Paraneoplastic Neurological Syndrome¶
VERSION: 1.1 CREATED: January 30, 2026 REVISED: January 30, 2026 STATUS: Draft - Pending Review
DIAGNOSIS: Paraneoplastic Neurological Syndrome
ICD-10: G13.0 (Paraneoplastic neuromyopathy and neuropathy), G13.1 (Other systemic atrophy primarily affecting CNS in neoplastic disease)
SYNONYMS: Paraneoplastic neurological syndrome, PNS, paraneoplastic syndrome, paraneoplastic encephalomyelitis, paraneoplastic cerebellar degeneration, PCD, paraneoplastic sensory neuropathy, paraneoplastic opsoclonus-myoclonus, anti-Hu syndrome, anti-Yo syndrome, anti-Ri syndrome, anti-CV2 syndrome, anti-amphiphysin syndrome, paraneoplastic limbic encephalitis, subacute cerebellar degeneration, subacute sensory neuronopathy, remote effect of cancer on nervous system
SCOPE: Diagnosis, cancer screening, immunotherapy, and symptom management of paraneoplastic neurological syndromes. Includes antibody panels (intracellular and cell-surface), malignancy workup (CT, PET-CT, organ-specific imaging), first-line immunotherapy (IV methylprednisolone, IVIG, PLEX), second-line immunosuppression (rituximab, cyclophosphamide), tumor-directed therapy coordination, and long-term monitoring. Covers key clinical phenotypes: limbic encephalitis, cerebellar degeneration, sensory neuropathy, opsoclonus-myoclonus, encephalomyelitis, and neuromuscular junction disorders. For autoimmune encephalitis with predominantly cell-surface antibodies (anti-NMDAR, LGI1, CASPR2), use "Autoimmune Encephalitis" template. For myasthenia gravis, use "Myasthenia Gravis" template. For Lambert-Eaton myasthenic syndrome, use dedicated LEMS template when available.
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 | ED | HOSP | OPD | ICU | Rationale | Target Finding |
|---|---|---|---|---|---|---|
| CBC with differential (CPT 85025) | STAT | STAT | ROUTINE | STAT | Baseline; infection screen; cytopenias from occult malignancy | Normal |
| CMP (BMP + LFTs) (CPT 80053) | STAT | STAT | ROUTINE | STAT | Metabolic screen; hepatic/renal function for immunotherapy; electrolyte abnormalities (hyponatremia in SIADH) | Normal |
| ESR (CPT 85652) | URGENT | ROUTINE | ROUTINE | URGENT | Inflammatory marker; elevated in malignancy and autoimmune conditions | Normal (<20 mm/hr) |
| CRP (CPT 86140) | URGENT | ROUTINE | ROUTINE | URGENT | Infection screen; systemic inflammation | Normal |
| TSH (CPT 84443) | URGENT | ROUTINE | ROUTINE | URGENT | Thyroid dysfunction as alternative etiology for encephalopathy or neuropathy | Normal |
| Blood glucose (CPT 82947) | STAT | STAT | ROUTINE | STAT | Metabolic encephalopathy screen; pre-steroid baseline | Normal |
| HbA1c (CPT 83036) | - | ROUTINE | ROUTINE | - | Glycemic status before high-dose steroids; diabetic neuropathy differential | <5.7% |
| LDH (CPT 83615) | URGENT | ROUTINE | ROUTINE | URGENT | Tumor marker; hemolysis screen; elevated in many malignancies | Normal |
| Magnesium (CPT 83735) | STAT | STAT | ROUTINE | STAT | Seizure threshold; neuromuscular function | Normal |
| Phosphorus (CPT 84100) | STAT | STAT | ROUTINE | STAT | Metabolic screen; weakness differential | Normal |
| PT/INR, aPTT (CPT 85610+85730) | STAT | STAT | - | STAT | Coagulopathy screen pre-LP; DIC from malignancy | Normal |
| Urinalysis with culture (CPT 81003+87086) | STAT | STAT | ROUTINE | STAT | UTI as encephalopathy trigger; exclude infection before immunotherapy | Negative |
| Blood cultures (x2 sets) (CPT 87040) | STAT | STAT | - | STAT | Rule out septic encephalopathy before immunotherapy | No growth |
| Lactate (CPT 83605) | STAT | STAT | - | STAT | Sepsis screen; metabolic screen | Normal (<2.0 mmol/L) |
| Procalcitonin (CPT 84145) | URGENT | URGENT | - | URGENT | Distinguish bacterial infection from paraneoplastic inflammation | Normal (<0.1 ng/mL) |
| Ammonia (CPT 82140) | STAT | STAT | - | STAT | Hepatic encephalopathy mimic | Normal |
| Urine drug screen (CPT 80307) | STAT | STAT | - | STAT | Toxic encephalopathy mimic | Negative |
| Pregnancy test (females of childbearing age) (CPT 81025) | STAT | STAT | ROUTINE | STAT | Teratogenicity of immunosuppressants; imaging planning | As applicable |
| Troponin (CPT 84484) | STAT | STAT | - | STAT | Cardiac involvement; autonomic instability assessment | Normal |
| CPK (CPT 82550) | URGENT | URGENT | ROUTINE | URGENT | Myositis (dermatomyositis overlap); seizure-related rhabdomyolysis | Normal |
| Uric acid (CPT 84550) | - | ROUTINE | ROUTINE | - | Tumor lysis risk if malignancy identified | Normal |
1B. Paraneoplastic Antibody Panel¶
| Test | ED | HOSP | OPD | ICU | Rationale | Target Finding |
|---|---|---|---|---|---|---|
| Anti-Hu (ANNA-1) antibody (serum AND CSF) (CPT 86255) | URGENT | URGENT | ROUTINE | URGENT | Most common intracellular antibody; associated with SCLC (>90%); encephalomyelitis, sensory neuropathy, cerebellar degeneration, autonomic neuropathy | Negative |
| Anti-Yo (PCA-1) antibody (serum AND CSF) (CPT 86255) | URGENT | URGENT | ROUTINE | URGENT | Paraneoplastic cerebellar degeneration; associated with ovarian cancer, breast cancer | Negative |
| Anti-Ri (ANNA-2) antibody (serum AND CSF) (CPT 86255) | URGENT | URGENT | ROUTINE | URGENT | Opsoclonus-myoclonus; brainstem encephalitis; associated with breast cancer, SCLC | Negative |
| Anti-CV2/CRMP5 antibody (serum AND CSF) | URGENT | URGENT | ROUTINE | URGENT | Encephalomyelitis, cerebellar degeneration, chorea, neuropathy, optic neuritis; associated with SCLC, thymoma | Negative |
| Anti-amphiphysin antibody (serum AND CSF) | URGENT | URGENT | ROUTINE | URGENT | Stiff-person syndrome; encephalomyelitis; associated with breast cancer, SCLC | Negative |
| Anti-Ma2/Ta antibody (serum AND CSF) | URGENT | URGENT | ROUTINE | URGENT | Limbic/diencephalic encephalitis; hypothalamic dysfunction; associated with testicular germ cell tumor (young males), lung cancer (older patients) | Negative |
| Anti-SOX1 antibody (serum) | - | URGENT | ROUTINE | URGENT | Lambert-Eaton overlap; SCLC marker; cerebellar degeneration | Negative |
| Anti-KLHL11 antibody (serum AND CSF) | - | URGENT | ROUTINE | URGENT | Brainstem/cerebellar syndrome; associated with testicular seminoma | Negative |
| Anti-NMDAR antibody (serum AND CSF) (CPT 86255) | URGENT | URGENT | ROUTINE | URGENT | Cell-surface; paraneoplastic with ovarian teratoma (young females); limbic encephalitis | Negative |
| Anti-LGI1 antibody (serum AND CSF) (CPT 86235) | URGENT | URGENT | ROUTINE | URGENT | Cell-surface; limbic encephalitis; faciobrachial dystonic seizures; associated with thymoma (~5-10%) | Negative |
| Anti-CASPR2 antibody (serum AND CSF) (CPT 86235) | URGENT | URGENT | ROUTINE | URGENT | Cell-surface; limbic encephalitis; Morvan syndrome; neuromyotonia; associated with thymoma (~20-30%) | Negative |
| Anti-GABA-B antibody (serum AND CSF) | URGENT | URGENT | ROUTINE | URGENT | Cell-surface; limbic encephalitis with seizures; 50% associated with SCLC | Negative |
| Anti-AMPAR antibody (serum AND CSF) | URGENT | URGENT | ROUTINE | URGENT | Cell-surface; limbic encephalitis; associated with thymoma, lung, breast cancer | Negative |
| Anti-GAD65 antibody (serum AND CSF) | URGENT | URGENT | ROUTINE | URGENT | High titers (>20 nmol/L): stiff-person, limbic encephalitis, cerebellar ataxia; low titers non-specific | Negative or low titer |
| Anti-VGCC antibody (P/Q-type and N-type) (serum) | URGENT | URGENT | ROUTINE | URGENT | Lambert-Eaton myasthenic syndrome (P/Q-type); cerebellar degeneration; ~60% LEMS cases associated with SCLC | Negative |
| Mayo Paraneoplastic Evaluation (serum) | URGENT | URGENT | ROUTINE | URGENT | Comprehensive panel: ANNA-1, ANNA-2, PCA-1, PCA-2, PCA-Tr, amphiphysin, CV2, GAD65, VGCC | All negative |
| Mayo Paraneoplastic Evaluation (CSF) | URGENT | URGENT | ROUTINE | URGENT | CSF panel: ANNA-1, ANNA-2, PCA-1, amphiphysin, CV2, GAD65 | All negative |
| ANA (CPT 86235) | URGENT | ROUTINE | ROUTINE | URGENT | Connective tissue disease with neurological involvement | Negative or low titer |
| Quantitative immunoglobulins (IgG, IgA, IgM) | - | ROUTINE | ROUTINE | - | Baseline before immunotherapy; IgA deficiency (IVIG contraindication) | Normal |
| Serum protein electrophoresis (SPEP) with immunofixation (CPT 86334) | - | ROUTINE | ROUTINE | - | Paraproteinemia-associated neuropathy; myeloma | Normal |
Note: ALWAYS send BOTH serum AND CSF for antibody testing. Intracellular antibodies (anti-Hu, anti-Yo, anti-Ri, anti-CV2, anti-amphiphysin) generally indicate T-cell mediated neuronal destruction with poor neurological prognosis even with treatment. Cell-surface antibodies (anti-NMDAR, anti-LGI1, anti-CASPR2, anti-AMPAR, anti-GABA-B) are antibody-mediated and more treatment-responsive. Results may take 1-3 weeks; do NOT wait for antibody results before initiating immunotherapy if clinical suspicion is high. Mayo panels preferred for comprehensive evaluation.
