01Approach to the Critical Patient/attcp41

Immediate priorities

›Time-critical threats requiring immediate action

›Acute vision loss suggesting ocular syphilis or optic neuritis

›Emergent ophthalmology consultation

›Same-day treatment initiation

›Altered mental status or seizures suggesting meningovascular syphilis or general paresis

›Immediate neurology consultation

›CT head to exclude mass lesion or haemorrhage before LP

›Stroke-like presentation in young patient suggesting meningovascular syphilis

›Activate stroke protocol

›MRI brain with DWI urgently

›Signs of meningismus suggesting syphilitic meningitis

›LP after neuroimaging

›IV penicillin G initiation once neurosyphilis confirmed

Key decision points

›Clinical reasoning framework for AR pupil

›AR pupil is a sign, not a diagnosis — mandates etiologic workup

›Classic AR pupil virtually pathognomonic of neurosyphilis until proven otherwise

›Light-near dissociation: poor or absent reaction to light, brisk near response

›Bilateral miotic irregular pupils with brisk near reflex — highest specificity for neurosyphilis

›Reactive syphilis serology with AR pupil requires LP for CSF analysis

›Normal MRI does not exclude neurosyphilis

Monitoring and escalation triggers

›Escalation criteria requiring higher level of care

›New or worsening cognitive decline — general paresis progression

›Neurology and infectious disease consultation

›Inpatient IV penicillin therapy

›Progressive gait ataxia or falls — tabes dorsalis

02History/hx54

Presenting symptoms

›Ophthalmic symptoms

›Blurred near vision or difficulty reading

›Photophobia or intolerance to bright light

›Floaters or visual field changes

›Eye pain or redness

›Neurologic symptoms of neurosyphilis

›Lightning pains in legs or trunk (tabes dorsalis)

›Gait unsteadiness or falling

›Urinary incontinence or retention

›Cognitive decline or memory loss

›Personality changes, depression, mania, or delusions of grandeur (general paresis)

›Tremor or dysarthria

›Headache (syphilitic meningitis)

STI and syphilis history

›Prior syphilis diagnosis and treatment

›Drug used, dose, and duration of prior treatment

›Incomplete treatment — major risk factor for neurosyphilis

›Prior positive RPR or VDRL titers

›Sexual history and risk factors

›Number of partners and MSM status

›Condom use consistency

›History of prior STIs

›Known HIV status and CD4 count

›Dermatologic history

›Painless genital ulcer (primary chancre)

›Maculopapular rash on palms and soles (secondary syphilis)

›Condylomata lata or mucous patches

03Physical Exam/exam37

Pupillary examination

›Core pupillary findings of Argyll Robertson pupil

›Miosis — small, often irregular pupils bilaterally

›Poor or absent direct and consensual light response

›Intact and brisk near response (accommodation-convergence reflex preserved)

›Light-near dissociation — hallmark finding

›Irregular pupil shape — asymmetric sphincter involvement

›Bilateral involvement — typical in neurosyphilis

Pharmacologic pupil testing

›Dilute pilocarpine 0.1% instillation

›Adie tonic pupil constricts due to denervation supersensitivity — positive response

›AR pupil does not constrict to dilute pilocarpine — key distinguishing test

›Positive response rules in Adie, not AR pupil

Slit-lamp and fundoscopy

›Anterior segment examination

›Iris atrophy or segmental sphincter palsy (suggests peripheral/ciliary ganglion lesion as in Adie)

›Anterior uveitis — associated with ocular syphilis

›Posterior segment examination

›Optic atrophy — seen in tabes dorsalis

›Papilledema — suggests raised intracranial pressure

›Chorioretinitis — associated with ocular syphilis

Cranial nerve assessment

›Targeted cranial nerve examination

›CN II: visual acuity, visual fields, colour vision

›CN III/IV/VI: extraocular movements and diplopia

›CN VIII: hearing assessment, whisper test

Neurologic examination

›Neurosyphilis-specific findings

04Differential Diagnosis/ddx36

Light-near dissociation differentials

›Neurosyphilis (tabes dorsalis, general paresis) — ICD-10: A52.1, A52.17

›Classic cause — bilateral, miotic, irregular pupils with brisk near response

›AR pupils found in most patients with tabes dorsalis

›Found in fewer than half of patients with general paresis

›Reactive serology and CSF abnormalities confirm diagnosis

›Adie tonic pupil — ICD-10: H57.09

›Key distinction: near response is tonic — slow, sustained constriction and slow redilation

