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neuro.ms-spms.v1PRODUCTION
neuro.ms-spms.v1

Secondary Progressive Multiple Sclerosis

neurologychronicadult
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Encounter flow

12/12 authored

Canonical 12-phase frame with authored status for this dossier.

Current phase

Frame

Detailed

Confirm SPMS conversion from RRMS — ≥6 mo progression independent of relapse (Lublin 2014); active vs non-active classification

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Advance rule
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Advance when

SPMS confirmed with active/non-active status

Patient inputs (19)

VZV-naive → vaccinate before S1P modulator (AAN 2024)

HBV reactivation on anti-CD20 (AAN 2024)

TB screen before immunosuppressive DMT (AAN 2024)

SPMS typically 10-20 y after RRMS diagnosis; usually 40s-50s

Depression highly comorbid in progressive MS; suicide risk elevated

Active SPMS (with relapse or new MRI lesion) qualifies for siponimod; non-active SPMS has limited DMT options

Confirm prior RRMS to establish SPMS conversion (vs PPMS primary progression)

Lublin 2014 — ≥6 mo progression without relapse defines SPMS conversion

Active SPMS = new T2 / gad+; baseline + annual (AAN 2024)

Lymphopenia surveillance on siponimod / cladribine

Siponimod hepatotoxicity (1% LFT >3× ULN); ocrelizumab LFT monitoring

EDSS upward trajectory marks progression; schema-blocked

Siponimod CYP2C9 *3/*3 contraindicates (EXPAND PMID 29576505)

Siponimod contraindicates 2nd/3rd degree AV block, recent MI/stroke/HF (EXPAND PMID 29576505)

Spasticity dominant phenotype — drives baclofen / tizanidine / BTX / pump decisions

Neurogenic bladder common — anticholinergic / BTX / catheterization

Cord atrophy strong disability predictor in progressive MS

SDMT preferred MS cognitive screen; schema-blocked

Fatigue dominant phenotype — amantadine / modafinil

* = hard-required. Engine cannot meaningfully run until these are filled.

Severity triggers (8)

8 need judgement
  • informationalsevereactive_spms_relapse_or_mri_activity
    Active SPMS — relapse in past 2 y OR new T2/gad+ lesion + progression — siponimod EXPAND-eligible (PMID 29576505)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereedss_progression_dominant
    EDSS step progression confirmed at 3 + 6 mo without intervening relapse — PIRA (progression independent of relapse activity)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderatenon_active_spms_symptomatic_focus
    Non-active SPMS — no relapse or MRI activity in past 2 y — symptomatic + rehab dominant; consider DMT discontinuation (AAN 2024)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderatepseudobulbar_affect_dextromethorphan_quinidine
    Pseudobulbar affect — uncontrolled laughing/crying episodes inappropriate to mood (TRANSIT trial)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderatespasticity_dominant_baclofen_tizanidine
    Spasticity dominant phenotype — limits ADL + gait + sleep — baclofen / tizanidine / BTX / intrathecal pump ladder
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderateneurogenic_bladder_anticholinergic_or_btx
    Neurogenic bladder — detrusor overactivity / DSD / retention — oxybutynin / mirabegron / BTX intradetrusor / catheterization
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderatecognitive_decline_neurorehab
    Cognitive decline — SDMT decline / processing speed / memory — cognitive rehab + treat depression + minimize anticholinergic burden
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmildfatigue_dominant_amantadine_or_modafinil
    Fatigue dominant phenotype — amantadine first-line; modafinil second; sleep hygiene + treat OSA
    Trigger could not be auto-evaluated — needs clinician judgement.

