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neuro.ms-ppms.v1PRODUCTION
neuro.ms-ppms.v1

Primary 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 PPMS — ≥1 y progressive disability from onset + no prior relapse; rule out mimics; active vs non-active classification per Lublin 2014 (PMID 24871874)

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Advance rule
Set
Advance when

PPMS confirmed; active vs non-active classified

Patient inputs (20)

AQP4-IgG positive → NMOSD pivot (different DMT — eculizumab/satralizumab/inebilizumab/rituximab; AVOID IFN/natalizumab) (Wingerchuk 2015 PMID 26092914)

HBV reactivation on anti-CD20 (AAN 2024)

Typical PPMS onset 40s; FDA ocrelizumab label age ≤55 for PPMS

M:F ~1:1 in PPMS (vs 3:1 F in RRMS)

Depression highly comorbid in progressive MS

PPMS by definition has no prior relapse history (rare exceptions: late relapse after years of PPMS)

Active PPMS = gad+ lesion OR new T2 in past 12 mo → ocrelizumab indicated (ORATORIO PMID 28002688)

Lublin 2014 — ≥1 y progressive disability from onset without relapse defines PPMS

Active PPMS = gad+ lesion OR new T2; annual MRI (AAN 2024)

Cervical cord lesions + atrophy are PPMS hallmark; baseline + annual

Subacute combined degeneration mimic (B12 deficiency); copper deficiency myelopathy; treat reversible

Tabes dorsalis / neurosyphilis mimic of progressive paraparesis

HIV myelopathy + HTLV-1-associated myelopathy (TSP) mimic

Lymphopenia surveillance on ocrelizumab

Ocrelizumab LFT monitoring

EDSS ≤6.5 required for ocrelizumab ORATORIO eligibility (FDA label); schema-blocked

Symptomatic phenotype drives baclofen / oxybutynin / amantadine / Nuedexta

CSF OCB positive supports MS over alternative; required for McDonald 2017 (PMID 29275977)

MOG-IgG positive → MOGAD (Banwell 2023)

Hypogammaglobulinemia on ocrelizumab — infection risk

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

Severity triggers (8)

8 need judgement
  • informationallife_threateningnmosd_mimic_pivot
    NMOSD mimic — LETM > 3 cord segments OR bilateral optic neuritis → AQP4-IgG + MOG-IgG urgent; AVOID IFN/natalizumab (worsen NMOSD)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereclassic_ppms_men_40s_onset
    Classic PPMS — middle-age male with insidious progressive paraparesis from onset ≥1 y without relapse (Lublin 2014 PMID 24871874)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereactive_ppms_lesion_or_relapse
    Active PPMS — gad+ lesion OR new T2 in past 12 mo OR rare relapse → ocrelizumab ORATORIO-eligible (PMID 28002688)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereedss_4_to_6_5_ocrelizumab_eligible
    EDSS 4-6.5 + age ≤55 + active disease → ocrelizumab eligible per ORATORIO inclusion criteria (PMID 28002688)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverecervical_cord_dominant
    Cervical cord-dominant progressive syndrome — atrophy + lesion + minimal brain involvement; spastic quadriparesis / paresis predominant
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereprogressive_paraparesis_dominant
    Progressive paraparesis dominant — gait + bowel/bladder + sexual dysfunction; rule out vascular myelopathy / B12 deficiency / hereditary spastic paraparesis / NMOSD
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderatenon_active_ppms
    Non-active PPMS — no gad+ or new T2 in past 12 mo → DMT not indicated per FDA label; symptomatic + rehab dominant
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderatecognitive_dominant
    Cognitive-dominant PPMS — frontal/subcortical pattern with progressive cognitive decline + minimal motor — neuropsych battery + cognitive rehab
    Trigger could not be auto-evaluated — needs clinician judgement.

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Recommended regimen

PPMS DMT — ocrelizumab ORATORIO first-line for active PPMS (PMID 28002688)
axis: ppms_dmtstep 1 - Step 1 — Active PPMS — ocrelizumab ORATORIO
Selected step "Step 1 — Active PPMS — ocrelizumab ORATORIO" — Active PPMS (gad+ lesion OR new T2 in past 12 mo) + age ≤55 + EDSS ≤6.5 + no anti-CD20 contraindication
  • ocrelizumab
    first line
    anti_CD20_mAb
    300 mg IV × 2 (2 weeks apart) then 600 mg IV q6 months • IV • q6 months
    triggers: active_PPMS_age_le_55_EDSS_le_6.5
    ORATORIO (Montalban NEJM 2017 PMID 28002688 NEEDS_SOURCE_REVIEW) — first and only FDA-approved DMT for PPMS; 24% RR reduction 12-wk CDP; ARR + MRI improvement; hypogammaglobulinemia surveillance
    rxcui 1876366
  • rituximab (off-label)
    second line
    anti_CD20_mAb
    1000 mg IV × 2 (2 weeks apart) then q6 months • IV • q6 months
    triggers: active_PPMS_inflammatory_younger, ocrelizumab_access_unavailable
    PROMISE (Hawker Ann Neurol 2009 PMID 19847908 NEEDS_SOURCE_REVIEW) — negative overall but signal in younger inflammatory subgroup; off-label in MS
    rxcui 121191

outpatient playbook — drug actions (11)