1C. Rare/Specialized (Refractory or Atypical)¶
| Test | ED | HOSP | OPD | ICU | Rationale | Target Finding |
|---|---|---|---|---|---|---|
| Anti-PCA-2 (MAP1B) antibody | - | EXT | EXT | - | Cerebellar degeneration; neuropathy; associated with SCLC | Negative |
| Anti-PCA-Tr (DNER) antibody | - | EXT | EXT | - | Cerebellar degeneration; associated with Hodgkin lymphoma | Negative |
| Anti-mGluR1 antibody | - | EXT | EXT | - | Cerebellar ataxia; Hodgkin lymphoma | Negative |
| Anti-mGluR5 antibody | - | EXT | EXT | - | Ophelia syndrome (limbic encephalitis + Hodgkin lymphoma) | Negative |
| Anti-GlyR (glycine receptor) antibody | - | EXT | EXT | - | Progressive encephalomyelitis with rigidity and myoclonus (PERM) | Negative |
| Anti-DPPX antibody | - | EXT | EXT | - | Encephalitis with hyperexcitability and GI symptoms | Negative |
| Anti-recoverin antibody | - | EXT | EXT | - | Cancer-associated retinopathy (CAR); SCLC | Negative |
| Anti-ANNA-3 antibody | - | EXT | EXT | - | Sensory neuropathy; SCLC | Negative |
| 14-3-3 protein (CSF) | - | EXT | EXT | - | Prion disease mimic in rapidly progressive cerebellar degeneration | Negative |
| RT-QuIC (CSF) | - | EXT | EXT | - | Prion disease exclusion | Negative |
| Paraneoplastic comprehensive panel (next-generation) | - | EXT | EXT | - | If standard panels negative and clinical suspicion remains high | All negative |
| Tumor markers: AFP, beta-hCG, CA-125, CA 19-9, CEA, PSA | - | ROUTINE | ROUTINE | - | Adjunctive tumor screening (not diagnostic alone); AFP/beta-hCG for germ cell tumors; CA-125 for ovarian | Normal |
2. DIAGNOSTIC IMAGING & STUDIES¶
2A. Essential/First-line¶
| Study | ED | HOSP | OPD | ICU | Timing | Target Finding | Contraindications |
|---|---|---|---|---|---|---|---|
| CT head without contrast (CPT 70450) | STAT | STAT | - | STAT | Immediate (ED triage) | Rule out mass, hemorrhage, hydrocephalus, brain metastases | None significant |
| MRI brain with and without contrast (CPT 70553) | URGENT | URGENT | ROUTINE | URGENT | Within 24h | Mesial temporal T2/FLAIR hyperintensity (limbic encephalitis); cerebellar atrophy (subacute cerebellar degeneration); leptomeningeal enhancement; brain metastases | GFR <30, gadolinium allergy, pacemaker |
| CT chest with contrast (CPT 71260) | URGENT | URGENT | ROUTINE | URGENT | Within 48h | Lung mass (SCLC, NSCLC); mediastinal mass (thymoma); hilar adenopathy | Contrast allergy, renal insufficiency |
| CT abdomen/pelvis with contrast (CPT 74178) | URGENT | URGENT | ROUTINE | URGENT | Within 48h | Ovarian mass, renal cell carcinoma, hepatic metastases, retroperitoneal lymphadenopathy | Contrast allergy, renal insufficiency |
| Chest X-ray (CPT 71046) | STAT | STAT | - | STAT | Immediate | Mediastinal mass; pulmonary mass; aspiration | Pregnancy (relative) |
| ECG (12-lead) (CPT 93000) | STAT | STAT | ROUTINE | STAT | Immediate | Autonomic dysfunction; arrhythmia; QTc prolongation | None |
2B. Extended¶
| Study | ED | HOSP | OPD | ICU | Timing | Target Finding | Contraindications |
|---|---|---|---|---|---|---|---|
| FDG-PET/CT (whole body) (CPT 78816) | - | ROUTINE | ROUTINE | - | Within 1-2 weeks; STAT if CT negative and high clinical suspicion | Occult malignancy not identified on CT; FDG-avid tumor; most sensitive modality for cancer screening in PNS | Uncontrolled diabetes, pregnancy |
| Pelvic/transvaginal ultrasound (females) | - | URGENT | ROUTINE | URGENT | Within 48h | Ovarian teratoma (anti-NMDAR); ovarian cancer (anti-Yo) | None significant |
| Testicular ultrasound (males <50) | - | URGENT | ROUTINE | URGENT | Within 48h | Testicular germ cell tumor (anti-Ma2, KLHL11); testicular seminoma | None significant |
| MRI spine with and without contrast (CPT 72156) | - | ROUTINE | ROUTINE | ROUTINE | Within 48-72h | Myelitis; radiculitis; cord compression from metastatic disease; cauda equina involvement | GFR <30, gadolinium allergy |
| NCS/EMG (CPT 95907-95913/95886) | - | URGENT | ROUTINE | URGENT | Within 3-7 days | Sensory neuronopathy pattern (non-length-dependent, asymmetric); sensorimotor neuropathy; neuromuscular junction defect (LEMS: low CMAP, incremental response on RNS); myopathy | None significant |
| EEG (routine or continuous) (CPT 95816) | URGENT | URGENT | ROUTINE | STAT | Within 24h if encephalopathy or seizures | Focal/generalized slowing; epileptiform discharges; subclinical seizures | None significant |
| Mammography/breast MRI | - | ROUTINE | ROUTINE | - | Within 1-2 weeks | Breast malignancy (anti-Ri, anti-amphiphysin, anti-AMPAR) | Implants (relative for MRI) |
2C. Rare/Specialized¶
| Study | ED | HOSP | OPD | ICU | Timing | Target Finding | Contraindications |
|---|---|---|---|---|---|---|---|
| FDG-PET brain | - | EXT | EXT | - | Within 1-2 weeks | Cerebellar hypermetabolism (early) or hypometabolism (late); mesial temporal metabolic changes | Uncontrolled diabetes; pregnancy |
| Repetitive nerve stimulation (RNS) (CPT 95937) | - | ROUTINE | ROUTINE | - | During NCS/EMG session | Decremental response at 3 Hz (MG); incremental response >100% at 50 Hz or post-exercise (LEMS) | None significant |
| CT-guided biopsy (identified tumor) | - | EXT | EXT | - | After tumor identified | Histopathological confirmation of malignancy | Coagulopathy, inaccessible location |
| Colonoscopy | - | EXT | EXT | - | If indicated by age/symptoms or specific antibody profile | Colorectal malignancy screening | Active bowel perforation |
| Ophthalmologic examination (ERG, fundoscopy) | - | ROUTINE | ROUTINE | - | If visual symptoms present | Cancer-associated retinopathy (anti-recoverin); optic neuritis (anti-CV2) | None significant |
| Polysomnography | - | - | EXT | - | If sleep disorder prominent | REM sleep behavior disorder; narcolepsy-like phenotype (anti-Ma2) | None significant |
