Encephalopathy, Autoimmune/Paraneoplastic Evaluation, Spinal Fluid

Message

This test is designed for patients age 18 and older. If your patient is under age 18, and you suspect an autoimmune neurological disorder, we recommend PCDEC (Pediatric Autoimmune Encephalopathy/CNS Disorder Evaluation, Spinal Fluid). Please consult our Neurology specialty website for more information.

Test Code

ENC2

Alias/See Also

Epic: LAB15753
Mayo: ENC2

CPT Codes
86255 x21 86341 x1 84182 AGNBC (if appropriate) 86256 AGNTC (if appropriate) 86255 AINCC (if appropriate) 86256 AMPIC (if appropriate) 84182 AMIBC (if appropriate) 84182 AN1BC (if appropriate) 86256 AN1TC (if appropriate) 84182 AN2BC (if appropriate) 86256 AN2TC (if appropriate) 86256 AN3TC (if appropriate) 86256 APHTC (if appropriate) 86256 CRMTC (if appropriate) 84182 CRMWC (if appropriate) 86255 DPPCC (if appropriate) 86256 DPPTC (if appropriate) 86256 GABIC (if appropriate) 86255 GFACC (if appropriate) 86256 GFATC (if appropriate) 86255 IG5CC (if appropriate) 86256 IG5TC (if appropriate) 86255 GL1CC (if appropriate) 86256 GL1TC (if appropriate) 86255 NCDCC (if appropriate) 86256 NCDTC (if appropriate) 86255 NFHCC (if appropriate) 86256 NIFTC (if appropriate) 86255 NFLCC (if appropriate) 86256 NMDIC (if appropriate) 84182 PC1BC (if appropriate) 86256 PC1TC (if appropriate) 86256 PC2TC (if appropriate) 84182 PCTBC (if appropriate) 86256 PCTTC (if appropriate) 86255 SP7CC (if appropriate) 86256 SP7TC (if appropriate)

Includes

PROFILE INFORMATION

Test Id	Reporting Name	Available Separately	Always Performed
AEECI	Encephalopathy, Interpretation, CSF	No	Yes
AMPCC	AMPA-R Ab CBA, CSF	No	Yes
AMPHC	Amphiphysin Ab, CSF	No	Yes
AGN1C	Anti-Glial Nuclear Ab, Type 1	No	Yes
ANN1C	Anti-Neuronal Nuclear Ab, Type 1	No	Yes
ANN2C	Anti-Neuronal Nuclear Ab, Type 2	No	Yes
ANN3C	Anti-Neuronal Nuclear Ab, Type 3	No	Yes
CS2CC	CASPR2-IgG CBA, CSF	No	Yes
CRMC	CRMP-5-IgG, CSF	No	Yes
DPPIC	DPPX Ab IFA, CSF	No	Yes
GABCC	GABA-B-R Ab CBA, CSF	No	Yes
GD65C	GAD65 Ab Assay, CSF	Yes	Yes
GFAIC	GFAP IFA, CSF	No	Yes
IG5IC	IgLON5 IFA, CSF	No	Yes
LG1CC	LGI1-IgG CBA, CSF	No	Yes
GL1IC	mGluR1 Ab IFA, CSF	No	Yes
NCDIC	Neurochondrin IFA, CSF	No	Yes
NIFIC	NIF IFA, CSF	No	Yes
NMDCC	NMDA-R Ab CBA, CSF	No	Yes
PCTRC	Purkinje Cell Cytoplasmc Ab Type Tr	No	Yes
PCA1C	Purkinje Cell Cytoplasmic Ab Type 1	No	Yes
PCA2C	Purkinje Cell Cytoplasmic Ab Type 2	No	Yes
SP7IC	Septin-7 IFA, CSF	No	Yes

