ICD-10: G73.1 (Lambert-Eaton syndrome), C34.90 (Malignant neoplasm of unspecified part of unspecified bronchus or lung - for paraneoplastic LEMS), G70.80 (Other specified myoneural disorders)
SCOPE: Diagnosis and management of Lambert-Eaton myasthenic syndrome in adults, including both paraneoplastic (P-LEMS, ~60% associated with small cell lung cancer) and autoimmune (A-LEMS) subtypes. Covers VGCC antibody testing, DELTA-P score calculation for paraneoplastic risk stratification, electrodiagnostic evaluation (repetitive nerve stimulation), cancer screening protocols, symptomatic treatment with 3,4-diaminopyridine, immunotherapy, and long-term monitoring. Excludes myasthenia gravis (separate template), botulism, and congenital myasthenic syndromes.
DEFINITIONS:
- P-LEMS: Paraneoplastic LEMS, associated with underlying malignancy (~60% SCLC)
- A-LEMS: Autoimmune LEMS, no associated malignancy (non-paraneoplastic)
- VGCC: Voltage-gated calcium channel (P/Q-type antibodies are diagnostic)
- DELTA-P Score: Dutch-English LEMS Tumor Association Prediction score for paraneoplastic risk
- Lambert sign: Hyporeflexia that improves or normalizes after brief maximal voluntary contraction (post-exercise facilitation)
- CMAP facilitation: >100% increment in compound muscle action potential amplitude after high-frequency (50 Hz) repetitive nerve stimulation or after 10-second maximal voluntary contraction
If initial CT chest negative and clinical suspicion high (DELTA-P >=2)
No occult malignancy
Annual screening required for at least 2 years
PET/CT (repeat if initial negative)
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ROUTINE
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Every 6 months for 2 years if DELTA-P >=3 and initial PET negative
No FDG-avid lesion
SCLC may be delayed in presentation; continuous vigilance
CT chest (low-dose screening)
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ROUTINE
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Every 6 months for 2 years from diagnosis; then annually for 2 more years (total 4 years screening)
No new lung nodules or mass
Per EFNS/PNS guidelines; P-LEMS risk persists for years
MRI brain with contrast (CPT 70553)
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ROUTINE
ROUTINE
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If neurological symptoms suggest brain metastases or paraneoplastic cerebellar degeneration
No metastases; no cerebellar atrophy
Gadolinium allergy, GFR <30, pacemaker
Bronchoscopy with biopsy
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ROUTINE
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If CT/PET shows suspicious pulmonary lesion
Tissue diagnosis; SCLC vs NSCLC
Coagulopathy; severe respiratory compromise
Mammography (females)
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ROUTINE
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As part of comprehensive malignancy screen
No malignancy
Per age-appropriate screening guidelines
Colonoscopy (age-appropriate)
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ROUTINE
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If no lung cancer found; screen for other malignancies
No malignancy
Bowel prep; coagulopathy
Note: Cancer screening protocol based on Titulaer et al. recommendations. If initial comprehensive screening is negative, repeat CT chest every 6 months for 2 years. If DELTA-P score >=3, repeat PET/CT at 3-6 months. ~3-5% of patients initially classified as A-LEMS are later diagnosed with cancer, usually within 2 years.