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Recommended regimen

SPMS DMT — siponimod first-line for active SPMS; symptomatic dominant for non-active (AAN 2024; EXPAND PMID 29576505)
axis: spms_dmtstep 1 - Step 1 — Active SPMS (relapse + progression) — siponimod EXPAND
Selected step "Step 1 — Active SPMS (relapse + progression) — siponimod EXPAND" — SPMS with relapse in past 2 y OR new T2/gad+ lesion + EDSS 3-6.5 + CYP2C9 not *3/*3
  • siponimod
    first line
    S1P_modulator
    0.25 mg titrate to 2 mg PO daily over 6 days (CYP2C9 *1/*3 or *2/*3 → 1 mg max) • PO • daily (max: 2 mg/day (1 mg if CYP2C9 *1/*3 or *2/*3))
    triggers: active_SPMS
    EXPAND (Kappos Lancet 2018 PMID 29576505 NEEDS_SOURCE_REVIEW) — first FDA-approved DMT for active SPMS; 21% relative risk reduction in 3-mo CDP; first-dose 6-h ECG monitoring
    rxcui 2121085
  • ocrelizumab (off-label active SPMS)
    second line
    anti_CD20_mAb
    300 mg IV × 2 then 600 mg q6 months • IV • q6 months
    triggers: active_SPMS_alt_to_siponimod
    OPERA extension supports off-label use in active SPMS; OPERA PMID 28002679
    rxcui 1876366
  • cladribine (active SPMS)
    second line
    purine_antimetabolite
    Weight-based 3.5 mg/kg cumulative oral • PO • pulsed years 1+2
    triggers: active_SPMS_oral_preference
    CLARITY extension supports active SPMS; PMID 20089960
    rxcui 44157

outpatient playbook — drug actions (11)

  1. 1. siponimod
    0.25 mg titrate to 2 mg PO daily • PO • daily
    trigger: Active SPMS
    EXPAND PMID 29576505; CYP2C9-driven dose
  2. 2. ocrelizumab (off-label active SPMS)
    600 mg IV q6 mo • IV infusion • q6 mo
    trigger: Active SPMS alt
    OPERA extension
  3. 3. baclofen
    10-20 mg PO TID • PO • TID
    trigger: Spasticity
    AAN 2024
  4. 4. tizanidine
    2-8 mg PO TID • PO • TID
    trigger: Spasticity baclofen-intolerant
    AAN 2024
  5. 5. oxybutynin
    5 mg PO BID-TID • PO • BID-TID
    trigger: Neurogenic bladder
    AUA 2024
  6. 6. mirabegron
    50 mg PO daily • PO • daily
    trigger: Anticholinergic-intolerant
    AUA 2024
  7. 7. amantadine
    100 mg PO BID • PO • BID
    trigger: Fatigue
    AAN 2024
  8. 8. modafinil
    100-200 mg PO morning • PO • morning
    trigger: Amantadine-intolerant
    AAN 2024
  9. 9. sertraline
    50-100 mg PO daily • PO • daily
    trigger: Depression
    APA 2024
  10. 10. dextromethorphan-quinidine (Nuedexta)
    20/10 mg PO BID • PO • BID
    trigger: Pseudobulbar affect
    TRANSIT FDA-approved
  11. 11. dalfampridine
    10 mg PO BID • PO • BID
    trigger: Gait impairment
    FDA-approved; eGFR ≥80; no seizure hx

Auto-drafted A&P note

outpatient

Subjective

- Possible entry pathways: RRMS patient with insidious progression ≥6 mo independent of relapses (Lublin 2014 PMID 24871874 NEEDS_SOURCE_REVIEW); EDSS step progression confirmed at 3 + 6 mo without intervening relapse — PIRA; Disproportionate cord/brain atrophy on annual MRI — neurodegenerative pattern.

Objective

- No vitals, labs, or imaging entered for this encounter.

Assessment

**Secondary Progressive Multiple Sclerosis** (neuro.ms-spms.v1).
Phenotype framing: Active SPMS (relapse / new MRI) vs non-active SPMS; RRMS-still vs SPMS-conversion (often retrospective); PIRA tracking; consider PPMS misclassification (rare after established RRMS)
Scope: Confirm SPMS conversion from RRMS — ≥6 mo progression independent of relapse (Lublin 2014); active vs non-active classification

No severity triggers fired against current inputs.

