history | Lyme serologies (ELISA + Western blot); CSF Lyme antibody index; CSF pleocytosis |
| Whipple disease | Oculomasticatory myorhythmia (pathognomonic); dementia; GI symptoms; arthritis | Whipple PCR (CSF/tissue); small bowel biopsy; PAS-positive macrophages |
| Behcet disease | Oral/genital ulcers; uveitis; CNS involvement; young adults; Mediterranean/Asian descent | Clinical criteria (recurrent ulcers); pathergy test; HLA-B51; CSF pleocytosis |
| Chronic meningitis (other causes) | Persistent headache, cranial neuropathies, CSF pleocytosis >4 weeks | Full chronic meningitis workup: syphilis, TB, fungal, Lyme, sarcoid, malignancy |
6. MONITORING PARAMETERS¶
| Parameter | Frequency | Target/Threshold | Action if Abnormal | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|
| Neurologic exam (mental status, cranial nerves, motor, sensory, gait) | q4-8h inpatient; each outpatient visit | Stable or improving | If declining: reassess treatment; repeat imaging; repeat LP | STAT | STAT | ROUTINE | STAT |
| Temperature (Jarisch-Herxheimer monitoring) | q2h for first 24h of treatment, then q4h | <38.5C; JH reaction peaks at 6-8h | Acetaminophen; IV fluids; if severe: corticosteroids; do NOT stop penicillin | STAT | STAT | - | STAT |
| Serum RPR/VDRL titer | Baseline, then at 3, 6, 12, and 24 months post-treatment | 4-fold decline (2 dilutions) by 6-12 months; seroreversion or stable low titer by 24 months | If no 4-fold decline by 6-12 months: consider treatment failure; repeat LP; retreat | - | ROUTINE | ROUTINE | - |
| CSF analysis (cell count, protein, VDRL) -- follow-up LP | At 6 months post-treatment; repeat q6 months until normal; some experts also check at 3, 12, 24 months | CSF WBC normalizes first (by 6 months); protein normalizes by 2 years; CSF VDRL should become non-reactive | If CSF WBC not declining at 6 months: retreat with IV penicillin 10-14 days; if HIV+, check at 3 months | - | - | ROUTINE | - |
| Serum potassium | Daily during IV penicillin (high-dose penicillin contains 1.7 mEq K+ per million units) | 3.5-5.0 mEq/L | If hyperkalemic: reduce potassium intake; cardiac monitoring; if hypokalemic: supplement | - | ROUTINE | - | STAT |
| Renal function (BUN, Cr) | Daily during IV penicillin; each outpatient visit | Stable | Dose adjust penicillin if renal impairment develops | - | ROUTINE | ROUTINE | STAT |
| Visual acuity and fundoscopic exam | Each visit if ocular syphilis | Improving or stable vision | Urgent ophthalmology re-evaluation if worsening; reassess corticosteroid dose | STAT | ROUTINE | ROUTINE | STAT |
| Audiometry | Baseline, then at 1, 3, 6, 12 months if otic syphilis | Stable or improving hearing thresholds | ENT re-evaluation; consider corticosteroid adjustment | - | ROUTINE | ROUTINE | - |
| HIV viral load and CD4 (if co-infected) | At syphilis diagnosis, then per HIV monitoring schedule | Suppressed viral load; CD4 >350 preferred | If unsuppressed HIV: higher risk of neurosyphilis treatment failure; optimize ART | - | ROUTINE | ROUTINE | - |
| Seizure monitoring | Clinical observation inpatient; EEG if seizures | No seizure activity | Adjust AED; if status epilepticus: follow SE protocol | STAT | STAT | ROUTINE | STAT |
| Blood pressure | q4h inpatient; each outpatient visit | Stable | If hypertensive crisis during JH reaction: treat symptomatically | STAT | ROUTINE | ROUTINE | STAT |
7. DISPOSITION CRITERIA¶
| Disposition | Criteria |
|---|---|
| Discharge home (with OPAT -- outpatient parenteral antibiotic therapy) | Neurologically stable; no active seizures; mild symptoms; reliable outpatient IV access (PICC line); home infusion services arranged; reliable patient with follow-up arranged; no significant comorbidities requiring monitoring |
| Admit to floor | Confirmed or highly suspected neurosyphilis requiring IV penicillin initiation; need for Jarisch-Herxheimer monitoring; moderate neurologic deficits; seizure monitoring; ocular or otic syphilis requiring urgent subspecialty evaluation |