›Pupil typically dilated, not miotic

›Usually unilateral

›Denervation supersensitivity to dilute pilocarpine 0.1% (constricts)

›Segmental iris sphincter palsy on slit-lamp

Dorsal midbrain causes

›Dorsal midbrain syndrome (Parinaud syndrome) — ICD-10: H51.8

›Associated upgaze palsy, convergence-retraction nystagmus, lid retraction

›Causes include pinealoma, stroke, multiple sclerosis, hydrocephalus

›Pupils typically mid-dilated and poorly reactive

›Multiple sclerosis — ICD-10: G35

›Demyelinating lesions near the Edinger-Westphal nucleus

›MRI brain with periventricular white matter lesions

›Sarcoidosis — ICD-10: D86.82

›Midbrain granulomas can produce AR-type pupils

›MRI may localize the lesion; serum ACE elevated

Autonomic neuropathy causes

›Diabetes mellitus — ICD-10: E11.40

›Autonomic neuropathy can cause tonic pupils

›Typically bilateral, may have other autonomic features

›Amyloidosis with autonomic neuropathy — ICD-10: E85.4

05Laboratory Tests/lt37

Syphilis serology

›Nontreponemal tests — quantitative titer required

›RPR (Rapid Plasma Reagin)

›Quantitative titer for monitoring treatment response

›May be nonreactive in late neurosyphilis due to waning titers

›4-fold decline by 12–24 months expected with successful treatment

›VDRL (Venereal Disease Research Laboratory)

›Alternative nontreponemal test

›Preferred in CSF analysis

›Treponemal confirmatory tests

›FTA-ABS (Fluorescent Treponemal Antibody Absorption)

›Highly sensitive, remains positive for life after infection

›TP-PA (Treponema Pallidum Particle Agglutination)

›Alternative confirmatory treponemal test

›Treponemal EIA or CIA — automated laboratory platforms

CSF analysis

›Lumbar puncture — indicated when AR pupil found with reactive syphilis serology

›CSF-VDRL

›Highly specific for neurosyphilis

›Sensitivity 30–70%

›Positive result confirms neurosyphilis

›CSF FTA-ABS

›Sensitivity 91–100%

›Specificity 55%

›High sensitivity makes negative result useful for exclusion

›CSF cell count

›Mononuclear pleocytosis typical

›Usually 6–200 cells/mm3

06Diagnostic Tests/dt65

Scoring Systems

›No validated single scoring system for AR pupil

›Diagnosis is clinical, based on characteristic pupillary findings

›Modified Neurosyphilis Diagnostic Criteria (CDC 2021 STI Guidelines)

›Reactive CSF-VDRL with compatible clinical syndrome — definitive

›CSF pleocytosis (>5 WBC/mm3) plus reactive treponemal serology — presumptive

›Risk stratification for neurosyphilis in HIV-positive patients

›CD4 ≤350 cells/mm3 increases risk

›RPR ≥1:32 increases risk

›Any neurologic or ophthalmic symptoms in HIV/syphilis co-infection — LP recommended

MRI

›MRI brain with contrast — first-line neuroimaging when neurosyphilis suspected

›Indications

›New focal neurologic deficits

›Cognitive decline

›Seizures

›Stroke-like presentation

›Findings in neurosyphilis

›Meningeal enhancement (meningovascular syphilis)

›Cerebral infarcts from endarteritis

›Cortical atrophy (general paresis)

›Cerebral gummas — rare

›Findings in non-syphilitic causes

›Pineal region mass — Parinaud syndrome

›Periventricular white matter lesions — multiple sclerosis

›Midbrain granulomas — sarcoidosis

›Limitation: normal MRI does not exclude neurosyphilis

›MRI spine

›Spinal cord atrophy in tabes dorsalis

›Posterior column involvement — demyelination and atrophy

CT

›CT head with and without contrast — use when MRI unavailable or urgent

›Indications

›Acute stroke-like presentation

›Altered mental status requiring rapid imaging

›Exclude mass lesion or haemorrhage before LP

›Limitation

›Less sensitive than MRI for midbrain pathology

›Cannot reliably detect meningeal enhancement

›May appear normal in neurosyphilis

›CT angiography (CTA) or MR angiography (MRA)