REFLEX TESTS

Test Id	Reporting Name	Available Separately	Always Performed
AGNBC	AGNA-1 Immunoblot, CSF	No	No
AINCC	Alpha Internexin CBA, CSF	No	No
AMPIC	AMPA-R Ab IF Titer Assay, CSF	No	No
AMIBC	Amphiphysin Immunoblot, CSF	No	No
AN1BC	ANNA-1 Immunoblot, CSF	No	No
AN2BC	ANNA-2 Immunoblot, CSF	No	No
CRMWC	CRMP-5-IgG Western Blot, CSF	Yes	No
DPPCC	DPPX Ab CBA, CSF	No	No
DPPTC	DPPX Ab IFA Titer, CSF	No	No
GABIC	GABA-B-R Ab IF Titer Assay, CSF	No	No
GFACC	GFAP CBA, CSF	No	No
GFATC	GFAP IFA Titer, CSF	No	No
IG5CC	IgLON5 CBA, CSF	No	No
IG5TC	IgLON5 IFA Titer, CSF	No	No
GL1CC	mGluR1 Ab CBA, CSF	No	No
GL1TC	mGluR1 Ab IFA Titer, CSF	No	No
NFHCC	NIF Heavy Chain CBA, CSF	No	No
NIFTC	NIF IFA Titer, CSF	No	No
NFLCC	NIF Light Chain CBA, CSF	No	No
NMDIC	NMDA-R Ab IF Titer Assay, CSF	No	No
PC1BC	PCA-1 Immunoblot, CSF	No	No
PCTBC	PCA-Tr Immunoblot, CSF	No	No
AGNTC	AGNA-1 Titer, CSF	No	No
AN1TC	ANNA-1 Titer, CSF	No	No
AN2TC	ANNA-2 Titer, CSF	No	No
AN3TC	ANNA-3 Titer, CSF	No	No
APHTC	Amphiphysin Ab Titer, CSF	No	No
CRMTC	CRMP-5-IgG Titer, CSF	No	No
NCDCC	Neurochondrin CBA, CSF	No	No
NCDTC	Neurochondrin IFA Titer, CSF	No	No
PC1TC	PCA-1 Titer, CSF	No	No
PC2TC	PCA-2 Titer, CSF	No	No
PCTTC	PCA-Tr Titer, CSF	No	No
SP7CC	Septin-7 CBA, CSF	No	No
SP7TC	Septin-7 IFA Titer, CSF	No	No

TESTING ALGORITHM

If client requests or if the immunofluorescence (IFA) patterns suggest collapsin response-mediator protein-5-IgG (CRMP-5-IgG), then CRMP-5-IgG IFA titer and CRMP-5-IgG Western blot will be performed at an additional charge.

If the IFA patterns suggest amphiphysin antibody, then amphiphysin IFA titer and amphiphysin immunoblot will be performed at an additional charge.

If the IFA pattern suggests antiglial nuclear antibody (AGNA-1), then AGNA-1 IFA titer and AGNA-1 immunoblot will be performed at an additional charge.

If the IFA pattern suggests antineuronal nuclear antibody type 1 (ANNA-1), then ANNA-1 IFA titer, ANNA-1 immunoblot, and ANNA-2 immunoblot will be performed at an additional charge.

If the IFA pattern suggests ANNA-2 antibody, then ANNA-2 IFA titer, ANNA-1 immunoblot, and ANNA-2 immunoblot will be performed at an additional charge.

If the IFA pattern suggests Purkinje cytoplasmic antibody type 1 (PCA-1), then PCA-1 IFA titer and PCA-1 immunoblot will be performed at an additional charge.

If the IFA pattern suggests PCA-2 antibody, then PCA-2 IFA titer will be performed at an additional charge.

If the IFA pattern suggests PCA-Tr antibody, then PCA-Tr IFA titer and PCA-Tr immunoblot will be performed at an additional charge.

If the IFA pattern suggests IgLON5 antibody, then IgLON5 IFA titer and IgLON5 cell-binding assay (CBA) will be performed at an additional charge.

If AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor antibody CBA is positive, then AMPA-receptor antibody IFA titer assay will be performed at an additional charge.