Acute LEMS exacerbation with significant functional impairment; rapid symptom control; pre-treatment or perioperative optimization
0.4 g/kg :: IV :: daily x 5 days :: 0.4 g/kg/day IV x 5 days (total 2 g/kg) OR 1 g/kg/day x 2 days; infuse over 4-6 hours; slow initial rate per protocol
IgA deficiency (check IgA level first); recent thrombotic event; renal failure (use sucrose-free formulation)
Pre-infusion: IgA level, renal function, CBC; during: vital signs q15 min first hour then q1h; headache; aseptic meningitis; thrombosis risk; renal function post-infusion
STAT
STAT
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STAT
Plasma exchange (PLEX) (CPT 36514)
IV
Acute LEMS exacerbation; alternative to IVIg; LEMS crisis with respiratory compromise; pre-thymectomy optimization if concurrent thymoma
1-1.5 plasma volumes :: IV :: every other day x 5-7 exchanges :: 5-7 exchanges over 10-14 days; exchange 1-1.5 plasma volumes per session every other day; albumin replacement preferred
Hemodynamic instability; sepsis; central line contraindication; heparin allergy
BP during exchange; electrolytes (Ca, K, Mg); coagulation studies; fibrinogen; line site infection; hypotension
STAT
STAT
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STAT
Normal saline IV
IV
Volume resuscitation for orthostatic hypotension from autonomic dysfunction
500-1000 mL :: IV :: bolus then maintenance :: 500-1000 mL NS bolus then 75-125 mL/hr maintenance as needed for orthostatic symptoms
First-line symptomatic treatment for LEMS; enhances presynaptic acetylcholine release by blocking potassium channels; improves strength and autonomic symptoms
5 mg :: PO :: TID :: Start 5 mg TID; increase by 5 mg per dose every 3-5 days; usual effective dose 15-20 mg TID-QID; max 80 mg/day (max 20 mg per single dose); take with food
Seizure history (lowers seizure threshold); concurrent use of drugs that lower seizure threshold; QT prolongation
ECG at baseline and after dose changes; seizure precautions; QTc monitoring; paresthesias (perioral, digital); GI upset
URGENT
URGENT
ROUTINE
URGENT
3,4-Diaminopyridine phosphate (Ruzurgi)
PO
Alternative formulation of amifampridine for LEMS; enhances presynaptic acetylcholine release by blocking potassium channels; improves strength and autonomic symptoms
5 mg :: PO :: TID :: Start 5 mg TID; increase by 5 mg per dose every 3-5 days; usual effective dose 15-20 mg TID-QID; max 80 mg/day (max 20 mg per single dose); take with food
Seizure history (lowers seizure threshold); concurrent use of drugs that lower seizure threshold; QT prolongation
ECG at baseline and after dose changes; seizure precautions; QTc monitoring; paresthesias (perioral, digital); GI upset
URGENT
URGENT
ROUTINE
URGENT
Pyridostigmine (Mestinon)
PO
Adjunctive symptomatic treatment; enhances postsynaptic acetylcholine effect; less effective in LEMS than in MG but may provide modest additional benefit when combined with 3,4-DAP
30 mg :: PO :: TID :: Start 30 mg TID; increase by 30 mg per dose every 2-3 days; usual effective dose 60 mg q4-6h; max 120 mg per dose; less effective as monotherapy in LEMS than MG
Mechanical GI/GU obstruction; uncontrolled asthma
Cholinergic side effects: diarrhea, cramping, salivation, bradycardia
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ROUTINE
ROUTINE
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Guanfacine
PO
Refractory dry mouth from autonomic dysfunction not responsive to 3,4-DAP; off-label use
1 mg :: PO :: daily :: Start 1 mg daily; may increase to 2 mg daily; used off-label for autonomic dry mouth
Hypotension; bradycardia; renal impairment
BP; HR; sedation
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ROUTINE
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Midodrine
PO
Orthostatic hypotension from autonomic dysfunction in LEMS
2.5 mg :: PO :: TID :: Start 2.5 mg TID; titrate by 2.5 mg per dose every 1-2 weeks; max 10 mg TID; avoid dosing within 4 hours of bedtime
Supine hypertension; urinary retention; severe organic heart disease; pheochromocytoma
Supine BP (check 1 hour after first dose); avoid supine position for 4h after dosing
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ROUTINE
ROUTINE
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Fludrocortisone
PO
Orthostatic hypotension refractory to midodrine; volume expansion
0.1 mg :: PO :: daily :: Start 0.1 mg daily; may increase to 0.2 mg daily; max 0.3 mg daily