›Indicated if meningovascular syphilis with stroke-like presentation suspected

›May show vessel wall irregularity or narrowing from syphilitic endarteritis

Ultrasound

›Ultrasound not a primary modality for AR pupil evaluation

›Orbital ultrasound — limited role

›Can assess optic nerve sheath diameter if raised ICP suspected

›Not specific for syphilitic optic neuropathy

›Carotid duplex — if meningovascular syphilis with large vessel involvement suspected

›Assess for atherosclerotic disease in differential of stroke

›Echocardiography — if cardiovascular syphilis (aortitis) suspected

›Assess for aortic regurgitation

›Aortic root dilatation

Additional special tests

›Pharmacologic pupil testing — key bedside differentiator

›Dilute pilocarpine 0.1% test

›Adie tonic pupil constricts (denervation supersensitivity)

›AR pupil does not constrict

›Positive response rules in Adie, not neurosyphilis

›Infrared pupillometry

›Quantitative, reproducible measurement of pupillary dynamics

›Can document light reflex amplitude and velocity

›Slit-lamp biomicroscopy

›Segmental iris sphincter palsy suggests peripheral/ciliary ganglion lesion (Adie)

›Central lesion in AR pupil produces global sphincter dysfunction

›Audiometry — if hearing loss or tinnitus present (otic syphilis)

›Formal visual field testing — perimetry if optic neuropathy suspected

›ECG — indicated if cardiovascular syphilis suspected

›Assess for LVH or conduction abnormalities from syphilitic aortitis

›Coronary ostial stenosis may produce ischaemic changes

07Disposition/dispo25

Admission indications

›Inpatient admission criteria

›Confirmed or highly suspected neurosyphilis requiring IV penicillin G

›Unless outpatient IV therapy infrastructure is available

›Acute vision loss or rapidly declining visual acuity

›Acute hearing loss (otic syphilis)

›Altered mental status, seizures, or stroke-like presentation

›Gait instability with fall risk or inability to ambulate safely

›Need for penicillin desensitization — allergic patient

Discharge criteria

›Discharge with urgent outpatient follow-up acceptable when

›Isolated AR pupil finding with stable neurologic examination

›No acute vision or hearing changes

›Pending serology results not yet reactive or awaited

›Patient reliable for close follow-up

›Outpatient IV therapy arranged if needed

Consultation requirements

›Specialist consultation before disposition

›Ophthalmology — slit-lamp, fundoscopy, ocular syphilis management

›Urgent (same-day) if any visual acuity change

›Neurology — if focal deficits, cognitive change, or LP planned

›Infectious disease — neurosyphilis treatment planning, HIV co-infection

›Public health — mandatory reporting, partner notification

Follow-up planning

›Post-treatment monitoring schedule

›Clinical and serologic reassessment at 3, 6, 9, 12, and 24 months

›Repeat LP at 6 months — CSF pleocytosis should normalize

›Serum RPR/VDRL should decline ≥4-fold by 12–24 months

08Treatment/t60

Neurosyphilis — first-line treatment

›IV aqueous crystalline penicillin G — definitive treatment for neurosyphilis

›Dosing regimen

›18–24 million units per day total dose

›3–4 million units IV every 4 hours

›Alternative: continuous IV infusion of 18–24 million units per day

›Duration

›10–14 days

›Evidence level

›Class I recommendation (CDC STI Guidelines 2021, MMWR)

›IDSA and NEJM 2019 Ropper review support this regimen

›Post-IV consolidation

›Consider benzathine penicillin G 2.4 million units IM x1 after completing IV course

›Provides comparable duration to late latent syphilis treatment

Penicillin allergy management

›Allergy assessment before alternative agents

›Thorough allergy history — most reported allergies are not true IgE-mediated

›Penicillin skin testing and oral amoxicillin challenge can safely clear >90% of patients

›Ceftriaxone — alternative for confirmed penicillin allergy

›Dose: 2 g IV once daily

›Duration: 10–14 days

›Evidence: less robust than penicillin; used when true IgE allergy confirmed

›Penicillin desensitization — preferred approach for true penicillin allergy

›Perform in monitored inpatient setting

›Oral or IV desensitization protocols available

›Doxycycline — not recommended for neurosyphilis

›200 mg/day for 28 days used for late latent syphilis only

›Not well-studied for neurosyphilis; CNS penetration unreliable

09Special Populations/sp42

Pregnancy

›Pregnancy and syphilis — high-risk scenario

›Syphilis in pregnancy can cause congenital syphilis, stillbirth, and neonatal death