If gamma-aminobutyric acid B (GABA-B) receptor antibody CBA is positive, then GABA-B-receptor antibody IFA titer assay will be performed at an additional charge.

If the IFA pattern suggests glial fibrillary acidic protein (GFAP) antibody, then GFAP IFA titer and GFAP CBA will be performed at an additional charge.

If N-methyl-D-aspartate (NMDA) receptor antibody CBA is positive, then NMDA-receptor antibody IFA titer assay will be performed at an additional charge.

If the IFA pattern suggests dipeptidyl-peptidase-like protein-6 (DPPX) antibody, then DPPX antibody CBA and DPPX IFA titer will be performed at an additional charge.

If the IFA pattern suggests metabotropic glutamate receptor 1 (mGluR1) antibody, then mGluR1 antibody CBA and mGluR1 IFA titer will be performed at an additional charge.

If the IFA pattern suggests neuronal intermediate filament (NIF) antibody, then alpha internexin CBA, NIF heavy chain CBA, NIF light chain CBA, and NIF IFA titer will be performed at an additional charge.

If the IFA pattern suggests neurochondrin antibody, then neurochondrin antibody CBA and neurochondrin IFA titer will be performed at an additional charge.

If the IFA pattern suggests septin-7 antibody, then septin-7 antibody CBA and septin-7 IFA titer will be performed at an additional charge.

For more information, see the following algorithms:
Autoimmune/Paraneoplastic Encephalopathy Evaluation Algorithm-Spinal Fluid
Central Nervous System Demyelinating Disease Diagnostic Algorithm
Meningitis/Encephalitis Panel Algorithm

Preferred Specimen

Specimen Type: Spinal fluid
Collection Container: Sterile container
Specimen Volume: 4 mL

Minimum Volume

2 mL

Transport Container

Sterile container

Specimen Stability

Specimen Type	Temperature	Time
CSF	Refrigerated (preferred)	28 days
	Frozen	28 days
	Ambient	72 hours

Reject Criteria (Eg, hemolysis? Lipemia? Thaw/Other?)

Gross hemolysis	Reject
Gross lipemia	Reject
Gross icterus	Reject

Methodology
AGN1C, AGNTC, AMPIC, AMPHC, APHTC, ANN1C, AN1TC, ANN2C, AN2TC, ANN3C, AN3TC, CRMTC, CRMC, DPPIC, DPPTC, GABIC, GFAIC, GFATC, IG5IC, IG5TC, GL1IC, GL1TC, NCDIC, NCDTC, NIFIC, NIFTC, NMDIC, PCA1C, PC1TC, PCA2C, PC2TC, PCTRC, PCTTC, SP7IC, SP7TC: Indirect Immunofluorescence Assay (IFA)

AMPCC, CS2CC, DPPCC, GABCC, GFACC, IG5CC, LG1CC, GL1CC, NCDCC, AINCC, NFLCC, NFHCC, NMDCC, SP7CC: Cell Binding Assay (CBA)

CRMWC: Western Blot (WB)

AGNBC, AMIBC, AN1BC, AN2BC, PC1BC, PCTBC: Immunoblot (IB)

GD65C: Radioimmunoassay (RIA)

Setup Schedule

Profile tests: Monday through Sunday; Reflex tests: Varies

Report Available

8 to 12 days

Limitations

CAUTIONS

Negative results do not exclude autoimmune encephalopathy or cancer.

This test does not detect Ma1 or Ma2 antibodies (also known as MaTa), which are sometimes associated with brainstem and limbic encephalitis in the context of testicular germ cell neoplasms. Scrotal ultrasound is advised for men who present with unexplained subacute encephalitis.