| Admit to ICU | Severe meningovascular syphilis with acute stroke; status epilepticus; acute vision loss requiring emergent management; penicillin desensitization protocol (requires continuous monitoring); severe Jarisch-Herxheimer reaction with hemodynamic instability; altered consciousness (GCS <13) |
| Transfer to higher level | Need for penicillin desensitization not available at current facility; need for neuro-ophthalmology not available; need for neurosurgery if hydrocephalus or mass lesion |
| Outpatient management | Asymptomatic neurosyphilis with mild CSF abnormalities; stable patient who can receive IV penicillin via OPAT or complete procaine penicillin IM + probenecid regimen; established diagnosis with completed inpatient treatment transitioning to monitoring |
8. EVIDENCE & REFERENCES¶
| Recommendation | Evidence Level | Source |
|---|---|---|
| IV penicillin G 18-24 million units/day x 10-14 days for neurosyphilis | Class I, Level A | CDC STI Treatment Guidelines 2021; Workowski et al. MMWR 2021 |
| CSF VDRL is the standard diagnostic test for neurosyphilis (highly specific but insensitive) | Class I, Level B | Marra et al. CID 2004 |
| CSF FTA-ABS has high negative predictive value (negative result essentially excludes neurosyphilis) | Class IIa, Level B | Marra et al. JID 2004 |
| CSF pleocytosis (WBC >5) is the most sensitive marker of active neurosyphilis | Class I, Level B | Marra et al. Neurology 2008 |
| Ceftriaxone 2g IV daily x 10-14 days as alternative to penicillin | Class IIa, Level B | Marra et al. CID 2000; CDC STI Guidelines 2021 |
| Serial CSF monitoring at 6-month intervals post-treatment | Class I, Level B | Marra et al. Neurology 2004 |
| HIV co-infection increases risk of neurosyphilis and treatment failure | Class I, Level B | Ghanem et al. CID 2008 |
| LP recommended for all HIV-positive patients with syphilis (especially CD4 <350 or RPR >=1:32) | Class IIa, Level B | Ghanem et al. STD 2009; CDC STI Guidelines 2021 |
| Ocular syphilis requires neurosyphilis treatment (IV penicillin) regardless of CSF findings | Class I, Level B | Oliver et al. STD 2016; CDC Clinical Advisory 2015 |
| Otic syphilis requires neurosyphilis treatment (IV penicillin) regardless of CSF findings | Class I, Level B | CDC STI Treatment Guidelines 2021 |
| Jarisch-Herxheimer reaction occurs in up to 50% of neurosyphilis patients | Class IIa, Level B | Expert consensus; Belum et al. Am J Med 2013 |
| Penicillin desensitization is safe and effective for penicillin-allergic patients requiring treatment | Class IIa, Level B | Wendel et al. NEJM 1985 |
| Four-fold decline in serum RPR by 6-12 months defines adequate treatment response | Class I, Level B | CDC STI Treatment Guidelines 2021 |
| CSF WBC should normalize within 6 months of successful treatment | Class I, Level B | Marra et al. Neurology 2004 |
| Retreatment indicated if CSF WBC has not declined at 6 months | Class IIa, Level B | CDC STI Guidelines 2021; Marra et al. CID 2004 |
| Doxycycline 200 mg BID x 28 days as third-line alternative (limited evidence) | Class IIb, Level C | Expert consensus; limited data for CNS penetration |
| All patients with syphilis should be tested for HIV | Class I, Level A | CDC STI Treatment Guidelines 2021; WHO Guidelines |
CHANGE LOG¶
v1.1 (January 30, 2026)
- Standardized structured dosing format for all Section 3B medications (gabapentin, pregabalin, carbamazepine, duloxetine, sertraline, quetiapine, oxybutynin) to use dose :: route :: frequency :: instructions format for clickable order sentences
- Added ICU venue column to Section 4B (Patient Instructions) and Section 4C (Lifestyle & Prevention) for complete 4-setting coverage
- Added REVISED date to header metadata
- Updated version to 1.1
v1.0 (January 30, 2026) - Initial template creation - Comprehensive coverage of early and late neurosyphilis subtypes - Ocular and otic syphilis included with management - Penicillin desensitization protocol (Appendix A) - CSF diagnostic interpretation guide - Treatment response monitoring with serial CSF analysis
APPENDIX A: PENICILLIN DESENSITIZATION PROTOCOL¶
Setting: ICU or monitored bed with continuous cardiac monitoring, pulse oximetry, and resuscitation equipment immediately available.