LUMBAR PUNCTURE¶
Indication: Essential for paraneoplastic workup; CSF antibody testing complements serum; rules out infectious or carcinomatous meningitis; supports inflammatory CNS process
Timing: URGENT in acute presentations; ROUTINE in outpatient evaluation
Volume Required: 20-30 mL (large volume for comprehensive antibody panel, cytology, and infectious workup)
| Study | ED | HOSP | OPD | ICU | Rationale | Target Finding |
|---|---|---|---|---|---|---|
| Opening pressure | URGENT | ROUTINE | ROUTINE | URGENT | Elevated ICP assessment; carcinomatous meningitis | 10-20 cm H2O |
| Cell count with differential (tubes 1 and 4) (CPT 89051) | STAT | STAT | ROUTINE | STAT | Lymphocytic pleocytosis supports inflammatory/autoimmune process | WBC 5-50 (lymphocyte-predominant); RBC 0 |
| Protein (CPT 84157) | STAT | STAT | ROUTINE | STAT | Mildly elevated in paraneoplastic; markedly elevated suggests carcinomatous meningitis or GBS | Normal to mildly elevated (usually <100 mg/dL) |
| Glucose with paired serum glucose (CPT 82945) | STAT | STAT | ROUTINE | STAT | Low glucose suggests carcinomatous meningitis or infection | Normal (>60% of serum) |
| Gram stain and bacterial culture (CPT 87205+87070) | STAT | STAT | ROUTINE | STAT | Rule out bacterial meningitis | No organisms |
| HSV 1/2 PCR (CPT 87529) | STAT | STAT | ROUTINE | STAT | Rule out HSV encephalitis (limbic encephalitis mimic) | Negative |
| VZV PCR | URGENT | URGENT | ROUTINE | URGENT | Varicella encephalitis/cerebellitis | Negative |
| Oligoclonal bands (CSF AND paired serum) (CPT 83916) | URGENT | ROUTINE | ROUTINE | URGENT | Intrathecal IgG synthesis; supports CNS inflammation | May show CSF-specific bands |
| IgG index | URGENT | ROUTINE | ROUTINE | URGENT | Intrathecal antibody synthesis | May be elevated |
| Cytology (CPT 88104) | URGENT | ROUTINE | ROUTINE | URGENT | Carcinomatous/lymphomatous meningitis | Negative |
| Flow cytometry | - | ROUTINE | ROUTINE | - | CNS lymphoma | Normal |
| Paraneoplastic antibody panel (CSF) | URGENT | URGENT | ROUTINE | URGENT | ANNA-1, ANNA-2, PCA-1, amphiphysin, CV2, GAD65, NMDAR, LGI1, CASPR2 -- CBA method | All negative |
| VDRL (CSF) (CPT 86592) | - | ROUTINE | ROUTINE | - | Neurosyphilis exclusion | Negative |
| AFB culture and smear (CPT 87116) | - | ROUTINE | - | - | TB meningitis if risk factors | Negative |
| 14-3-3 protein | - | EXT | EXT | - | Prion disease mimic in rapidly progressive cerebellar syndrome | Negative |
Special Handling: Send minimum 2 mL CSF to each reference lab. Store extra CSF (frozen at -20C) for future testing. Antibody results take 1-3 weeks. Cytology requires rapid transport (<1 hour). Send both serum and CSF simultaneously for antibody testing.
Contraindications: Elevated ICP without imaging (get CT first), coagulopathy (INR >1.5, platelets <50K), skin infection at LP site, posterior fossa mass with risk of herniation
3. TREATMENT¶
3A. Acute/Emergent¶
| Treatment | Route | Indication | Dosing | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|
| Methylprednisolone IV | IV | First-line immunotherapy for acute paraneoplastic neurological syndrome; reduces CNS inflammation | 1000 mg :: IV :: daily x 3-5 days :: 1000 mg IV daily for 3-5 days; infuse over 1-2 hours | Active untreated infection; uncontrolled diabetes; psychosis from steroids | Glucose q6h (target <180); BP; mood/sleep; I/O; GI prophylaxis | URGENT | STAT | - | STAT |
| Omeprazole (GI prophylaxis during steroids) | PO/IV | Stress ulcer prevention during high-dose corticosteroids | 40 mg :: IV/PO :: daily :: 40 mg IV/PO daily during steroid course and taper | PPI allergy | None routine | URGENT | STAT | ROUTINE | STAT |
| Insulin sliding scale | SC | Steroid-induced hyperglycemia management | Per protocol :: SC :: PRN :: Per institutional sliding scale protocol if glucose >180 mg/dL | Hypoglycemia risk | Glucose q6h; adjust per response | URGENT | STAT | - | STAT |
| IVIG (intravenous immunoglobulin) | IV | First-line immunotherapy; antibody-mediated mechanism; given concurrently or sequentially with IV steroids | 0.4 g/kg :: IV :: daily x 5 days :: 0.4 g/kg/day IV x 5 days (total 2 g/kg); infuse per weight-based protocol; premedicate with acetaminophen, diphenhydramine | IgA deficiency (anaphylaxis risk); recent thromboembolic event; renal failure | Renal function daily; headache (aseptic meningitis); thrombosis; volume overload; check IgA level before first dose | - | STAT | - | STAT |
| Plasmapheresis (PLEX) | IV | First-line immunotherapy; removes pathogenic antibodies; preferred for cell-surface antibody syndromes | 1-1.5 plasma volumes :: IV :: every other day x 5-7 exchanges :: 5-7 exchanges over 10-14 days; 1-1.5 plasma volumes per exchange; albumin replacement preferred | Hemodynamic instability; sepsis; coagulopathy; poor vascular access | BP during exchanges; electrolytes (Ca, K, Mg); coagulation (fibrinogen); line site; citrate reactions | - | STAT | - | STAT |
| Lorazepam (acute seizure) | IV | Seizure management in paraneoplastic limbic encephalitis | 4 mg :: IV :: push PRN seizure :: 0.1 mg/kg IV (max 4 mg/dose); may repeat x1 in 5 min; max 8 mg total | Respiratory depression; acute narrow-angle glaucoma | Respiratory status; sedation level; airway patency | STAT | STAT | - | STAT |
Note: Immunotherapy should be initiated as soon as paraneoplastic syndrome is clinically suspected. Do NOT wait for antibody results. The most critical intervention is identifying and treating the underlying tumor -- tumor-directed therapy (surgery, chemotherapy, radiation) is the primary treatment and improves neurological outcomes. Cell-surface antibody syndromes are more responsive to immunotherapy than intracellular antibody syndromes.