Reference Range

Test ID	Reporting name	Methodology	Reference value
AEECI	Encephalopathy, Interpretation, CSF	Medical interpretation	NA
AMPCC	AMPA-R Ab CBA, CSF	CBA	Negative
AMPHC	Amphiphysin Ab, CSF	IFA	Negative
AGN1C	Anti-Glial Nuclear Ab, Type 1	IFA	Negative
ANN1C	Anti-Neuronal Nuclear Ab, Type 1	IFA	Negative
ANN2C	Anti-Neuronal Nuclear Ab, Type 2	IFA	Negative
ANN3C	Anti-Neuronal Nuclear Ab, Type 3	IFA	Negative
CS2CC	CASPR2-IgG CBA, CSF	CBA	Negative
CRMC	CRMP-5-IgG, CSF	IFA	Negative
DPPIC	DPPX Ab IFA, CSF	IFA	Negative
GABCC	GABA-B-R Ab CBA, CSF	CBA	Negative
GD65C	GAD65 Ab Assay, CSF	RIA	< or =0.02 nmol/L Reference values apply to all ages.
GFAIC	GFAP IFA, CSF	IFA	Negative
IG5IC	IgLON5 IFA, CSF	IFA	Negative
LG1CC	LGI1-IgG CBA, CSF	CBA	Negative
NCDIC	Neurochondrin IFA, CSF	IFA	Negative
GL1IC	mGluR1 Ab IFA, CSF	IFA	Negative
NIFIC	NIF IFA, CSF	IFA	Negative
NMDCC	NMDA-R Ab CBA, CSF	CBA	Negative
PCTRC	Purkinje Cell Cytoplasmc Ab Type Tr	IFA	Negative
PCA1C	Purkinje Cell Cytoplasmic Ab Type 1	IFA	Negative
PCA2C	Purkinje Cell Cytoplasmic Ab Type 2	IFA	Negative
SP7IC	Septin-7 IFA, CSF	IFA	Negative

Reflex Information:

Test ID	Reporting name	Methodology	Reference value
AGNBC	AGNA-1 Immunoblot, CSF	IB	Negative
AGNTC	AGNA-1 Titer, CSF	IFA	<1:2
AINCC	Alpha Internexin CBA, CSF	CBA	Negative
AMPIC	AMPA-R Ab IF Titer Assay, CSF	IFA	<1:2
AMIBC	Amphiphysin Immunoblot, CSF	IB	Negative
AN1BC	ANNA-1 Immunoblot, CSF	IB	Negative
AN1TC	ANNA-1 Titer, CSF	IFA	<1:2
AN2BC	ANNA-2 Immunoblot, CSF	IB	Negative
AN2TC	ANNA-2 Titer, CSF	IFA	<1:2
AN3TC	ANNA-3 Titer, CSF	IFA	<1:2
APHTC	Amphiphysin Ab Titer, CSF	IFA	<1:2
CRMTC	CRMP-5-IgG Titer, CSF	IFA	<1:2
CRMWC	CRMP-5-IgG Western Blot, CSF	WB	Negative
DPPCC	DPPX Ab CBA, CSF	CBA	Negative
DPPTC	DPPX Ab IFA Titer, CSF	IFA	<1:2
GABIC	GABA-B-R Ab IF Titer Assay, CSF	IFA	<1:2
GFACC	GFAP CBA, CSF	CBA	Negative
GFATC	GFAP IFA Titer, CSF	IFA	<1:2
IG5CC	IgLON5 CBA, CSF	CBA	Negative
IG5TC	IgLON5 IFA Titer, CSF	IFA	<1:2
GL1CC	mGluR1 Ab CBA, CSF	CBA	Negative
GL1TC	mGluR1 Ab IFA Titer, CSF	IFA	<1:2
NCDCC	Neurochondrin CBA, CSF	CBA	Negative
NCDTC	Neurochondrin IFA Titer, CSF	IFA	<1:2
NFLCC	NIF Light Chain CBA, CSF	CBA	Negative
NIFTC	NIF IFA Titer, CSF	IFA	<1:2
NMDIC	NMDA-R Ab IF Titer Assay, CSF	IFA	<1:2
PC1BC	PCA-1 Immunoblot, CSF	IB	Negative
PC1TC	PCA-1 Titer, CSF	IFA	<1:2
PC2TC	PCA-2 Titer, CSF	IFA	<1:2
PCTBC	PCA-Tr Immunoblot, CSF	IB	Negative
PCTTC	PCA-Tr Titer, CSF	IFA	<1:2
SP7CC	Septin-7 CBA, CSF	CBA	Negative
SP7IC	Septin-7 IFA Titer, CSF	IFA	<1:2

