Table 1.

List of heterogeneous etiologies of NORSE/FIRES and the diagnostic tests to consider (4, 8, 9, 11–26).

Section 1: Initial metabolic/infectious work up

Blood: CBC, BMP, LFT, BUN, Electrolytes (Ca, Mg, Phos), ESR, CRP, bacterial and fungal cultures Serum: RPR-VDRL, HIV-1/2 immunoassay with confirmatory viral load if appropriate, PPD placement, IgG and IgM testing for Chlamydia pneumoniae, Bartonella henselae, Mycoplasma pneumonia, Coxiella burnetii, Shigella species, and Chlamydia psittaci Anti-neuronal surface antibody panel and onconeural antibodies (see below) Cytokines (see below) Nares: Respiratory viral DFA panel

Section 2: CSF studies

Cell count and differential count, protein, glucose, lactate and pyruvate (ratio lactate/pyruvate). Bacterial and fungal stains and cultures. PCR for HSV1, HSV2, VZV, EBV, HIV, C. pneumoniae, B. henselae, C.burnetti, C psittaci, Shigella species, VDRL, M Tb PCR. Immunoelectrophoresis/electrofocusing and cytology Anti-neuronal surface antibody panel and onconeural antibodies (see below) Cytokines (see below) Store CSF for metagenomic next-generation sequencing

Section 3: Focused testing for high-risk features

Recommended in immunocompromised patients: Serologic: IgG Cryptococcus species, IgM and IgG Histoplasma capsulatum, IgG Toxoplasma gondii Sputum: M Tb Gene Xpert (molecular test for tuberculosis) CSF: Eosinophils, silver stain for CNS fungi, PCR for JC virus, CMV, EBV, HHV6, EEE, Enterovirus, Influenza A/B, HIV, WNV, Parvovirus. Listeria Ab, Measles (Rubeola), Toxoplasma IgG Stool: Adenovirus PCR, Enterovirus PCR Recommended if geographic/seasonal/occupational risk of exposure: Serum: buffy coat and peripheral smear (for parasitic infections such as malaria, babesiosis, toxoplasmosis etc.), Lyme EIA with IgM and IgG reflex, Acanthamoeba spp., Balamuthia mandrillaris, Baylisascaris procyonis Serum and CSF: samples to CDC DVBID Arbovirus Diagnostic Laboratory, CSF and serum Rickettsial disease panel, Flavivirus panel, Bunyavirus panel Other optional: see attached table for further geographical/zoonotic risk factors

Section 4: Additional zoonotic/geographic exposure considerations

Ingestion: Unpasteurized milk: Tick-borne virus, C. burnetii Star fruit: caramboxin, oxalic acid Geographical factors: (residence, recent travel) Africa: West Nile virus Australia: Murray Valley Encephalitis virus, Japanese Encephalitis virus, Hendra virus, Eastern Equine virus, Western Equine virus, Venezuelian Equine virus Central and South America: Saint-Louis virus, Rickettsia spp. West Nile virus, Tick-borne virus, Ehrlichia chaffeensis/Anaplasma phagocytophilum Europe: Japanese virus West Nile virus India, Nepal: Tick-borne virus Middle East, Russia, Southeast Asia, China, Pacific Rim: Japanese virus, Tick-borne virus, Nipah virus Seasonal factors: Late summer/early fall or winter: arboviruses, enteroviruses, influenza virus Animal exposure: Cats—B. henselae, T. gondii Horses—Eastern Equine virus, Western Equine virus, Venezuelian Equine virus, Hendra virus Raccoons—Baylisascaris procyonis Rodents—Bartonella Quintana, Eastern Equine virus, Western Equine virus, Tick-borne virus, Powassan virus, LaCrosse virus Sheep and goats—C. Burnetii Swine—Japanese virus, Nipah virus Insect exposure, including travel to infested area: Mosquitoes: EEE, WEE, Venezuelan Equine virus, Saint-Louis virus, Murray Valley virus, Japanese virus, West Nile virus, La Crosse virus Tick-borne virus, Powassan virus, Rickettsia spp. Ticks: E. Chaffeensis/A. Phagocytophilum

Section 5: Status epilepticus caused by drugs, toxins, or related to medical intervention

Drugs: Antibiotics: cephalosporins, carbapenems, quinolones isoniazid, mefloquine, chloroquine Antidepressants/antipsychotics: bupropion, tricyclic antidepressants especially amoxapine, selective serotonin reuptake inhibitors, venlafaxine, lithium Chemotherapy: platinum-based agents cytarabine, gemcitabine irinotecan interferon-alpha, interleukin-2 Humanized monoclonal antibodies: bevacizumab, ipilimumab, rituximab, infliximab Tyrosine kinase inhibitors: imatinib, pazopanib, sorafenib, sunitinib, GMCSF, ifosfamide Immunosuppressive and immunomodulatory drugs: cyclosporine, tacrolimus, sirolimus, intravenous immune globulins, anti-TNF-alpha (etanercept), anti-lymphocyte globulin, high-dose steroids, immune checkpoint inhibitors, CAR-T cell related encephalopathy syndrome (CRES) with Chimeric Antigen Related-T cell therapy Other medications: lindane, permethrin, flumazenil, 4-aminopyridine (dalfampridine), sulfasalazine, theophylline, anti-histamines, opiates (morphine, tramadol) Complementary and alternative medicines: Borage oil, neem oil Environmental toxins: Lead, aluminum star fruit (oxalic acid, caramboxin), organophosphates, organochlorines and pyrethroids Biotoxins: Scorpion toxin, anatoxin, ciguatoxin, domoic acid and cyanide Substances: Benzodiazepines, amphetamines, cocaine, fentanyl, alcohol, ecstasy, heavy metals, synthetic cannabinoids, bath salts, LSD, heroin, PCP, marijuana Consider: Extended opiate and overdose panel