3B. Symptomatic Treatments¶
| Treatment | Route | Indication | Dosing | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|
| Levetiracetam | IV/PO | Seizure management in paraneoplastic limbic encephalitis; preferred first-line ASM | 500 mg :: IV/PO :: BID :: Load: 1000-1500 mg IV; Maintenance: 500 mg BID, titrate to 1000-1500 mg BID; max 3000 mg/day | Renal impairment (adjust dose per CrCl) | Behavioral changes (rage, irritability); suicidality; renal function | STAT | STAT | ROUTINE | STAT |
| Lacosamide | IV/PO | Second-line ASM for seizures; favorable drug interaction profile with immunotherapy | 100 mg :: IV/PO :: BID :: Load: 200-400 mg IV; Maintenance: 100 mg BID, titrate to 200 mg BID; max 400 mg/day | Second/third degree AV block; severe hepatic impairment | ECG (PR prolongation); dizziness; cardiac monitoring during load | URGENT | URGENT | ROUTINE | URGENT |
| Gabapentin | PO | Neuropathic pain from paraneoplastic sensory neuropathy | 300 mg :: PO :: TID :: Start 300 mg qHS; titrate by 300 mg q1-3d; max 3600 mg/day divided TID | Renal impairment (adjust per CrCl) | Sedation; dizziness; peripheral edema; respiratory depression (with opioids) | - | ROUTINE | ROUTINE | ROUTINE |
| Pregabalin | PO | Neuropathic pain from paraneoplastic sensory neuropathy; alternative to gabapentin | 75 mg :: PO :: BID :: Start 75 mg BID; may increase q1wk to 150-300 mg BID; max 600 mg/day | Renal impairment (adjust per CrCl); angioedema history | Sedation; dizziness; weight gain; peripheral edema | - | ROUTINE | ROUTINE | - |
| Duloxetine | PO | Neuropathic pain; concurrent depression management | 30 mg :: PO :: daily :: Start 30 mg daily x 1 week; increase to 60 mg daily; max 120 mg/day | Severe hepatic impairment; concurrent MAOIs; uncontrolled narrow-angle glaucoma | LFTs; BP; sodium (hyponatremia risk); suicidality | - | ROUTINE | ROUTINE | - |
| Clonazepam | PO | Opsoclonus-myoclonus symptom relief; myoclonus management | 0.5 mg :: PO :: BID :: Start 0.5 mg BID; titrate by 0.5 mg q3d; max 6 mg/day | Severe hepatic impairment; acute narrow-angle glaucoma; respiratory depression | Sedation; tolerance; dependence; respiratory depression | - | ROUTINE | ROUTINE | ROUTINE |
| Meclizine | PO | Vertigo and vestibular symptoms from cerebellar involvement | 25 mg :: PO :: TID PRN :: 25 mg PO q8h PRN vertigo; max 75 mg/day | Concurrent anticholinergic use; urinary retention; glaucoma | Sedation; anticholinergic effects | URGENT | ROUTINE | ROUTINE | - |
| Ondansetron | IV/PO | Nausea/vomiting from cerebellar involvement or brainstem dysfunction | 4 mg :: IV/PO :: q8h PRN :: 4-8 mg IV/PO q8h PRN nausea; max 24 mg/day | QTc prolongation; concomitant apomorphine | QTc if risk factors; constipation | STAT | ROUTINE | ROUTINE | STAT |
| Amitriptyline | PO | Neuropathic pain; insomnia from paraneoplastic sensory neuropathy | 10 mg :: PO :: qHS :: Start 10 mg qHS; titrate by 10-25 mg q1-2wk; max 150 mg/day | Cardiac conduction abnormality; recent MI; urinary retention; glaucoma; elderly | ECG if dose >100 mg/day; anticholinergic effects; QTc monitoring | - | ROUTINE | ROUTINE | - |
| Baclofen | PO | Stiffness/spasticity from paraneoplastic stiff-person spectrum or myelopathy | 5 mg :: PO :: TID :: Start 5 mg TID; titrate by 5 mg/dose q3d; max 80 mg/day | Renal impairment; abrupt withdrawal risk (seizures, hallucinations) | Sedation; weakness; hepatic function; do NOT stop abruptly | - | ROUTINE | ROUTINE | ROUTINE |
| Diazepam | PO | Stiff-person spectrum; muscle spasms; paraneoplastic rigidity | 2 mg :: PO :: BID :: Start 2 mg BID; titrate to effect; max 40 mg/day | Severe respiratory depression; myasthenia gravis; acute narrow-angle glaucoma | Sedation; respiratory depression; tolerance; dependence | - | ROUTINE | ROUTINE | ROUTINE |
| Melatonin | PO | Sleep-wake disturbance; circadian dysregulation | 3 mg :: PO :: qHS :: Start 3 mg qHS; may increase to 5-10 mg qHS | None significant | Sleep quality; no significant drug interactions | - | ROUTINE | ROUTINE | ROUTINE |
| Sertraline | PO | Depression and anxiety associated with chronic paraneoplastic neurological syndrome | 25 mg :: PO :: daily :: Start 25-50 mg daily; increase by 25-50 mg q1-2wk; max 200 mg/day | Concurrent MAOIs; QT prolongation (rare) | Suicidality monitoring; hyponatremia (SIADH); GI side effects | - | ROUTINE | ROUTINE | - |
Note: Symptomatic treatments provide supportive care while immunotherapy and tumor-directed therapy address the underlying cause. Avoid carbamazepine/oxcarbazepine if hyponatremia is present (common in paraneoplastic SIADH). Benzodiazepines are first-line for stiff-person spectrum disorders. Neuropathic pain management follows standard guidelines but may be refractory to conventional agents if the underlying tumor is not treated.
3C. Second-Line/Refractory¶
| Treatment | Route | Indication | Dosing | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|
| Rituximab | IV | Second-line immunotherapy for refractory paraneoplastic syndrome; B-cell depletion; more effective for cell-surface antibody syndromes | 375 mg/m2 :: IV :: weekly x 4 doses :: 375 mg/m2 IV weekly x 4 doses OR 1000 mg IV x 2 doses (day 0 and day 14); premedicate with methylprednisolone 100 mg, acetaminophen, diphenhydramine | Active hepatitis B; severe active infection; live vaccines within 4 weeks | Hepatitis B serology (before first dose); CBC q2-4 weeks; immunoglobulin levels q3 months; CD19/CD20 B-cell counts; infusion reactions; PML surveillance | - | URGENT | ROUTINE | URGENT |
| Cyclophosphamide | IV | Second-line immunotherapy for refractory paraneoplastic syndrome; used for intracellular antibody syndromes unresponsive to first-line | 750 mg/m2 :: IV :: monthly x 6 cycles :: 750 mg/m2 IV monthly x 6 cycles; pre-hydrate with 1L NS; administer with MESNA (uroprotection) | Pregnancy; active infection; bone marrow failure; bladder outlet obstruction | CBC weekly x 4 weeks after each cycle (nadir day 10-14); urinalysis; BMP; LFTs; fertility counseling; hemorrhagic cystitis prevention | - | URGENT | ROUTINE | URGENT |
| Oral prednisone taper | PO | Transition from IV methylprednisolone; sustained immunosuppression during tumor workup | 1 mg/kg :: PO :: daily :: 1 mg/kg/day (max 60 mg) x 2 weeks; taper by 10 mg/week to 20 mg; then by 5 mg/week to discontinuation or low-dose maintenance | Active infection; uncontrolled diabetes; avascular necrosis | Glucose; BP; bone density if prolonged; mood; weight; adrenal insufficiency on taper | - | ROUTINE | ROUTINE | - |
| Repeated IVIG cycles | IV | Maintenance immunotherapy for partially responsive paraneoplastic syndrome | 0.4 g/kg :: IV :: daily x 5 days q4 weeks :: 0.4 g/kg/day x 5 days (repeat q4 weeks) or 1 g/kg x 2 days q4 weeks | IgA deficiency; thromboembolic history | Renal function; headache; IgG trough levels; infusion reactions | - | URGENT | ROUTINE | URGENT |
| Repeated PLEX cycles | IV | Maintenance plasmapheresis for partially responsive paraneoplastic syndrome | 1-1.5 plasma volumes :: IV :: every other day x 5 exchanges q4-6 weeks :: 5 exchanges (repeat q4-6 weeks as needed); 1-1.5 plasma volumes per exchange; albumin replacement preferred | Hemodynamic instability; sepsis; coagulopathy | BP during exchanges; electrolytes (Ca, K, Mg); coagulation (fibrinogen); line site; citrate reactions | - | URGENT | - | URGENT |
| Tocilizumab | IV | Third-line immunotherapy for refractory cases; IL-6 receptor blockade | 8 mg/kg :: IV :: q4 weeks :: 8 mg/kg IV every 4 weeks (max 800 mg/dose) | Active infection; hepatic impairment (ALT >5x ULN); diverticulitis; concurrent live vaccines | CBC, LFTs, lipids q4-8 weeks; infection surveillance; GI perforation risk; neutropenia | - | EXT | EXT | EXT |
Note: Second-line therapy should be initiated if no improvement within 2-4 weeks of first-line therapy OR if clinically worsening. For intracellular antibody syndromes (anti-Hu, anti-Yo, anti-Ri), neurological prognosis is often poor despite aggressive immunotherapy -- tumor treatment remains the primary therapeutic intervention. For cell-surface antibody syndromes, escalation to rituximab is associated with improved outcomes. Cyclophosphamide is considered when rituximab fails or for aggressive intracellular antibody syndromes.