*Methodology abbreviations:
Immunofluorescence assay (IFA)
Cell-binding assay (CBA)
Western blot (WB)
Radioimmunoassay (RIA)
Immunoblot (IB)

Neuron-restricted patterns of IgG staining that do not fulfill criteria for ANNA-1, ANNA-2, ANNA-3, CRMP-5-IgG, PCA-1, PCA-2, or PCA-Tr may be reported as "unclassified anti-neuronal IgG." Complex patterns that include nonneuronal elements may be reported as "uninterpretable."

Note: CRMP-5 titers lower than 1:2 are detectable by recombinant CRMP-5 Western blot analysis. CRMP-5 Western blot analysis will be done on request on stored spinal fluid (held 4 weeks). This supplemental testing is recommended in cases of chorea, vision loss, cranial neuropathy, and myelopathy. Call the Neuroimmunology Laboratory at 800-533-1710 to request CRMP-5 Western blot.

INTERPRETATION

Neuronal, glial, and muscle autoantibodies are valuable serological markers of autoimmune encephalopathy and of a patient's immune response to cancer. These autoantibodies are usually accompanied by subacute neurological symptoms and signs are not found in healthy subjects. It is not uncommon for more than 1 of the following autoantibody specificities to be detected in patients with an autoimmune encephalopathy:
-Plasma membrane autoantibodies: These are all potential effectors of neurological dysfunction: N-methyl-D-aspartate (NMDA) receptor; 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl) propanoic acid (AMPA) receptor; gamma-amino butyric acid (GABA-B) receptor; neuronal ACh receptor.
-Neuronal nuclear autoantibodies: type 1 (ANNA-1), type 2 (ANNA-2), or type 3 (ANNA-3)
-Neuronal or muscle cytoplasmic antibodies: amphiphysin, Purkinje cell antibodies (PCA-1 and PCA-2), collapsin response-mediator protein-5 (CRMP-5), or glutamic acid decarboxylase (GAD65).

Clinical Significance

USEFUL FOR

Evaluating new onset encephalopathy (noninfectious or metabolic) comprising confusional states, psychosis, delirium, memory loss, hallucinations, movement disorders, sensory or motor complaints, seizures, dyssomnias, ataxias, nausea, vomiting, inappropriate antidiuresis, coma, dysautonomias, or hypoventilation using spinal fluid specimens

The following accompaniments should increase of suspicion for autoimmune encephalopathy:
-Headache
-Autoimmune stigmata (personal or family history or signs of diabetes mellitus, thyroid disorder, vitiligo, poliosis [premature graying], myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus)
-History of cancer
-Smoking history (20 or more pack-years) or other cancer risk factors
-Inflammatory cerebrospinal fluid (or isolated protein elevation)
-Neuroimaging signs suggesting inflammation

Evaluating limbic encephalitis (noninfectious)

Directing a focused search for cancer

Investigating encephalopathy appearing during or after cancer therapy and not explainable by metastasis or drug effect

CLINICAL INFORMATION

Autoimmune encephalopathies extend beyond the classically recognized clinical and radiological spectrum of "limbic encephalitis." They encompass a diversity of neurological presentations with subacute or insidious onset, including confusional states, psychosis, delirium, memory loss, hallucinations, movement disorders, sensory or motor complaints, seizures, dyssomnias, ataxias, eye movement problems, nausea, vomiting, inappropriate antidiuresis, coma, dysautonomias, or hypoventilation. A diagnosis of autoimmune encephalopathy should be suspected based on the clinical course, coexisting autoimmune disorder (eg, thyroiditis, diabetes), serological evidence of autoimmunity, spinal fluid evidence of intrathecal inflammation, neuroimaging or electroencephalographic abnormalities, and favorable response to trial of immunotherapy.