  1. 1. ocrelizumab (active PPMS)
    300 mg IV × 2 then 600 mg IV q6 mo • IV infusion • q6 mo
    trigger: Active PPMS age ≤55 EDSS ≤6.5
    ORATORIO PMID 28002688
  2. 2. rituximab (off-label)
    1000 mg IV × 2 then q6 mo • IV • q6 mo
    trigger: Ocrelizumab access unavailable / inflammatory younger
    PROMISE signal subgroup
  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 BID-TID • PO • BID-TID
    trigger: Bladder
    AUA 2024
  6. 6. mirabegron
    50 mg daily • PO • daily
    trigger: Anticholinergic-intolerant
    AUA 2024
  7. 7. amantadine
    100 mg BID • PO • BID
    trigger: Fatigue
    AAN 2024
  8. 8. modafinil
    100-200 mg morning • PO • morning
    trigger: Amantadine-intolerant
    AAN 2024
  9. 9. sertraline
    50-100 mg daily • PO • daily
    trigger: Depression
    APA 2024
  10. 10. Nuedexta
    20/10 mg BID • PO • BID
    trigger: PBA
    TRANSIT
  11. 11. dalfampridine
    10 mg BID • PO • BID
    trigger: Gait impairment
    FDA-approved

Auto-drafted A&P note

outpatient

Subjective

- Possible entry pathways: Progressive paraparesis or cord syndrome from onset ≥1 y without relapse (Lublin 2014 PMID 24871874 NEEDS_SOURCE_REVIEW); Cervical cord-dominant progressive syndrome — MRI shows cord atrophy + cord lesions, minimal brain; Cognitive-dominant PPMS — frontal/subcortical pattern without relapse.

Objective

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

Assessment

**Primary Progressive Multiple Sclerosis** (neuro.ms-ppms.v1).
Phenotype framing: PPMS vs NMOSD vs MOGAD vs HTLV-1 TSP vs B12/copper deficiency vs hereditary spastic paraparesis vs ALS vs cervical spondylotic myelopathy vs vascular myelopathy (AAN 2024)
Scope: Confirm PPMS — ≥1 y progressive disability from onset + no prior relapse; rule out mimics; active vs non-active classification per Lublin 2014 (PMID 24871874)

No severity triggers fired against current inputs.

Plan

Regimen axis: **PPMS DMT — ocrelizumab ORATORIO first-line for active PPMS (PMID 28002688)** — step "Step 1 — Active PPMS — ocrelizumab ORATORIO".
1. ocrelizumab 300 mg IV × 2 (2 weeks apart) then 600 mg IV q6 months IV q6 months (anti_CD20_mAb, first line) — ORATORIO (Montalban NEJM 2017 PMID 28002688 NEEDS_SOURCE_REVIEW) — first and only FDA-approved DMT for PPMS; 24% RR reduction 12-wk CDP; ARR + MRI improvement; hypogammaglobulinemia surveillance
2. rituximab (off-label) 1000 mg IV × 2 (2 weeks apart) then q6 months IV q6 months (anti_CD20_mAb, second line) — PROMISE (Hawker Ann Neurol 2009 PMID 19847908 NEEDS_SOURCE_REVIEW) — negative overall but signal in younger inflammatory subgroup; off-label in MS

Setting playbook (outpatient) — MS clinic q3-6 mo — ocrelizumab for active PPMS, symptomatic management, neurorehab coordination, depression + cognition screening, advance directives at EDSS ≥7 (AAN 2024)
3. ocrelizumab (active PPMS) 300 mg IV × 2 then 600 mg IV q6 mo IV infusion q6 mo — Active PPMS age ≤55 EDSS ≤6.5 (ORATORIO PMID 28002688)
4. rituximab (off-label) 1000 mg IV × 2 then q6 mo IV q6 mo — Ocrelizumab access unavailable / inflammatory younger (PROMISE signal subgroup)
5. baclofen 10-20 mg PO TID PO TID — Spasticity (AAN 2024)
6. tizanidine 2-8 mg PO TID PO TID — Spasticity baclofen-intolerant (AAN 2024)
7. oxybutynin 5 mg BID-TID PO BID-TID — Bladder (AUA 2024)
8. mirabegron 50 mg daily PO daily — Anticholinergic-intolerant (AUA 2024)
9. amantadine 100 mg BID PO BID — Fatigue (AAN 2024)
10. modafinil 100-200 mg morning PO morning — Amantadine-intolerant (AAN 2024)
11. sertraline 50-100 mg daily PO daily — Depression (APA 2024)
12. Nuedexta 20/10 mg BID PO BID — PBA (TRANSIT)
13. dalfampridine 10 mg BID PO BID — Gait impairment (FDA-approved)