3D. Disease-Modifying / Long-Term Immunosuppression¶
| Treatment | Route | Indication | Dosing | Pre-Treatment Requirements | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|---|
| Rituximab (maintenance) | IV | Long-term immunosuppression for relapse prevention in cell-surface antibody paraneoplastic syndromes | 500 mg :: IV :: q6 months :: 500-1000 mg IV every 6 months; re-dose based on CD19/CD20 B-cell repopulation or clinical relapse | Hepatitis B/C serology; quantitative immunoglobulins; CBC; LFTs; chest X-ray; TB screening (QuantiFERON); vaccinations current (no live vaccines within 4 weeks) | Active hepatitis B; severe active infection; live vaccines within 4 weeks; severe hypogammaglobulinemia (IgG <300) | CD19/CD20 counts q3 months; immunoglobulin levels q3-6 months; hepatitis B surveillance; infection monitoring; PML surveillance; CBC q3 months | - | - | ROUTINE | - |
| Mycophenolate mofetil (CellCept) | PO | Steroid-sparing immunosuppression for maintenance; prevents relapse | 500 mg :: PO :: BID :: Start 500 mg PO BID; increase to 1000 mg PO BID over 2-4 weeks; target 1500-3000 mg/day | CBC; LFTs; pregnancy test (females); contraception plan | Pregnancy (Category D -- teratogenic); active infection | CBC q2 weeks x 3 months, then monthly; LFTs; GI symptoms; infection surveillance; pregnancy prevention | - | - | ROUTINE | - |
| Azathioprine (Imuran) | PO | Steroid-sparing immunosuppression; alternative to mycophenolate | 50 mg :: PO :: daily :: Start 50 mg PO daily; increase by 50 mg every 2 weeks to target 2-3 mg/kg/day | TPMT genotype/activity (mandatory before starting); CBC; LFTs | TPMT deficiency (myelosuppression risk); pregnancy (relative); concurrent allopurinol (reduce dose by 75%) | TPMT genotype before starting; CBC q2 weeks x 2 months, then monthly; LFTs; pancreatitis; infection surveillance | - | - | ROUTINE | - |
| Oral prednisone (low-dose maintenance) | PO | Low-dose maintenance immunosuppression while steroid-sparing agent reaches full effect | 5 mg :: PO :: daily :: 5-10 mg PO daily; aim to taper off within 3-6 months if on steroid-sparing agent | Baseline glucose; BP; DEXA if anticipated use >3 months | Poorly controlled diabetes; active infection; avascular necrosis | Glucose; BP; bone density (DEXA if >3 months); weight; mood; cataracts; adrenal assessment on taper | - | - | ROUTINE | - |
| IVIG (maintenance) | IV | Maintenance immunotherapy for partially responsive paraneoplastic syndrome; especially cell-surface antibody syndromes | 0.4 g/kg :: IV :: q4 weeks :: 0.4 g/kg IV every 4 weeks OR 1 g/kg IV every 4-6 weeks; adjust per response | IgA level; renal function; CBC; coagulation screen | IgA deficiency; thromboembolic history; renal failure | Renal function; headache; IgG trough levels; infusion reactions; thrombosis surveillance | - | - | ROUTINE | - |
| Calcium + Vitamin D (bone protection) | PO | Osteoporosis prevention during prolonged steroid use | 1000-1200 mg calcium + 1000-2000 IU vitamin D :: PO :: daily :: Calcium 1000-1200 mg/day + Vitamin D 1000-2000 IU/day | 25-OH Vitamin D level; calcium level; DEXA baseline if steroid use >3 months | Hypercalcemia; kidney stones; hypervitaminosis D | 25-OH Vitamin D level; calcium; DEXA q1-2 years | - | ROUTINE | ROUTINE | - |
Note: Long-term immunosuppression is guided by antibody subtype, tumor status, and clinical response. Cell-surface antibody syndromes (anti-NMDAR, anti-LGI1, anti-CASPR2) are more amenable to chronic immunosuppression. Intracellular antibody syndromes (anti-Hu, anti-Yo) have limited benefit from maintenance immunotherapy once neuronal damage has occurred. Duration of therapy is individualized -- typically minimum 2 years for responsive syndromes. Monitor for immunosuppression-related complications (infection, secondary malignancy). Tumor surveillance must continue alongside immunosuppression.
4. OTHER RECOMMENDATIONS¶
4A. Referrals & Consults¶
| Recommendation | ED | HOSP | OPD | ICU |
|---|---|---|---|---|
| Neurology (neuroimmunology/neuro-oncology) consult for diagnosis confirmation, antibody interpretation, immunotherapy guidance, and longitudinal care | STAT | STAT | ROUTINE | STAT |
| Oncology consult for tumor identification, staging, and treatment planning (surgery, chemotherapy, radiation) | URGENT | URGENT | ROUTINE | URGENT |
| Gynecologic oncology referral for ovarian teratoma screening and resection in females with anti-NMDAR or anti-Yo antibodies | - | URGENT | URGENT | URGENT |
| Urology referral for testicular ultrasound and germ cell tumor evaluation in males <50 with anti-Ma2 or anti-KLHL11 antibodies | - | URGENT | ROUTINE | - |
| Pulmonology consult for respiratory function monitoring and ventilator management in cases with respiratory failure | - | URGENT | - | STAT |
| Hematology/apheresis service for PLEX coordination and vascular access | - | URGENT | - | URGENT |
| Epilepsy/EEG service for seizure management and continuous EEG monitoring in limbic encephalitis | STAT | STAT | ROUTINE | STAT |
| Psychiatry consult for behavioral/psychiatric manifestations and medication management in paraneoplastic encephalitis | URGENT | URGENT | ROUTINE | URGENT |
| Physical therapy for gait training, balance rehabilitation, and fall prevention in cerebellar degeneration and sensory neuropathy | - | ROUTINE | ROUTINE | ROUTINE |
| Occupational therapy for ADL assessment, adaptive strategies, and upper extremity coordination training | - | ROUTINE | ROUTINE | ROUTINE |
| Speech-language pathology for swallowing evaluation, language rehabilitation, and cognitive-linguistic therapy in encephalitis cases | - | ROUTINE | ROUTINE | ROUTINE |
| Neuropsychology for formal cognitive assessment, rehabilitation planning, and serial monitoring | - | - | ROUTINE | - |
| Pain management referral for refractory neuropathic pain not responding to first-line and second-line agents | - | ROUTINE | ROUTINE | - |
| Social work for family support, insurance navigation, disability resources, and long-term care planning | - | ROUTINE | ROUTINE | - |
| Palliative care for refractory cases, symptom management, and goals of care discussion in progressive intracellular antibody syndromes | - | EXT | ROUTINE | EXT |
| Rehabilitation medicine for comprehensive inpatient or outpatient rehab program coordination | - | ROUTINE | ROUTINE | - |
| Endocrinology for steroid-induced hyperglycemia management and hypothalamic dysfunction in anti-Ma2 cases | - | ROUTINE | ROUTINE | - |
| Ophthalmology for visual symptom evaluation, cancer-associated retinopathy screening, and optic neuritis assessment | - | ROUTINE | ROUTINE | - |
4B. Patient/Family Instructions¶
| Recommendation | ED | HOSP | OPD | ICU |
|---|---|---|---|---|
| Return to ED immediately for new seizures, sudden behavioral changes, worsening weakness, difficulty breathing, or loss of consciousness (may indicate disease progression or autonomic crisis) | Y | Y | Y | - |
| Paraneoplastic neurological syndrome is caused by the immune system attacking the nervous system in response to an underlying cancer -- treating the cancer is the most important step in treatment | Y | Y | Y | Y |
| Neurological recovery depends on antibody type: cell-surface antibody syndromes often improve with treatment; intracellular antibody syndromes may have limited neurological recovery despite tumor treatment | - | Y | Y | Y |
| Do NOT drive until cleared by neurology due to risk of seizures, cerebellar dysfunction, or cognitive impairment | Y | Y | Y | - |