Detection of one or more neural autoantibodies aids the diagnosis of autoimmune encephalopathy and may guide a search for cancer. Pertinent autoantibody specificities include:
-Neurotransmitter receptors and ion channels such as neuronal voltage-gated potassium channels (and interacting synaptic and axonal proteins, leucine-rich glioma inactivated 1 [LGI1] protein and contactin associated protein 2 [CASPR2]), ionotropic glutamate receptors (N-methyl-D-aspartate receptor [NMDA] and 2-amino-3-[5-methyl-3-oxo-1,2- oxazol-4-yl] propanoic acid [AMPA]), metabotropic gamma-aminobutyric acid (GABA)-B receptors
-Enzymes, signaling molecules, and RNA-regulatory proteins in the cytoplasm and nucleus of neurons (glutamic acid decarboxylase 65 [GAD65], collapsin response-mediator protein-5 neuronal [CRMP-5], antineuronal nuclear antibody-type 1 [ANNA-1], and ANNA-2)

Importantly, autoimmune encephalopathies are reversible. Misdiagnosis as a progressive (currently irreversible) neurodegenerative condition is not uncommon and has devastating consequences for the patient. Clinicians must consider the possibility of an autoimmune etiology in the differential diagnoses of encephalopathy. For example, a potentially reversible disorder justifies a trial of immunotherapy for the detection of neural autoantibodies in patients presenting with symptoms of personality change, executive dysfunction, and psychiatric manifestations.

A triad of clues helps to identify patients with an autoimmune encephalopathy:
1) Clinical presentation (subacute symptoms, onset rapidly progressive course, and fluctuating symptoms) and radiological findings consistent with inflammation
2) Detection of neural autoantibodies in serum or cerebrospinal fluid (CSF)
3) Favorable response to a trial of immunotherapy

Detection of neural autoantibodies in serum or CSF informs the physician of a likely autoimmune etiology, may heighten suspicion for a paraneoplastic basis, and guide the search for cancer. Neurological accompaniments of neural autoantibodies are generally not syndromic but diverse and multifocal. For example, LGI1 antibody was initially considered to be specific for autoimmune limbic encephalitis, but, over time, other presentations have been reported, including rapidly progressive course of cognitive decline mimicking neurodegenerative dementia. Comprehensive antibody testing is more informative than selective testing for 1 or 2 neural antibodies. Some antibodies strongly predict an underlying cancer. For example, small-cell lung carcinoma (ANNA-1, CRMP-5-IgG), ovarian teratoma (NMDA-R), and thymoma (CRMP-5 IgG).

An individual patient's profile autoantibody may be informative for a specific cancer type. For example, in a patient presenting with encephalitis who has CRMP 5 IgG, and subsequent testing reveals muscle acetylcholine receptor (AChR) binding antibody, the findings should raise a high suspicion for thymoma. Testing of CSF for autoantibodies is particularly helpful when serum testing is negative, though in some circumstances testing both serum and CSF simultaneously is pertinent. Testing of CSF is recommended for some antibodies in particular (such as NMDA-R antibody and glial fibrillary acidic protein [GFAP]-IgG) because CSF testing is both more sensitive and specific. In contrast, serum testing for LGI1 antibody is more sensitive than CSF testing.

Performing Laboratory
Mayo Clinic Laboratories - Rochester
3050 Superior Drive NW
Rochester, MN 55901

Additional Information
Encephalopathy, Autoimmune/Paraneoplastic Evaluation, Spinal Fluid

Last Updated: August 17, 2023
Last Review: N. Wolford, August 17, 2023

The CPT Codes provided in this document are based on AMA guidelines and are for informational purposes only. CPT coding is the sole responsibility of the billing party. Please direct any questions regarding coding to the payor being billed. Any Profile/panel component may be ordered separately. Reflex tests are performed at an additional charge.