Prerequisites: - Two patent IV lines - Epinephrine 1:1000 (0.3 mg IM) at bedside - Diphenhydramine 50 mg IV available - Methylprednisolone 125 mg IV available - Crash cart available - Informed consent obtained - Allergist/immunologist consultation
Protocol (Oral Desensitization -- Preferred):
| Step | Penicillin V (units/mL) | Volume (mL) | Dose (units) | Cumulative Dose |
|---|---|---|---|---|
| 1 | 1,000 | 0.1 | 100 | 100 |
| 2 | 1,000 | 0.2 | 200 | 300 |
| 3 | 1,000 | 0.4 | 400 | 700 |
| 4 | 1,000 | 0.8 | 800 | 1,500 |
| 5 | 1,000 | 1.6 | 1,600 | 3,100 |
| 6 | 1,000 | 3.2 | 3,200 | 6,300 |
| 7 | 1,000 | 6.4 | 6,400 | 12,700 |
| 8 | 10,000 | 1.2 | 12,000 | 24,700 |
| 9 | 10,000 | 2.4 | 24,000 | 48,700 |
| 10 | 10,000 | 4.8 | 48,000 | 96,700 |
| 11 | 80,000 | 1.0 | 80,000 | 176,700 |
| 12 | 80,000 | 2.0 | 160,000 | 336,700 |
| 13 | 80,000 | 4.0 | 320,000 | 656,700 |
| 14 | 80,000 | 8.0 | 640,000 | 1,296,700 |
Instructions: - Administer each dose orally at 15-minute intervals - Monitor vital signs before each dose and 15 minutes after - Total protocol duration: approximately 4 hours - If reaction occurs at any step: treat reaction, then resume at the SAME dose after reaction resolves - After completing protocol: administer IV penicillin G at full therapeutic dose within 30 minutes - Patient must remain on continuous penicillin; any gap >8 hours requires repeat desensitization - Desensitization is temporary and must be repeated if penicillin is interrupted and restarted
Reference: Adapted from Wendel et al. NEJM 1985
APPENDIX B: NEUROSYPHILIS CLINICAL SUBTYPES¶
| Subtype | Timing After Primary | Key Clinical Features | CSF Findings | Imaging |
|---|---|---|---|---|
| Asymptomatic neurosyphilis | Any stage | No neurologic symptoms; CSF abnormalities only | Pleocytosis; elevated protein; reactive VDRL | Usually normal |
| Syphilitic meningitis | Months to years | Headache, cranial neuropathies (CN VII, VIII most common), neck stiffness, photophobia | Lymphocytic pleocytosis; elevated protein; reactive VDRL | Meningeal enhancement |
| Meningovascular syphilis | 5-12 years | Stroke (especially in young patient without vascular risk factors); prodromal headache/personality change weeks before stroke; Heubner arteritis (large vessels) and Nissl-Alzheimer arteritis (small vessels) | Pleocytosis; elevated protein; reactive VDRL | Cerebral infarction; vessel wall enhancement; stenosis |
| General paresis (dementia paralytica) | 10-25 years | Progressive dementia; personality change; psychiatric symptoms (grandiosity, psychosis, depression); Argyll Robertson pupils (accommodate but do not react to light); tremor; dysarthria; seizures | Pleocytosis; elevated protein; reactive VDRL; elevated IgG | Frontotemporal atrophy; mesial temporal signal change |
| Tabes dorsalis | 15-30 years | Lightning (lancinating) pains; sensory ataxia (positive Romberg); absent DTRs; Argyll Robertson pupils; Charcot joints; bladder dysfunction; visceral crises (gastric) | May have minimal pleocytosis; protein mildly elevated; VDRL may be non-reactive in late disease | Dorsal column atrophy (posterior spinal cord) |
| Ocular syphilis | Any stage | Uveitis (anterior, posterior, panuveitis); optic neuritis; retinal vasculitis; vision loss; may occur WITHOUT other CNS involvement | CSF may be NORMAL; treat as neurosyphilis regardless | Optic nerve enhancement; retinal changes on fundoscopy |
| Otic syphilis | Any stage | Sensorineural hearing loss (unilateral or bilateral); tinnitus; vertigo; may occur WITHOUT other CNS involvement | CSF may be NORMAL; treat as neurosyphilis regardless | Usually normal MRI; cochlear enhancement rare |
| Gummatous neurosyphilis | 3-15 years | Space-occupying lesion (gumma); seizures; focal deficits; mimics brain tumor | Pleocytosis; elevated protein | Ring-enhancing or homogeneously enhancing mass; dural-based |