›Neurosyphilis in pregnancy managed with IV penicillin G — same dosing regimen

›18–24 million units/day for 10–14 days

›Penicillin is the only validated treatment in pregnancy

›Penicillin allergy in pregnancy — mandatory desensitization

›Doxycycline and other alternatives contraindicated in pregnancy

›Refer to tertiary centre for inpatient desensitization

›Jarisch-Herxheimer reaction in pregnancy

›Can cause uterine contractions and preterm labour

›Fetal monitoring recommended after first treatment dose

›Congenital syphilis consideration

›Newborn of mother with syphilis requires evaluation and treatment

›AR pupils in neonates or children — congenital syphilis must be excluded

›Screening — universal syphilis serology in first trimester and third trimester

Geriatric

›Older adults — specific considerations

›Neurosyphilis may present as dementia, personality change, or gait disorder

›Misattributed to Alzheimer disease or vascular dementia

›Syphilis serology in unexplained cognitive decline is warranted

›Tabes dorsalis features overlap with peripheral neuropathy from diabetes or age

›Examine carefully for AR pupils and light-near dissociation

›IV penicillin G — renal function may be reduced

›Dose adjustment not typically required but monitor renal function closely

›Risk of electrolyte disturbance with high-dose penicillin

›Jarisch-Herxheimer reaction poorly tolerated in elderly with cardiac or respiratory disease

›Enhanced monitoring during first 24 hours

10Background/b60

Epidemiology

›Syphilis incidence trends

›Global resurgence of syphilis since early 2000s after near elimination

›United States: syphilis rates increasing steadily — over 200,000 cases reported in 2023

›MSM and people with HIV disproportionately affected

›Congenital syphilis also rising — reflecting inadequately treated maternal syphilis

›Neurosyphilis epidemiology

›Occurs in approximately 5–10% of untreated syphilis patients

›With declining syphilis incidence historically, AR pupil from neurosyphilis became rare

›Re-emerging as syphilis incidence rises globally

›HIV co-infection — increases risk of early neurologic invasion

›AR pupil prevalence by syndrome

›Found in majority of patients with tabes dorsalis

›Found in fewer than 50% of patients with general paresis

›Other causes of light-near dissociation increasingly encountered as AR differential broadens

Pathophysiology

›Mechanism of Argyll Robertson pupil

›Treponema pallidum invades the central nervous system

›Neuroinvasion can occur within weeks of primary infection

›May remain subclinical for years before producing symptoms

›Putative lesion site — rostral midbrain periaqueductal gray matter

›Disrupts the pupillary light reflex pathway

›Spares the near reflex pathway (pretectal-olivary nucleus affected; Edinger-Westphal nucleus near-reflex arm preserved)

›Light reflex pathway disrupted

›Retina → optic nerve → chiasm → pretectal nucleus → Edinger-Westphal nucleus

›Lesion interrupts this arc before or at pretectal nucleus

›Near reflex pathway preserved

›Convergence-accommodation arc travels separately from pupillary light arc

›Intact arc produces brisk near response despite absent light response

›Iris sphincter muscle may also show direct infiltration or ischaemia

›Produces miosis and irregularity of the pupil margin

›Tabes dorsalis pathophysiology

›Posterior column and posterior root degeneration

›Loss of proprioception and vibration sense

›Absent deep tendon reflexes (afferent arc disrupted)

›Lightning pains from sensory root inflammation

›General paresis pathophysiology

›Direct cortical invasion by T. pallidum

›Progressive neuronal loss and gliosis

›Frontal and temporal lobe predominant — accounts for personality and cognitive features

Therapeutic Considerations

›Penicillin G rationale

›Only agent proven to achieve treponemicidal CSF levels reliably

›T. pallidum remains fully sensitive to penicillin — no resistance documented

›CSF penicillin levels must exceed MIC (0.018 mcg/mL) throughout treatment

›IM benzathine penicillin G achieves inadequate CSF levels — not used for neurosyphilis

›Treatment response and prognosis

›AR pupils may persist even after successful eradication of neurosyphilis

›Pupillary damage is often structural and irreversible

›Neurologic symptoms (cognitive decline, gait) may stabilize or partially improve