Plan

Regimen axis: **SPMS DMT — siponimod first-line for active SPMS; symptomatic dominant for non-active (AAN 2024; EXPAND PMID 29576505)** — step "Step 1 — Active SPMS (relapse + progression) — siponimod EXPAND".
1. siponimod 0.25 mg titrate to 2 mg PO daily over 6 days (CYP2C9 *1/*3 or *2/*3 → 1 mg max) PO daily (S1P_modulator, first line) — EXPAND (Kappos Lancet 2018 PMID 29576505 NEEDS_SOURCE_REVIEW) — first FDA-approved DMT for active SPMS; 21% relative risk reduction in 3-mo CDP; first-dose 6-h ECG monitoring
2. ocrelizumab (off-label active SPMS) 300 mg IV × 2 then 600 mg q6 months IV q6 months (anti_CD20_mAb, second line) — OPERA extension supports off-label use in active SPMS; OPERA PMID 28002679
3. cladribine (active SPMS) Weight-based 3.5 mg/kg cumulative oral PO pulsed years 1+2 (purine_antimetabolite, second line) — CLARITY extension supports active SPMS; PMID 20089960

Setting playbook (outpatient) — MS clinic q3-6 mo — DMT (siponimod for active SPMS), symptomatic management, neurorehab coordination, depression + cognition screening, advance directives at EDSS ≥7 (AAN 2024)
4. siponimod 0.25 mg titrate to 2 mg PO daily PO daily — Active SPMS (EXPAND PMID 29576505; CYP2C9-driven dose)
5. ocrelizumab (off-label active SPMS) 600 mg IV q6 mo IV infusion q6 mo — Active SPMS alt (OPERA extension)
6. baclofen 10-20 mg PO TID PO TID — Spasticity (AAN 2024)
7. tizanidine 2-8 mg PO TID PO TID — Spasticity baclofen-intolerant (AAN 2024)
8. oxybutynin 5 mg PO BID-TID PO BID-TID — Neurogenic bladder (AUA 2024)
9. mirabegron 50 mg PO daily PO daily — Anticholinergic-intolerant (AUA 2024)
10. amantadine 100 mg PO BID PO BID — Fatigue (AAN 2024)
11. modafinil 100-200 mg PO morning PO morning — Amantadine-intolerant (AAN 2024)
12. sertraline 50-100 mg PO daily PO daily — Depression (APA 2024)
13. dextromethorphan-quinidine (Nuedexta) 20/10 mg PO BID PO BID — Pseudobulbar affect (TRANSIT FDA-approved)
14. dalfampridine 10 mg PO BID PO BID — Gait impairment (FDA-approved; eGFR ≥80; no seizure hx)

Non-pharmacologic actions:
- PT/OT bid-weekly programs
- Cognitive rehab if SDMT decline
- Neuropsychology referral if cognitive impairment
- Spasticity clinic (BTX, pump consideration)
- Urology + urodynamics for refractory bladder
- Pelvic floor PT
- SLP for dysphagia + speech
- Vocational rehab + disability paperwork
- Wheelchair + assistive device fitting
- Caregiver support + respite
- Advance directives + capacity assessment at EDSS ≥7
- Palliative referral at severe disability

AVOID / contraindication checks:
- CYP2C9_3_3_contraindicates_siponimod (EXPAND PMID 29576505)
- Siponimod_first_dose_6h_ECG_monitoring (EXPAND PMID 29576505)
- Siponimod_contraindicate_AV_block_recent_MI_stroke_HF (FDA label)
- VZV_vaccination_before_siponimod (AAN 2024)
- Macular_edema_screen_baseline_and_q3_mo_initial_siponimod (AAN 2024)
- LFT_q3_to_6_mo_on_siponimod (AAN 2024)
- HBV_screen_before_anti_CD20 (AAN 2024)
- TB_screen_before_DMT (AAN 2024)
- Lymphocyte_count_nadir_monitor_siponimod_cladribine (AAN 2024)
- Cladribine_6mo_washout_before_conception (AAN 2024)