Autoimmune LEMS (A-LEMS) with inadequate response to 3,4-DAP alone; bridge to steroid-sparing agent; NOT first-line for P-LEMS (treat cancer first)
10-20 mg :: PO :: daily :: Start 10-20 mg daily; increase by 10 mg every 5-7 days to 0.5-1 mg/kg/day; maintain 4-8 weeks then taper by 5-10 mg/month to lowest effective dose
Active untreated infection; uncontrolled diabetes; psychosis history
Glucose; BP; mood/sleep; weight; bone density; GI prophylaxis
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ROUTINE
ROUTINE
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IVIg (maintenance)
IV
Chronic immunomodulation for LEMS with ongoing functional impairment despite 3,4-DAP and oral immunotherapy
1 g/kg :: IV :: every 4 weeks :: 1 g/kg IV every 4 weeks (may adjust to 0.4-1 g/kg based on response); infuse over 4-6 hours
IgA deficiency; recent thrombotic event; renal failure
Renal function; IgA level; vital signs during infusion; headache; thrombosis risk
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ROUTINE
ROUTINE
ROUTINE
Plasma exchange (maintenance)
IV
Chronic LEMS refractory to IVIg and oral immunotherapy
1 plasma volume :: IV :: every 2-4 weeks :: Single volume exchange every 2-4 weeks; adjust frequency based on clinical response and antibody levels; albumin replacement
Steroid-sparing agent for A-LEMS; long-term immunosuppression to reduce VGCC antibody production; onset 6-18 months
50 mg :: PO :: daily :: Start 50 mg daily; increase by 50 mg every 1-2 weeks to target 2-3 mg/kg/day (typically 150-250 mg/day); onset 6-18 months
TPMT genotype/activity BEFORE starting (mandatory); CBC; LFTs; hepatitis B/C screen; TB test
TPMT deficiency (homozygous); concurrent allopurinol (reduce dose by 75%); pregnancy (relative); active infection
TPMT genotype before starting; CBC q1-2 weeks during titration then monthly; LFTs monthly; amylase/lipase if abdominal pain; lymphocyte count target 600-1000
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ROUTINE
ROUTINE
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Mycophenolate mofetil (CellCept)
PO
Steroid-sparing agent for A-LEMS; alternative to azathioprine; onset 6-12 months
500 mg :: PO :: BID :: Start 500 mg BID; increase to 1000 mg BID after 2 weeks; target 2000-3000 mg/day; onset 6-12 months
CBC; LFTs; hepatitis B/C screen; pregnancy test (females); TB test
Pregnancy (Category D - teratogenic); concurrent azathioprine; active infection
CBC q2 weeks x 3 months then monthly; LFTs; GI side effects (diarrhea, nausea); lymphopenia; REMS pregnancy prevention
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ROUTINE
ROUTINE
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Rituximab (Rituxan)
IV
Refractory A-LEMS not responding to conventional immunosuppressants; may be used earlier in severe cases; less evidence than in MG but reported efficacy
375 mg/m2 :: IV :: weekly x 4 weeks :: 375 mg/m2 IV weekly x 4 weeks; OR 1000 mg IV x 2 doses 14 days apart; re-dose when CD19/CD20 recover or clinical worsening; onset 3-6 months
HBV serology (HBsAg, anti-HBc, anti-HBs); hepatitis C screen; HIV test; CBC; immunoglobulins; TB test; vaccinations up to date
Active hepatitis B; active infection; severe immunodeficiency; PML history
Trough levels; renal function q2 weeks then monthly; BP; electrolytes (K, Mg); lipids; gingival hyperplasia; hirsutism
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ROUTINE
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Cyclophosphamide
IV
Severe refractory LEMS not responding to other immunosuppressants; reserved for life-threatening or disabling disease
500-1000 mg/m2 :: IV :: monthly x 6 months :: Pulse IV 500-1000 mg/m2 monthly x 6 months; OR oral 1-2 mg/kg/day; reserved for refractory cases; MESNA uroprotection with IV dosing
Standard first-line for SCLC in P-LEMS; treatment of underlying malignancy is the primary therapy for paraneoplastic LEMS; neurological symptoms often improve with cancer treatment
Per oncology protocol :: IV :: per oncology :: Cisplatin 60-80 mg/m2 day 1 + etoposide 100-120 mg/m2 days 1-3 q21d x 4-6 cycles; defer to oncology for specific regimen
Oncology staging; LEMS diagnosis confirmation; LEMS-specific caution: avoid neuromuscular blocking agents if surgery needed
Per oncology assessment
Neuromuscular function during treatment; FVC if respiratory symptoms; electrolytes; renal function; myelosuppression