Non-pharmacologic actions:
- PT/OT bid-weekly
- Cognitive rehab if SDMT decline
- Spasticity clinic (BTX, intrathecal pump consideration)
- Urology + urodynamics
- Pelvic floor PT
- SLP for dysphagia
- Vocational rehab
- Wheelchair/scooter fitting
- Caregiver support + respite
- Advance directives at EDSS ≥7
- Palliative referral at severe disability

AVOID / contraindication checks:
- Ocrelizumab_age_gt_55_FDA_label_limit (FDA label)
- Ocrelizumab_EDSS_gt_6.5_FDA_label_limit (FDA label)
- Ocrelizumab_no_active_disease_FDA_label_not_indicated (FDA label)
- HBV_screen_before_ocrelizumab_reactivation (AAN 2024)
- VZV_screen_and_vaccinate_before_ocrelizumab (AAN 2024)
- TB_quantiferon_before_ocrelizumab (AAN 2024)
- Hypogammaglobulinemia_surveillance_ocrelizumab (AAN 2024)
- Infusion_reaction_pre_medicate_methylprednisolone_antihistamine_acetaminophen (FDA label)
- Vaccinations_4_to_6_wk_before_ocrelizumab (AAN 2024)
- Cyclophosphamide_bladder_bone_marrow_infertility_secondary_malignancy (AAN 2024)
- Rituximab_off_label_in_MS_no_FDA_approval (AAN 2024)

Monitoring

Regimen monitoring:
- CBC lymphocyte count q3 to 6 mo (AAN 2024)
- LFT q3 to 6 mo (AAN 2024)
- IgG annually on ocrelizumab (AAN 2024)
- annual brain MRI with gad (AAN 2024)
- annual cervical cord MRI (AAN 2024)
- EDSS at each visit (schema-blocked — see depth bundle)
- SDMT T25FW 9HPT annually MSFC (schema-blocked)
- infection surveillance (AAN 2024)

Setting (outpatient) monitoring:
- EDSS + MSFC q3-6 mo (schema-blocked)
- Annual MRI
- CBC + LFT q3-6 mo
- IgG annually
- PVR + UA q6 mo if catheterizing

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

Monitoring phase: CBC + LFT q3-6 mo; IgG annually; annual MRI brain + cord; 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 — ocrelizumab for active PPMS, 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 decline
- LTC at EDSS ≥7.5 with caregiver inability
- Hospice at severe + recurrent + goals-of-care aligned

Escalation triggers (move to higher acuity):
- Rare acute relapse → route to neuro.ms-flare.core.v1
- Continued progression on ocrelizumab → cyclophosphamide consideration
- Severe pressure injury → admit
- Aspiration / pulmonary decline → admit
- Refractory spasticity → intrathecal pump
- Refractory bladder → BTX + cath program
- Severe depression → ED + psych
- Infusion reaction → stop + emergency Rx

Earlier-Return Triggers

Return-precaution thresholds (watch for):
- [LIFE_THREATENING] NMOSD mimic — LETM > 3 cord segments OR bilateral optic neuritis → AQP4-IgG + MOG-IgG urgent; AVOID IFN/natalizumab (worsen NMOSD)
- [SEVERE] Classic PPMS — middle-age male with insidious progressive paraparesis from onset ≥1 y without relapse (Lublin 2014 PMID 24871874)
- [SEVERE] Active PPMS — gad+ lesion OR new T2 in past 12 mo OR rare relapse → ocrelizumab ORATORIO-eligible (PMID 28002688)

Citations

- AAN 2024 MS DMT guideline + ECTRIMS 2024 + ORATORIO ocrelizumab PPMS (Montalban NEJM 2017 PMID 28002688) [PMID:28002688](https://pubmed.ncbi.nlm.nih.gov/28002688/)
- Cited evidence (PMID 19847908) [PMID:19847908](https://pubmed.ncbi.nlm.nih.gov/19847908/)
- Cited evidence (PMID 24871874) [PMID:24871874](https://pubmed.ncbi.nlm.nih.gov/24871874/)
- Cited evidence (PMID 29275977) [PMID:29275977](https://pubmed.ncbi.nlm.nih.gov/29275977/)
- Cited evidence (PMID 26092914) [PMID:26092914](https://pubmed.ncbi.nlm.nih.gov/26092914/)

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