Monitoring

Regimen monitoring:
- CBC lymphocyte count q3 to 6 mo (AAN 2024)
- LFT q3 to 6 mo (AAN 2024)
- OCT or dilated fundus baseline and q3 mo initial siponimod (FDA label)
- annual brain MRI (AAN 2024)
- annual cervical cord MRI (AAN 2024)
- EDSS at each visit PIRA tracking (schema-blocked — see depth bundle)
- SDMT cognitive screen annually (schema-blocked)
- urodynamics if bladder dysfunction (AUA 2024)

Setting (outpatient) monitoring:
- EDSS + MSFC components q3-6 mo (schema-blocked)
- PIRA confirmation 3- and 6-mo step progression
- MRI annually
- CBC + LFT q3-6 mo
- OCT q3 mo initial on siponimod
- PVR + UA q6 mo if catheterizing

Follow-up plan: PT/OT/SLP; spasticity clinic + intrathecal baclofen pump consideration if refractory; pulmonary surveillance (FVC); palliative + advance directives at EDSS ≥7; caregiver support (AAN 2024)
- Close-out criterion: Multidisciplinary follow-up scheduled

Monitoring phase: CBC + LFT q3-6 mo; annual MRI; EDSS / SDMT / T25FW / 9HPT (schema-blocked) at each visit; pressure injury surveillance; UA + bladder scan q6 mo; depression + cognitive screen annually (AAN 2024)

Disposition

Current setting: outpatient — MS clinic q3-6 mo — DMT (siponimod for active SPMS), symptomatic management, neurorehab coordination, depression + cognition screening, advance directives at EDSS ≥7 (AAN 2024)

Disposition criteria:
- Continue indefinite MS clinic q3-6 mo
- Home health intensification at progressive decline
- Long-term care at EDSS ≥7.5 with caregiver inability
- Hospice at severe disability + recurrent complications

Escalation triggers (move to higher acuity):
- Acute relapse → route to neuro.ms-flare.core.v1
- Rapid EDSS jump → neuro + MRI urgent
- Severe pressure injury stage III/IV → wound + admit
- Aspiration / pulmonary decline → SLP + pulmonology
- Refractory spasticity → intrathecal baclofen pump
- Refractory bladder → BTX + cathter program
- Severe depression / suicidality → ED + psych

Earlier-Return Triggers

Return-precaution thresholds (watch for):
- [SEVERE] Active SPMS — relapse in past 2 y OR new T2/gad+ lesion + progression — siponimod EXPAND-eligible (PMID 29576505)
- [SEVERE] EDSS step progression confirmed at 3 + 6 mo without intervening relapse — PIRA (progression independent of relapse activity)
- [MODERATE] Non-active SPMS — no relapse or MRI activity in past 2 y — symptomatic + rehab dominant; consider DMT discontinuation (AAN 2024)

Citations

- AAN 2024 MS DMT guideline + ECTRIMS 2024 + EXPAND siponimod (Kappos Lancet 2018 PMID 29576505) [PMID:29576505](https://pubmed.ncbi.nlm.nih.gov/29576505/)
- Cited evidence (PMID 28002679) [PMID:28002679](https://pubmed.ncbi.nlm.nih.gov/28002679/)
- Cited evidence (PMID 32757523) [PMID:32757523](https://pubmed.ncbi.nlm.nih.gov/32757523/)
- Cited evidence (PMID 29545067) [PMID:29545067](https://pubmed.ncbi.nlm.nih.gov/29545067/)
- Cited evidence (PMID 24871874) [PMID:24871874](https://pubmed.ncbi.nlm.nih.gov/24871874/)

Last reconciled with current guidelines: 2026-05-22.
References