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ROUTINE
ROUTINE
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Radiation therapy (SCLC)
EXT
Limited-stage SCLC with or without concurrent chemotherapy; palliative radiation for extensive-stage
Per radiation oncology protocol :: EXT :: per oncology :: Concurrent chemoradiation for limited stage; palliative for extensive stage; prophylactic cranial irradiation per oncology
SCLC maintenance (atezolizumab, durvalumab); CRITICAL WARNING: may worsen LEMS or trigger myasthenic crisis; only under joint neuro-oncology management
Per oncology protocol :: IV :: per oncology :: Per oncology; MUST be administered with close neuromuscular monitoring; have IVIg/PLEX available
Baseline FVC; neuromuscular assessment; joint neuro-oncology plan
Pre-existing myasthenic crisis; uncontrolled LEMS; use only with neuromuscular specialist co-management
FVC before each cycle; MG-ADL equivalent assessment; creatine kinase; troponin (myocarditis); monitor for rapid neurological deterioration
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EXT
EXT
EXT
Note: Treatment of underlying malignancy is the most important therapy in P-LEMS. LEMS symptoms often improve significantly with successful cancer treatment. Immunosuppressive therapy (azathioprine, mycophenolate, rituximab) should be used cautiously in P-LEMS as it may impair anti-tumor immunity. Immune checkpoint inhibitors may paradoxically worsen paraneoplastic neurological syndromes.
Return to ED immediately if difficulty breathing, worsening weakness preventing walking, or inability to swallow (may indicate LEMS crisis or cancer progression)
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Return to ED if new severe weakness, falls, or inability to rise from chair (proximal weakness progression)
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Take 3,4-diaminopyridine (amifampridine) exactly as prescribed; do NOT exceed 20 mg per single dose or 80 mg/day (seizure risk)
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Take 3,4-diaminopyridine with food to reduce GI side effects (nausea, abdominal discomfort)
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Report any seizures, tingling around the mouth, or numbness in fingers immediately (may indicate 3,4-DAP toxicity)
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Carry LEMS medical alert identification at all times (anesthesia and medication precautions critical)
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Provide LEMS medication list to ALL healthcare providers (emergency, dental, surgical) - many medications worsen neuromuscular junction disorders
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Attend ALL scheduled cancer screening appointments even if feeling well (cancer may develop years after LEMS diagnosis)
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Report any new cough, weight loss, fatigue, chest pain, or hemoptysis immediately (may indicate lung cancer)
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Rise slowly from sitting or lying position to avoid falls from orthostatic hypotension (stand at bed/chair edge for 30 seconds before walking)
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Increase fluid and salt intake to help manage orthostatic hypotension from autonomic dysfunction (unless restricted by other conditions)
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Plan activities for times of best strength; use energy conservation techniques; rest between tasks
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Do NOT stop immunosuppressant medications abruptly without physician guidance (disease flare risk)
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Avoid extreme heat, hot baths, and saunas (may worsen weakness)
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Report excessive dry mouth, constipation, or urinary symptoms to neurologist (autonomic dysfunction may require treatment adjustment)
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Avoid alcohol (potentiates weakness and interacts with medications)
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Understand that LEMS symptoms may improve if underlying cancer is successfully treated (for P-LEMS patients)
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Stop smoking immediately if current smoker (reduces cancer risk and may slow disease progression)
