Paraneoplastic Neurological Syndrome¶
VERSION: 1.1 CREATED: January 30, 2026 REVISED: January 30, 2026 STATUS: Approved
DIAGNOSIS: Paraneoplastic Neurological Syndrome
ICD-10: G13.0 (Paraneoplastic neuromyopathy and neuropathy), G13.1 (Other systemic atrophy primarily affecting CNS in neoplastic disease)
CPT CODES: 85025 (CBC with differential), 80053 (CMP (BMP + LFTs)), 85652 (ESR), 86140 (CRP), 84443 (TSH), 82947 (Blood glucose), 83036 (HbA1c), 83615 (LDH), 83735 (Magnesium), 84100 (Phosphorus), 87040 (Blood cultures (x2 sets)), 83605 (Lactate), 84145 (Procalcitonin), 82140 (Ammonia), 80307 (Urine drug screen), 81025 (Pregnancy test (females of childbearing age)), 84484 (Troponin), 82550 (CPK), 84550 (Uric acid), 86255 (Anti-Hu (ANNA-1) antibody (serum AND CSF)), 86235 (Anti-LGI1 antibody (serum AND CSF)), 86334 (Serum protein electrophoresis (SPEP) with immunofixation), 70450 (CT head without contrast), 70553 (MRI brain with and without contrast), 71260 (CT chest with contrast), 74178 (CT abdomen/pelvis with contrast), 71046 (Chest X-ray), 93000 (ECG (12-lead)), 78816 (FDG-PET/CT (whole body)), 72156 (MRI spine with and without contrast), 95816 (EEG (routine or continuous)), 95937 (Repetitive nerve stimulation (RNS)), 89051 (Cell count with differential (tubes 1 and 4)), 84157 (Protein), 82945 (Glucose with paired serum glucose), 87529 (HSV 1/2 PCR), 83916 (Oligoclonal bands (CSF AND paired serum)), 88104 (Cytology), 86592 (VDRL (CSF)), 87116 (AFB culture and smear)
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