›Advanced disease rarely fully resolves

›Serologic response monitored by nontreponemal titers

›4-fold decline by 12–24 months indicates adequate treatment

›Treponemal tests remain positive for life regardless of treatment

›HIV and neurosyphilis treatment considerations

›Same IV penicillin regimen used in HIV-positive patients

›Some guidelines recommend LP for all HIV-positive patients with syphilis of unknown duration

›Antiretroviral therapy should be continued during syphilis treatment

›IRIS (immune reconstitution inflammatory syndrome) — rare concern

›Public health considerations

›Syphilis is a mandatory reportable disease in all jurisdictions

›Partner notification essential — sexual contacts within 12 months should be tested and treated

›Pre-exposure counselling on safe sexual practices

11Patient Discharge Instructions/pdi28

copy discharge instructions

›Diagnosis explanation

›You have been assessed for Argyll Robertson pupil — a condition where your pupils do not respond normally to light

›This finding is most commonly caused by syphilis affecting the nervous system (neurosyphilis)

›Further testing is needed to confirm the cause and begin treatment

›Medication instructions

›If neurosyphilis is confirmed, treatment requires IV penicillin given in hospital for 10–14 days

›Complete the full course of antibiotics — stopping early may result in treatment failure

›You may experience fever, chills, and rash within the first 24 hours of treatment (Jarisch-Herxheimer reaction) — this is expected; take paracetamol and drink fluids

›Activity and follow-up

›Attend all scheduled blood test and clinic appointments

›Repeat blood tests are required at 3, 6, 9, 12, and 24 months after treatment

›A repeat spinal fluid test (lumbar puncture) will be arranged at 6 months

›Ophthalmology and neurology follow-up appointments as arranged

›Partner notification

›Syphilis is a sexually transmitted infection — your sexual partners need to be tested and treated

›Public health will contact you to assist with partner notification

›Use condoms consistently during and after treatment

›Return to emergency department immediately if

›New or worsening vision loss

›New hearing loss or vertigo

›Worsening headache, confusion, or personality changes

›New weakness, numbness, or difficulty walking

›High fever or rash after starting antibiotics

›Seizure or loss of consciousness

›Expected course

›Your pupil abnormality may persist even after successful treatment — this does not mean treatment has failed

›Neurologic symptoms may stabilize but advanced damage may not fully reverse

12References/r32

Guidelines and key sources

›Ropper AH. Neurosyphilis. New England Journal of Medicine 2019

›Comprehensive review of neurosyphilis diagnosis and IV penicillin G treatment regimen

›NEJM 2019; 381:1358–1363

›Workowski KA, Bachmann LH, Chan PA, et al. Sexually Transmitted Infections Treatment Guidelines 2021

›CDC MMWR 2021 — definitive US treatment guidelines for neurosyphilis

›Recommends IV crystalline penicillin G 18–24 million units/day for 10–14 days

›PMCID: PMC8344968

›Hamill MM, Ghanem KG, Tuddenham S. State-of-the-Art Review: Neurosyphilis

›Clinical Infectious Diseases 2024 — contemporary epidemiology and management

›PMID: 37593890

›Thompson HS, Kardon RH. The Argyll Robertson Pupil

›Journal of Neuro-Ophthalmology 2006 — seminal review of AR pupil pathophysiology and differential

›PMID: 16845316

›Dacso CC, Bortz DL. Significance of the Argyll Robertson Pupil in Clinical Medicine

›American Journal of Medicine 1989 — clinical review of AR pupil and neurosyphilis correlation

›PMID: 2643871

Supporting references

›Chevalier FJ, Bacon O, Johnson KA, Cohen SE. Syphilis. JAMA 2025

›Contemporary clinical overview of syphilis diagnosis and management

›Peeling RW, Mabey D, Chen XS, Garcia PJ. Syphilis. Lancet 2023

›Global epidemiology and resurgence review

›PMID: 37481272

›Miller NR, Newman NJ. The Eye in Neurological Disease. Lancet 2004

›Neuro-ophthalmologic conditions including AR pupil differential diagnosis

›PMID: 15582062

›Tuddenham S, Hamill MM, Ghanem KG. Diagnosis and Treatment of Sexually Transmitted Infections: A Review. JAMA 2022

›Systematic review of STI management including syphilis

Evidence & Review

Evidence & Review