Section 6: Neurologic exam

Acute lower motor neuron syndrome: Japanese Encephalitis virus, West Nile virus, Tick-borne virus, Enterovirus (serotype 71, coxsackie) Acute parkinsonism: Japanese virus, Saint-Louis virus, West Nile virus, Nipah virus, T. Gondii Prominent oro-lingual dyskinesias, catatonia, neuropsychiatric and autonomic dysfunction: anti-NMDA receptor encephalitis Facio-brachial dystonic seizures, piloerection, paroxysmal dizzy spells and hyponatremia: anti-LGI-1 encephalitis Stiff person syndrome, hyperekplexia: anti-GAD 65 Mood changes and movement disorder: anti-mGLU-R Sensory neuronopathy/autonomic dysfunction: ANNA-1/anti-Hu Stiff person syndrome, progressive encephalomyelitis with rigidity and myoclonus, transverse myelitis: anti-amphiphysin antibody, anti-glycine Ataxia—Epstein-Barr virus, mitochondrial disorder

Section 7: EEG findings

Extreme delta brush: anti-NMDA receptor encephalitis Frontal-central slow wave contralateral to tonic-dystonic seizures: anti-LGI1 encephalitis Extreme spindles: M. pneumoniae Parieto-occipital epileptiform discharges and seizures: mitochondrial disorder including POLG1, PRES

Section 8: MRI findings

Prominent mesial temporal lobe involvement: paraneoplastic and autoimmune limbic encephalitis, anti-VGKC complex encephalitis (e.g., anti-LGI-1, anti-CASPR2) Basal ganglia: Saint-Louis encephalitis virus, La Crosse virus, Murray Valley virus, acute necrotizing encephalopathy of childhood (RANBP2 mutation) Posterior reversible encephalopathy syndrome (PRES) images: symmetrical cortical and subcortical hyperintense signals on T2 and FLAIR-weighted images in the parieto-occipital lobes of both hemispheres Stroke-like images: POLG1, MELAS

Section 9: Auto-immune/paraneoplastic

Serum and CSF paraneoplastic and autoimmune epilepsy antibody panel: Antibodies to LGI-1, CASPR2, Ma2/Ta, DPPX, GAD65, NMDA, AMPA, GABA-B, GABA-A, glycine receptor, anti-Tr, amphiphysin, CV-2/CRMP-5, Neurexin-3alpha, adenylate kinase, anti-neuronal nuclear antibody types 1/2/3 (Hu, Yo and Ri), Purkinje cell cytoplasmic antibody types 1,2, GFAP-alpha, anti-SOX1, N-type calcium channel Ab, PQ-type calcium channel Other serologies: ANA, ANCA, anti-thyroid antibodies, anti-TG anti-dsDNA, ESR, CRP, ENA, SPEP, IFE, antibodies to Jo-1, Ro, La, Scl-70, RA factor, ACE, anti-endomysium antibodies, cold and warm agglutinins Optional: consider storing extra frozen CSF and serum for possible further autoimmune testing in a research lab Neoplastic: CT chest/abdomen/pelvis, scrotal ultrasound, mammogram, pelvic MRI, CSF cytology and flow cytometry Optional: bone marrow biopsy; whole body PET-CT; cancer serum markers.

Section 10: Metabolic/genetic

Metabolic: See section 1 Ammonia, porphyria screen (spot urine), plasma and CSF lactate and pyruvate Consider: Vitamin B1 level, B12 level, pyridoxine, folate, CPK, troponin; tests for mitochondrial disorder (lactate, pyruvate, MR spectroscopy, muscle biopsy), tests for MAS/HLH (serum triglycerides and sIL2-r) Genetic: Screens for MERRF, MELAS, POLG1 and VLCFA screen. Consider ceruloplasmin and 24-h urine copper Consider whole exome or whole genome sequencing (also look for gene polymorphisms in IL1B, IL6, IL10, TNFA, IL1RN, SCN1A and SCN2A), mitochondrial genome sequencing, CGH array and genetics consult

Section 11: Cytokine assay

Cytokine assay for quantitative measure of-IL-1β, IL-1Ra, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17A, CCL2/MCP-1, CCL3/MIP-1α, granulocyte colony stimulating factor (G-CSF), vascular endothelial growth factor (VEGF) and tumor necrosis factor-α (TNF-α), interferon gamma IFN-g Consider repeating the analyses during SE course