| Report any signs of infection (fever >100.4F, cough, dysuria, rash) immediately while on immunotherapy as immune suppression increases infection risk | - | Y | Y | - |
| Avoid live vaccines while on immunosuppressive therapy; inform all healthcare providers of immunosuppression status | - | Y | Y | - |
| Do not stop anti-seizure medications abruptly (risk of rebound seizures) | - | Y | Y | - |
| Keep a symptom diary documenting neurological changes, seizure frequency, and functional status to track treatment response | - | Y | Y | - |
| Cancer screening follow-up appointments are critical -- repeat imaging every 6 months for at least 2 years if initial tumor screen is negative | - | Y | Y | - |
| Avoid alcohol and recreational drugs (lower seizure threshold, interact with medications, and may mask neurological changes) | - | Y | Y | - |
| Pregnancy must be avoided during immunotherapy; discuss contraception with neurology and OB/GYN | - | Y | Y | - |
| Fall prevention measures at home (remove throw rugs, install grab bars, adequate lighting) due to cerebellar ataxia and sensory neuropathy | - | Y | Y | - |
| Medical alert bracelet recommended (paraneoplastic syndrome, seizure risk, immunosuppressed) | - | Y | Y | - |
| Cognitive rehabilitation exercises as directed by occupational therapy and neuropsychology | - | Y | Y | - |
4C. Lifestyle & Prevention¶
| Recommendation | ED | HOSP | OPD | ICU |
|---|---|---|---|---|
| Smoking cessation to reduce lung cancer risk and improve overall oncologic outcomes | - | Y | Y | - |
| Low-sodium diet to reduce fluid retention on corticosteroids and manage steroid-induced hypertension | - | Y | Y | - |
| Low-impact exercise (swimming, stationary bike, seated exercises) to maintain strength and cardiovascular fitness within functional limitations | - | Y | Y | - |
| Energy conservation with scheduled rest periods to manage cancer-related and treatment-related fatigue | - | Y | Y | - |
| Aspiration precautions including modified diet texture and supervised meals if bulbar dysfunction present | - | Y | Y | Y |
| Frequent repositioning every 2 hours to prevent pressure ulcers during immobility | - | Y | - | Y |
| Calcium and vitamin D supplementation for bone protection during prolonged corticosteroid use | - | Y | Y | - |
| Nutritional optimization with dietitian consultation to maintain weight and support immune function during treatment | - | Y | Y | Y |
| Home safety evaluation to remove fall hazards and install assistive devices for cerebellar ataxia and peripheral neuropathy | - | - | Y | - |
| CPAP compliance if obstructive sleep apnea identified during evaluation to prevent nocturnal hypoxia | - | Y | Y | Y |
=============================================================== SECTION B: REFERENCE (Expand as Needed) ===============================================================
5. DIFFERENTIAL DIAGNOSIS¶
| Alternative Diagnosis | Key Distinguishing Features | Tests to Differentiate |
|---|---|---|
| Autoimmune encephalitis (non-paraneoplastic) | Cell-surface antibody positive but no tumor found; younger patients; prodromal illness | Full antibody panel; comprehensive tumor screening; PET-CT; repeat imaging if initially negative |
| Primary CNS lymphoma | Progressive encephalopathy, periventricular enhancing mass, immunocompromised | CSF cytology/flow cytometry; FDG-PET; brain biopsy; EBV PCR in CSF |
| Brain metastases | Known primary cancer; ring-enhancing lesions on MRI; often multifocal | Contrast-enhanced MRI brain; CT chest/abdomen/pelvis; biopsy if needed |
| Carcinomatous/leptomeningeal meningitis | Cranial neuropathies; radiculopathy; CSF with low glucose, high protein, positive cytology | CSF cytology (repeat x3 if initially negative); gadolinium-enhanced MRI brain and spine |
| Prion disease (CJD) | Rapidly progressive dementia; myoclonus; cortical ribboning on DWI; periodic sharp wave complexes on EEG | 14-3-3; RT-QuIC; MRI DWI cortical ribboning; EEG periodic discharges |
| Multiple sclerosis | Relapsing-remitting course; typical MRI lesion distribution (periventricular, juxtacortical, infratentorial) | MRI brain/spine; oligoclonal bands; McDonald criteria |
| Neurosarcoidosis | Cranial neuropathies; hypothalamic dysfunction; leptomeningeal enhancement; hilar adenopathy | ACE level; chest CT; biopsy (non-caseating granulomas) |
| CNS vasculitis | Headache; stroke-like episodes; multifocal infarcts; elevated inflammatory markers | Angiography (beading); brain/leptomeningeal biopsy; ESR/CRP |
| Viral encephalitis (HSV, VZV, other) | Acute fever; temporal lobe involvement (HSV); CSF pleocytosis | HSV PCR; VZV PCR; specific viral serologies |
| Hashimoto encephalopathy (SREAT) | Encephalopathy with very high anti-TPO; steroid-responsive; no tumor | Anti-TPO; anti-thyroglobulin; dramatic steroid response; negative tumor screen |
| Neurosyphilis | Cognitive decline; psychiatric symptoms; Argyll Robertson pupils | RPR/VDRL; CSF VDRL; FTA-ABS |
| Vitamin B12 deficiency | Subacute combined degeneration; posterior column dysfunction; megaloblastic anemia | B12 level; methylmalonic acid; MRI spine (dorsal column signal) |
| Toxic/metabolic neuropathy (alcohol, chemotherapy) | Temporal correlation with exposure; length-dependent pattern | History; drug levels; NCS/EMG pattern |
| Lambert-Eaton myasthenic syndrome (paraneoplastic) | Proximal weakness; autonomic dysfunction; facilitation on repetitive nerve stimulation | Anti-VGCC antibodies; RNS with incremental response; CT chest for SCLC |
| Myasthenia gravis | Fatigable weakness; ptosis; diplopia; decrement on RNS | Anti-AChR; anti-MuSK; RNS; edrophonium test |
| Spinocerebellar ataxia (genetic) | Family history; slowly progressive; genetic testing | Genetic panel (SCA 1, 2, 3, 6, 7); MRI cerebellar atrophy |
6. MONITORING PARAMETERS¶
6A. Acute Phase Monitoring (Inpatient)¶
| Parameter | Frequency | Target/Threshold | Action if Abnormal | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|
| Neurologic examination (mental status, cranial nerves, cerebellar testing, motor, sensory, reflexes) | Q4-6h (ICU); Q8-12h (floor) | Stable or improving | If worsening: urgent re-imaging; escalate immunotherapy; consider ICU transfer | STAT | STAT | - | STAT |
| Modified Rankin Scale (mRS) | Baseline, then weekly | Improvement over weeks-months | Document trajectory; guide treatment escalation | - | ROUTINE | ROUTINE | ROUTINE |
| Blood glucose | Q6h during IV steroids | <180 mg/dL | Insulin sliding scale; endocrine consult if persistent >250 | URGENT | STAT | - | STAT |
| Blood pressure | Q1h (ICU); Q4h (floor) | SBP 100-180; MAP >65 | Autonomic dysregulation treatment per protocol | STAT | ROUTINE | - | STAT |
| Heart rate and rhythm | Continuous telemetry if inpatient | HR 60-100; sinus rhythm | Treat autonomic instability; cardiology consult if sustained arrhythmia | STAT | STAT | - | STAT |
| Temperature | Q4h; continuous in ICU | 36.0-37.5 C | Rule out infection; cooling measures if central hyperthermia | STAT | ROUTINE | - | STAT |
| Respiratory function (RR, SpO2, NIF if neuromuscular) | Q4h (ICU); Q shift (floor) | RR <20; SpO2 >94%; NIF >-30 cm H2O | NIF worsening: intubation threshold; ICU transfer | STAT | ROUTINE | - | STAT |
| Seizure log | Continuous if epileptiform | Decreasing frequency/severity | Escalate ASMs; continuous EEG; re-assess immunotherapy | STAT | STAT | - | STAT |
| Sodium (Na) | Q6-12h if hyponatremia | Na >130 mEq/L | Correct per protocol; fluid restriction if SIADH | URGENT | ROUTINE | - | URGENT |
| Renal function (BUN/Cr) | Daily during IVIG; q48h otherwise | Stable | Hold IVIG if Cr rising; hydration; nephrology consult | URGENT | ROUTINE | - | URGENT |