Smoking cessation mandatory given strong association between LEMS, SCLC, and tobacco use (reduces ongoing cancer risk)
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Low-impact exercise (swimming, stationary bike, yoga) to maintain strength and mobility without overexertion given proximal weakness
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Energy conservation with scheduled rest periods to manage fatigue and optimize function throughout the day
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Home safety evaluation to remove fall hazards given proximal leg weakness and orthostatic hypotension (secure rugs, install grab bars, adequate lighting)
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Compression stockings (waist-high, 30-40 mmHg) for orthostatic hypotension management from autonomic dysfunction
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Elevate head of bed 10-20 degrees to reduce nocturnal supine hypertension while managing orthostatic hypotension
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Increase dietary fluid intake to 2-3 L/day and liberal salt intake (unless contraindicated) for orthostatic hypotension
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High-fiber diet with adequate hydration for constipation management from autonomic dysfunction
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Regular dental care and oral hygiene given xerostomia (dry mouth) from autonomic dysfunction (increased caries risk)
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Vitamin D supplementation if deficient (1000-2000 IU daily) to support immune function and bone health, especially if on chronic steroids
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Calcium supplementation (1000-1200 mg daily) if on chronic corticosteroids for bone protection
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Annual influenza vaccination (inactivated form) and COVID-19 vaccination as recommended; avoid live vaccines if on immunosuppression
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Aspiration precautions including thickened liquids and chin tuck positioning if dysphagia present from bulbar involvement
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4D. Medications to Avoid or Use with Caution in LEMS¶
Medication/Class
Risk Level
Details
Safe Alternative (if applicable)
NEUROMUSCULAR BLOCKING AGENTS
Succinylcholine
HIGH
Unpredictable response in LEMS; may have prolonged block
Non-depolarizing agents at markedly reduced dose with sugammadex available
May worsen paraneoplastic neurological syndromes; can trigger myasthenic crisis; use only with joint neuro-oncology management
If required for cancer treatment, close neuromuscular monitoring mandatory
OTHER
Botulinum toxin
HIGH
Blocks presynaptic ACh release; CONTRAINDICATED in LEMS
Physical therapy; oral medications for spasticity
Quinine/tonic water
MODERATE
NMJ blocking effect
Avoid quinine-containing beverages
Note: LEMS patients are exquisitely sensitive to neuromuscular blocking agents due to presynaptic defect. ALL anesthesia providers must be informed of LEMS diagnosis before any surgical procedure. Calcium channel blockers (especially verapamil and diltiazem) are particularly dangerous in LEMS as they directly worsen the underlying pathophysiology.
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SECTION B: REFERENCE (Expand as Needed)
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Fatigable weakness that WORSENS with exertion (opposite of LEMS); ptosis and diplopia prominent (rare in LEMS); normal or brisk reflexes; no autonomic dysfunction; no cancer association (except thymoma)
AChR/MuSK antibodies positive; RNS shows decrement at low-rate WITHOUT significant increment at high-rate; CMAP amplitudes normal at rest
Botulism
Acute onset descending paralysis; dilated/fixed pupils; recent ingestion of contaminated food or wound; autonomic dysfunction present; NO prior NMJ disease
Stool/serum botulinum toxin assay; EMG shows BSAP pattern with incremental response similar to LEMS but acute onset
Polymyositis/Dermatomyositis
Proximal weakness without fatigability; elevated CK (often >1000); skin findings in DM (heliotrope rash, Gottron papules); no autonomic dysfunction; no NMJ abnormalities on RNS
Progressive weakness with fasciculations; UMN signs (hyperreflexia, Babinski); no autonomic dysfunction; no fatigability pattern; EMG shows active denervation
