Table 1

Investigations/diagnoses to be considered

ScreenDisease/agent tested
Section 1:
initial workup
Recommended in most or all patients:
Whole blood/serum: full blood count, bacterial and fungal cultures, RPR-VDRL, HIV-1/2 immunoassay with confirmatory viral load if appropriate.
Serum: IgG and IgM testing (acute and convalescent) for Chlamydia pneumoniae, Bartonella henselae, Mycoplasma pneumoniae, Coxiella burnetii, shigella species and Chlamydia psittaci.
Nares or nasopharyngeal swab (the latter preferred): respiratory viral direct fluorescent antibody panel; SARS-CoV-2 PCR.
Cell counts, protein and glucose, bacterial and fungal stains and cultures.
RT-PCR for HIV, PCR for HSV1, HSV2, varicella zoster virus, Epstein-Barr virus, M.Tb; consider Western Nile virus, VDRL, encephalitis panel.
PCR for Chlamydia pneumoniae and Chlamydia psittaci, Bartonella henselae, Mycoplasma pneumoniae, Coxiella burnetii and shigella species.
Autoimmune epilepsy panel (see section 2).
Consider metagenomics for any non-human nucleic acid material.
Consider cytokine profile (section 7).
Consider cytology and flow cytometry.
Recommended in immunocompromised patients:
Serum: IgG cryptococcus species, IgM and IgG Histoplasma capsulatum, IgG Toxoplasma gondii.
Sputum: M Tb gene Xpert.
CSF: eosinophils, silver stain for CNS fungi, PCR for JC virus, cytomegalovirus, Epstein-Barr virus, HHV6, eastern equine encephalitis, enterovirus, influenza A/B, HIV, Western Nile virus, parvovirus. listeria, measles (rubeola).
Stool: adenovirus PCR, enterovirus PCR.
Recommended if geographic/seasonal/occupational risk of exposure:
  • Serum buffy coat and peripheral smear.

  • Lyme enzyme immunoassay with IgM and IgG reflex.

  • Hepatitis C immunoassay and viral load if appropriate.

  • Send further serum and CSF samples to CDC DVBID Arbovirus Diagnostic Laboratory, CSF and serum rickettsial disease panel, flavivirus panel, bunyavirus panel.

  • Serum testing for acanthamoeba spp, Balamuthia mandrillaris, Baylisascaris procyonis.

  • Other.

Consider CSF metagenomics for any infectious genetic material.
Optional: see attached Table 2 for further geographical/zoonotic risk factors.
Section 2:
auto-immune/ paraneoplastic
Serum and CSF paraneoplastic and autoimmune epilepsy antibody panel.
To include antibodies to: LGI-1, CASPR2, Ma1, Ma2/TaDPPX, GAD65, NMDA, AMPA, GABA-B, GABA-A, glycine receptor, 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 Ab, PQ-type calcium channel, acetylcholine receptor (muscle) binding Ab, Ach-R ganglionic neuronal Ab, AQP4, MOG Ab, IgLON5 Ab, D2R Ab.
Additional serological studies-serum.
(likely not pathogenic but hint towards an autoimmune cause)
ANA (detection and identification), ANCA, anti-thyroid antibodies (anti-thyroglobulin, anti-TPO), anti-endomysial, ESR, C reactive protein, SPEP, IFE, RA, ACE, cold and warm agglutinins, tests for MAS/HLH (serum triglycerides and sIL2-r, ferritin).
Suggestion: store extra frozen CSF and serum for possible further autoimmune testing in a research lab.
Section 3: neoplastic Recommended:
CT scan of chest/abdomen/pelvis, pelvic or scrotal ultrasound, mammogram, CSF cytology, flow cytometry, cancer serum markers. Pelvic MR. Whole body PET-CT if above tests are not conclusive.
Optional: bone marrow biopsy.
Section 4: metabolic Recommended:
Whole blood/serum: BUN/Cr, LDH, liver function tests, electrolytes, Ca/Mg/Phosphate, ammonia.
Urine: porphyria screen (spot urine), UA with microscopic urinalysis.
Consider: vitamin B1 level, B12 level, homocysteine, folate, lactate, pyruvate, CK, troponin; tests for mitochondrial disorder (lactate, pyruvate, MR spectroscopy, muscle biopsy).
Section 5: toxicological Recommended:
Benzodiazepines, amphetamines, cocaine, fentanyl, alcohol, ecstasy, heavy metals, synthetic cannabinoids, bath salts.
Consider: extended opiate and overdose panel, LSD, heroin, PCP, marijuana.
Section 6:
Consider: obtain genetics consult, if possible. Genetic screens for mitochondrial disorders (MERRF, MELAS, POLG1, SURF1, MT-ATP6) and VLCFA screen. Consider ceruloplasmin and 24-hour urinary copper.
Consider mendeliome or whole exome sequencing (also look for gene polymorphisms in IL-1B, IL-6, IL-10, TNF-alpha, HMBG1, TLR4, IL1RN, SCN1A and SCN2A), mitochondrial genome sequencing and CGH array.
Section 7: cytokine assay Serum and CSF: cytokine assay for quantitative measure of IL‐1β, IL-1Ra, IL‐2, IL‐4, IL‐5, IL‐6, IL‐10, IL‐12, IL-17, granulocyte‐macrophage colony stimulating factor, tumour necrosis factor‐α, HMGB1, CCL2, CXCL8, CXCL9, CXCL10, CXCL11.
  • Adapted with permission from the NORSE Institute. See for additional information and tables and future updates. Table 1 is from the last update of September 2020.

  • CSF, cerebrospinal fluid; IL, interleukin; TNF, tumour necrosis factor.