| CBC with differential | Q48h during immunotherapy | WBC >3.0; ANC >1.5; Plt >100 | Hold immunotherapy if critically low; growth factor support | - | ROUTINE | - | ROUTINE |
| LFTs | Q48-72h during acute treatment | ALT/AST <3x ULN | Dose adjustment or hold hepatotoxic medications | - | ROUTINE | - | ROUTINE |
| Fibrinogen (during PLEX) | Before each exchange | >100 mg/dL | Hold PLEX if <100; FFP replacement | - | ROUTINE | - | ROUTINE |
| I/O and daily weight | Daily | Euvolemic | Adjust fluids; diuretics if fluid overload | - | ROUTINE | - | ROUTINE |
6B. Outpatient/Long-Term Monitoring¶
| Parameter | Frequency | Target/Threshold | Action if Abnormal | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|
| Neurologic examination (cognition, cerebellar function, sensory, motor, gait) | Monthly x 6 months; then q3 months x 2 years; then q6 months | Stable or sustained improvement | If worsening: repeat antibody titers; re-image for tumor; escalate immunotherapy | - | - | ROUTINE | - |
| Modified Rankin Scale (mRS) | Each visit | Improving toward mRS 0-2 | Document trajectory; adjust rehabilitation goals | - | - | ROUTINE | - |
| Tumor surveillance imaging (CT or PET-CT per antibody protocol) | q6 months x 2 years if initial tumor screen negative; annually thereafter x 2 more years | No new tumor identified | If tumor found: urgent oncology referral and surgical resection | - | - | ROUTINE | - |
| Serum antibody titers | q3-6 months x 2 years; then annually | Decreasing or stable | Rising titers may precede clinical relapse or new tumor; increase surveillance | - | - | ROUTINE | - |
| MRI brain with and without contrast | 3-6 months post-treatment; then annually x 3 years | Stable or improved | New/worsening lesions: relapse workup; repeat antibody testing | - | - | ROUTINE | - |
| CBC with differential | Q2-4 weeks on mycophenolate/azathioprine; then monthly; q3 months on rituximab | WBC >3.0; ANC >1.5; Plt >100 | Hold/reduce immunosuppression; growth factor support | - | - | ROUTINE | - |
| LFTs | Monthly x 3 months on azathioprine/mycophenolate; then q3 months | ALT/AST <3x ULN | Dose reduction or switch agent | - | - | ROUTINE | - |
| Immunoglobulin levels (IgG, IgA, IgM) | Q3-6 months on rituximab | IgG >400 mg/dL | Immunoglobulin replacement if recurrent infections with hypogammaglobulinemia | - | - | ROUTINE | - |
| CD19/CD20 B-cell counts | Q3 months on rituximab | Depleted (<1%) during active treatment | Guide re-dosing interval | - | - | ROUTINE | - |
| DEXA scan (bone density) | Baseline if steroids >3 months; repeat q1-2 years | T-score >-2.5 | Bisphosphonate therapy; calcium/vitamin D optimization | - | - | ROUTINE | - |
| Neuropsychological testing | Baseline (when able); 6 months; 12 months; annually | Improving cognitive domains | Guide cognitive rehabilitation; inform return to work planning | - | - | ROUTINE | - |
| NCS/EMG (if neuropathy) | 3-6 months; then annually | Stable or improved amplitudes | Worsening suggests ongoing neuronal damage; escalate treatment | - | - | ROUTINE | - |
| EEG (routine, if seizure history) | 3-6 months; then as needed | Improved background; no epileptiform activity | Adjust ASMs; consider repeat immunotherapy if worsening | - | - | ROUTINE | - |
| ASM drug levels (if applicable) | Per drug-specific schedule | Therapeutic range | Adjust dose; assess adherence | - | - | ROUTINE | - |
7. DISPOSITION CRITERIA¶
| Disposition | Criteria |
|---|---|
| Discharge home | Stable or improving neurological examination; no active seizures; able to perform basic ADLs safely; reliable follow-up within 1-2 weeks; outpatient infusion arranged if needed; family/caregiver education completed; no significant autonomic instability; tumor workup initiated or completed |
| Admit to floor (neurology/medicine) | New-onset paraneoplastic syndrome requiring expedited workup; immunotherapy initiation (IV steroids, IVIG); seizures requiring medication adjustment; moderate functional impairment; active tumor screening and biopsy coordination |
| Admit to ICU | Severe autonomic instability (hemodynamic swings, arrhythmias); respiratory failure requiring ventilatory support; refractory status epilepticus; altered consciousness (GCS <12); severe encephalitis requiring continuous EEG; rapidly progressive neurological decline |
| Transfer to higher level of care | PLEX or continuous EEG not available; neuroimmunology or neuro-oncology specialist not available; need for tumor resection at specialized center; requires ICU capabilities not available at current facility |
| Inpatient rehabilitation | Medically stable; significant functional deficits (cerebellar ataxia, sensory neuropathy, cognitive impairment) requiring intensive therapy; unable to safely return home; expected to benefit from structured rehabilitation |
| Outpatient follow-up | All patients: neurology follow-up within 1-2 weeks; oncology follow-up per tumor type; infusion center for maintenance immunotherapy; neuropsychology referral; rehabilitation services; tumor surveillance per antibody protocol (Section 4C equivalent) |
| Readmission criteria | New or worsening seizures; behavioral/cognitive regression; fever or signs of infection on immunotherapy; suspected relapse (any new neurological symptoms); newly identified tumor requiring urgent intervention |
8. EVIDENCE & REFERENCES¶
| Recommendation | Evidence Level | Source |
|---|---|---|
| Updated diagnostic criteria for paraneoplastic neurological syndromes (PNS-Care 2021) | Expert Consensus, Class III | Graus F et al. J Neurol Neurosurg Psychiatry 2021;92:1135-1145 |
| Classical paraneoplastic antibodies: anti-Hu, anti-Yo, anti-Ri, anti-CV2, anti-amphiphysin | Class II-III | Dalmau J & Rosenfeld MR. Lancet Neurol 2008;7:327-340 |
| Cell-surface antibodies more treatment-responsive than intracellular antibodies | Class II-III | Dalmau J & Graus F. N Engl J Med 2018;378:840-851 |
| Anti-Hu syndrome: encephalomyelitis and SCLC association | Class III | Dalmau J et al. Medicine 1992;71:59-72 |
| Anti-Yo paraneoplastic cerebellar degeneration and gynecologic cancer | Class III | Peterson K et al. Neurology 1992;42:1931-1937 |
| Anti-Ri opsoclonus-myoclonus and breast cancer | Class III | Pittock SJ et al. Ann Neurol 2003;53:580-587 |
| Anti-CV2/CRMP5 neuropathy and SCLC | Class III | Honnorat J et al. Ann Neurol 2009;65:370-380 |
| Anti-Ma2 limbic encephalitis and testicular germ cell tumor | Class III | Dalmau J et al. Brain 2004;127:1831-1844 |
| Anti-VGCC and Lambert-Eaton myasthenic syndrome with SCLC | Class II | Titulaer MJ et al. J Clin Oncol 2011;29:902-908 |
| LEMS DELTA-P score for SCLC prediction | Class II | Titulaer MJ et al. Neurology 2011;76:1410-1415 |
| FDG-PET/CT superior to CT for occult tumor detection in PNS | Class II | Berner U et al. J Neurol 2017;264:984-994 |
| Repeat tumor screening q6 months for 2+ years if initial screen negative | Expert Consensus | Graus F et al. J Neurol Neurosurg Psychiatry 2021 |
| First-line immunotherapy: IV steroids, IVIG, PLEX | Class III, Expert Consensus | Rosenfeld MR & Dalmau J. Curr Treat Options Neurol 2003;5:69-77 |
| Tumor treatment improves neurological outcome | Class II-III | Dalmau J et al. Brain 2004;127:1831-1844 |
| Rituximab for refractory paraneoplastic syndromes | Class IV, Case Series | Shams'ili S et al. J Neurol 2006;253:1624-1629 |
| Cyclophosphamide for intracellular antibody syndromes | Class IV, Expert Consensus | Dalmau J & Graus F. N Engl J Med 2018 |