EMG/NCS: active denervation, fasciculations, normal NMJ studies; no VGCC antibodies
Mild symptoms; stable on 3,4-DAP; adequate oral intake; no respiratory compromise (FVC >60% predicted); cancer screening plan in place; reliable follow-up within 1-2 weeks; understands return precautions
Admit to floor (general neurology)
New diagnosis requiring expedited workup; moderate proximal weakness limiting ambulation; initiating IVIg or immunotherapy; significant autonomic dysfunction requiring stabilization; new cancer diagnosis requiring coordination
Admit to step-down/telemetry
Declining FVC or NIF trending toward danger zone; moderate-severe orthostatic hypotension with syncope; starting PLEX; cardiac arrhythmias from autonomic dysfunction
Admit to ICU
FVC <30% predicted or <1 L; NIF weaker than -25 cm H2O; progressive respiratory failure; severe autonomic instability (symptomatic bradycardia, sustained hypotension); concurrent SCLC with acute complications; myasthenic crisis-like presentation
Transfer to higher level
Neuromuscular specialist not available; PLEX needed but unavailable; ICU capability needed; oncology expertise needed for SCLC management
Discharge from hospital
FVC stable and improving; adequate oral intake; stable on oral medications; cancer screening/treatment plan in place; outpatient follow-up scheduled within 1-2 weeks; patient and family educated on LEMS management and cancer screening importance
v1.1 (January 30, 2026)
- Standardized all treatment table dosing to structured 4-field format: [dose] :: [route] :: [frequency] :: [full_instructions]
- Fixed PLEX route from "-" to "IV" in sections 3A and 3C (enables order sentence generation)
- Eliminated cross-references in Ruzurgi row ("Same as Firdapse") -- each row now self-contained with full contraindications, monitoring, and indication
- Merged Section 3E (Cancer-Directed Treatment) into Section 3D with Pre-Treatment Requirements column for consistency with standard 3A-3D structure
- Cleaned medication names in Treatment column (removed parenthetical descriptors from column, moved to Indication)
- Fixed dose-tier listings (e.g., "5 mg TID; 10 mg TID; 15 mg TID") to single starting dose in structured format with titration in full_instructions field
v1.0 (January 30, 2026)
- Initial creation
- Section 1: 43 laboratory tests across 3 tiers (16 core, 19 extended, 8 rare/specialized)
- P/Q-type VGCC antibody, SOX1 antibody, N-type VGCC as core diagnostics
- Comprehensive paraneoplastic antibody panel (ANNA-1, CRMP-5, amphiphysin, Zic4)
- Tumor markers (NSE, ProGRP, CEA, PSA) for malignancy screening
- Section 2: Imaging and studies across 4 tiers plus bedside tests
- 2A: CT chest, CXR, PET/CT, ECG as essential
- 2B: RNS (low-rate and high-rate), post-exercise facilitation, baseline CMAP, EMG/NCS, SFEMG, autonomic testing
- 2C: Cancer screening protocol (serial CT, PET/CT, bronchoscopy, mammography, colonoscopy)
- 2D: Bedside tests (Lambert sign, proximal strength, grip, FVC, NIF, orthostatic vitals, pupillary exam, dry mouth)
- Section 3: Treatment across 4 subsections
- 3A: Acute/emergent (IVIg, PLEX, IV fluids)
- 3B: Symptomatic (3,4-DAP/amifampridine, pyridostigmine, midodrine, fludrocortisone, GI treatments, artificial tears/saliva, sildenafil)
- 3C: Second-line (prednisone, maintenance IVIg, maintenance PLEX)
- 3D: Disease-modifying/immunosuppressive + cancer-directed (azathioprine, mycophenolate, rituximab, cyclosporine, cyclophosphamide, chemotherapy, radiation, checkpoint inhibitors) with Pre-Treatment Requirements
- Section 4: Recommendations across 4 subsections
- 4A: 17 referrals including oncology, smoking cessation, palliative care
- 4B: 18 patient instructions with cancer screening emphasis
- 4C: 13 lifestyle modifications including orthostatic management
- 4D: Medications to avoid table organized by drug class with LEMS-specific risks
- Section 5: 14 differential diagnoses including MG, botulism, inflammatory myopathies, CIDP, ALS
- Section 6: Monitoring parameters
- 6A: 12 acute monitoring parameters
- 6B: 17 chronic monitoring parameters including cancer screening schedule
- Section 7: Disposition criteria (6 levels)
- Section 8: 28 evidence citations
- DELTA-P score reference table included
- LEMS-specific medication avoidance table (calcium channel blockers highlighted as particularly dangerous)