| Poor neurological prognosis with intracellular antibodies despite treatment | Class II-III | Graus F et al. Brain 2001;124:1138-1148 |
| Paraneoplastic cerebellar degeneration: irreversible Purkinje cell loss | Class III | Rosenfeld MR et al. Brain 2012;135:1255-1263 |
| Anti-SOX1 as SCLC marker | Class III | Sabater L et al. J Neuroimmunol 2008;201-202:67-72 |
| Anti-KLHL11 and testicular seminoma | Class III | Mandel-Brehm C et al. N Engl J Med 2019;381:47-56 |
| Levetiracetam as preferred ASM in autoimmune/paraneoplastic seizures | Expert Consensus | Britton J. Handb Clin Neurol 2016;133:219-245 |
| Subacute sensory neuronopathy (Denny-Brown syndrome) | Class III | Camdessanche JP et al. J Neurol Neurosurg Psychiatry 2002;73:179-183 |
| Paraneoplastic opsoclonus-myoclonus in adults | Class III | Bataller L et al. Ann Neurol 2001;49:214-219 |
| Ovarian teratoma resection improves anti-NMDAR outcomes | Class II | Titulaer MJ et al. Lancet Neurol 2013;12:157-165 |
| GABA-B encephalitis and SCLC association (~50%) | Class III | Lancaster E et al. Lancet Neurol 2010;9:67-76 |
| Comprehensive review of paraneoplastic neurological syndromes | Expert Review | Dalmau J & Graus F. N Engl J Med 2018;378:840-851 |
CLINICAL DECISION SUPPORT NOTES¶
Antibody Classification and Prognostic Implications¶
Intracellular (Onconeural) Antibodies -- T-cell mediated; poor neurological prognosis:
| Antibody | Primary Syndrome | Most Common Tumor | Neurological Prognosis |
|---|---|---|---|
| Anti-Hu (ANNA-1) | Encephalomyelitis, sensory neuropathy, autonomic neuropathy | SCLC (>90%) | Poor; often progressive despite treatment |
| Anti-Yo (PCA-1) | Cerebellar degeneration | Ovarian, breast cancer | Poor; irreversible Purkinje cell loss |
| Anti-Ri (ANNA-2) | Opsoclonus-myoclonus, brainstem encephalitis | Breast, SCLC | Moderate; some improvement with tumor treatment |
| Anti-CV2/CRMP5 | Encephalomyelitis, neuropathy, chorea, optic neuritis | SCLC, thymoma | Poor to moderate |
| Anti-amphiphysin | Stiff-person syndrome, encephalomyelitis | Breast, SCLC | Moderate; stiff-person may respond to IVIG |
| Anti-Ma2/Ta | Limbic/diencephalic encephalitis | Testicular germ cell, lung | Moderate; improves with tumor resection (young males) |
Cell-Surface Antibodies -- Antibody-mediated; better treatment response:
| Antibody | Primary Syndrome | Paraneoplastic Tumor (if any) | Neurological Prognosis |
|---|---|---|---|
| Anti-NMDAR | Encephalitis (psychosis, seizures, dyskinesias) | Ovarian teratoma (~40% females) | Good with immunotherapy + tumor resection |
| Anti-LGI1 | Limbic encephalitis, FBDS, hyponatremia | Thymoma (~5-10%) | Good with immunotherapy |
| Anti-CASPR2 | Limbic encephalitis, Morvan syndrome, neuromyotonia | Thymoma (~20-30%) | Good with immunotherapy |
| Anti-GABA-B | Limbic encephalitis with seizures | SCLC (~50%) | Moderate; depends on tumor response |
| Anti-AMPAR | Limbic encephalitis (relapsing) | Thymoma, lung, breast | Moderate; tends to relapse |
| Anti-VGCC (P/Q) | LEMS, cerebellar degeneration | SCLC (~60% of LEMS) | LEMS: good with treatment; cerebellar: poor |
Key Clinical Principles¶
- Neurological symptoms often precede cancer diagnosis -- in up to 70% of PNS cases, the neurological syndrome is the presenting feature
- Treat the tumor first -- tumor-directed therapy (surgery, chemotherapy, radiation) is the most important intervention for neurological improvement
- Cell-surface > intracellular for treatment response -- syndromes mediated by cell-surface antibodies are more responsive to immunotherapy
- Repeat cancer screening -- if initial screen is negative but paraneoplastic antibody is positive, repeat imaging q6 months for at least 2 years (up to 4 years for high-risk antibodies)
- Do NOT wait for antibody results -- if clinical suspicion is high, initiate immunotherapy empirically
- Multidisciplinary approach -- neurology, oncology, rehabilitation, and supportive care are all essential
Tumor Screening Protocol Summary¶
| If antibody positive... | Primary screen | Secondary screen | Repeat if negative |
|---|---|---|---|
| Anti-Hu, Anti-CV2 | CT chest | FDG-PET/CT | q6 months x 4 years |
| Anti-Yo | CT abdomen/pelvis, pelvic US | Mammography, FDG-PET/CT | q6 months x 2 years |
| Anti-Ri | Mammography, CT chest | FDG-PET/CT | q6 months x 4 years |
| Anti-amphiphysin | Mammography, CT chest | FDG-PET/CT | q6 months x 4 years |
| Anti-Ma2 (males <50) | Testicular US | CT chest, FDG-PET/CT | q6 months x 4 years |
| Anti-Ma2 (older) | CT chest | FDG-PET/CT | q6 months x 4 years |
| Anti-KLHL11 | Testicular US | FDG-PET/CT | Repeat if relapse |
| Anti-NMDAR (females) | Pelvic MRI or US | CT chest/abdomen/pelvis | q6 months x 2 years |
| Anti-GABA-B | CT chest | FDG-PET/CT | q6 months x 4 years |
| Anti-VGCC (with LEMS) | CT chest | FDG-PET/CT; DELTA-P score | q6 months x 4 years |
| Anti-SOX1 | CT chest | FDG-PET/CT | q6 months x 4 years |
CHANGE LOG¶
v1.1 (January 30, 2026)
- Standardized all dosing fields across Sections 3A, 3B, 3C, 3D to structured format: [standard_dose] :: [route] :: [frequency] :: [full_instructions]
- Fixed empty frequency fields in dosing format (all medications now have populated frequency field)
- Removed multiple dose tiers from standard_dose field; starting dose used as standard_dose with titration in instructions
- Added CPT code for uric acid (CPT 84550) in Section 1A
- Added ICU column to Section 4B (Patient/Family Instructions) and Section 4C (Lifestyle & Prevention) for table consistency
- Fixed cross-reference "Same as PET/CT" in Section 2C FDG-PET brain row; replaced with explicit contraindications
- Fixed cross-reference "Same as first-line PLEX" in Section 3C Repeated PLEX row; replaced with explicit monitoring parameters
- Corrected Section 3D Oral prednisone row: moved contraindications from Pre-Treatment Requirements to Contraindications column; added proper pre-treatment requirements
- Corrected Section 3D Calcium + Vitamin D row: moved contraindications from Pre-Treatment Requirements to Contraindications column; added proper pre-treatment requirements
- Added aspiration precautions and repositioning to ICU setting in Section 4C
- Updated version to 1.1
v1.0 (January 30, 2026) - Initial template creation - Section 1: 21 core labs (1A), 20 paraneoplastic antibody panel tests (1B), 12 rare/specialized tests (1C) - Section 2: 6 essential imaging/studies (2A), 7 extended (2B), 6 rare/specialized (2C), 16 LP/CSF studies - Section 3: 4 subsections: - 3A: 6 acute/emergent treatments (IV methylprednisolone, GI prophylaxis, insulin, IVIG, PLEX, lorazepam) - 3B: 13 symptomatic treatments (ASMs, neuropathic pain, stiff-person, vestibular, nausea, mood, sleep) - 3C: 6 second-line/refractory agents (rituximab, cyclophosphamide, oral prednisone taper, repeated IVIG, repeated PLEX, tocilizumab) - 3D: 6 disease-modifying/long-term immunosuppression agents with pre-treatment requirements (rituximab maintenance, mycophenolate, azathioprine, low-dose prednisone, IVIG maintenance, calcium/vitamin D) - Section 4: 19 referrals (4A), 14 patient/family instructions (4B), 10 lifestyle/prevention measures (4C) - Section 5: 16 differential diagnoses with distinguishing features - Section 6: 14 acute monitoring parameters (6A), 14 outpatient/long-term monitoring parameters (6B) - Section 7: 7 disposition criteria - Section 8: 26 evidence references with PubMed links - Clinical Decision Support Notes: Antibody classification tables (intracellular vs cell-surface), key clinical principles, tumor screening protocol summary