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Test Code LABDMC1 Dementia, Autoimmune Evaluation, Spinal Fluid

Additional Codes

Test Name in EPIC EPIC Test Code Mnemonic Mayo Test ID
DEMENTIA, AUTOIMMUNE EVALUATION, SPINAL FLUID LABDMC1 DMC1 DMC1

 

Useful For

Investigating new onset dementia and cognitive impairment plus 1 or more of the following accompaniments:

Rapid onset and progression

Fluctuating course

Psychiatric accompaniments (psychosis, hallucinations)

Movement disorder (myoclonus, tremor, dyskinesias)

Headache

Autoimmune stigmata (personal history or family history or signs of diabetes mellitus,  thyroid disorder, vitiligo, poliosis [premature graying], myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus)

Smoking history (20+ pack years) or other cancer risk factors

History of cancer

Inflammatory cerebral spinal fluid

Neuroimaging findings atypical for degenerative etiology

Profile Information

Test ID Reporting Name Available Separately Always Performed
ADMCI Dementia, Interpretation, CSF No Yes
NMDCC NMDA-R Ab CBA, CSF No Yes
VGKCC VGKC-complex Ab IPA, CSF No Yes
LG1CC LGI1-IgG CBA, CSF No Yes
CS2CC CASPR2-IgG CBA, CSF No Yes
GD65C GAD65 Ab Assay, CSF Yes Yes
GABCC GABA-B-R Ab CBA, CSF No Yes
AMPCC AMPA-R Ab CBA, CSF 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
AGN1C Anti-Glial Nuclear Ab, Type 1 No Yes
PCA2C Purkinje Cell Cytoplasmic Ab Type 2 No Yes
PCTRC Purkinje Cell Cytoplasmc Ab Type Tr No Yes
AMPHC Amphiphysin Ab, CSF No Yes
CRMC CRMP-5-IgG, CSF No Yes

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
WBNC Paraneoplas Autoantibody WBlot,CSF No No
CRMWC CRMP-5-IgG Western Blot, CSF Yes No
ABLTC Amphiphysin Western Blot, CSF No No
NMOFC NMO/AQP4 FACS, CSF Yes No
NMOTC NMO/AQP4 FACS Titer, CSF No No
AMPIC AMPA-R Ab IF Titer Assay, CSF No No
GABIC GABA-B-R Ab IF Titer Assay, CSF No No
NMDIC NMDA-R Ab IF Titer Assay, CSF No No
PCA1C Purkinje Cell Cytoplasmic Ab Type 1 No No

Testing Algorithm

If indirect immunofluorescence assay (IFA) (ANNA-1, ANNA-2, ANNA-3, PCA-2, PCA-Tr, Amphiphysin, CRMP-5-IgG, AGNA-1) is indeterminate, paraneoplastic autoantibody Western blot is performed at an additional charge.

 

If client requests or if IFA patterns suggest CRMP-5-IgG, CRMP-5-IgG Western blot is performed at an additional charge.

 

If IFA patterns suggest amphiphysin antibody, amphiphysin Western blot is performed at an additional charge.

 

If IFA pattern suggest NMO/AQP4-IgG, NMO/AQP4-IgG FACS is performed at an additional charge.

 

If NMO/AQP4-IgG FACS screen assay requires further investigation, then NMO/AQP4-IgG FACS titration assay is performed at an additional charge.

 

If IFA pattern suggest AMPA-Receptor antibody and AMPA-Receptor antibody CBA is positive, AMPA-Receptor antibody IF titer assay is performed at an additional charge.

 

If IFA pattern suggest GABA-B-Receptor antibody and GABA-B-R Receptor Ab antibody is positive, GABA-B-R Receptor Ab antibody IF titer assay is performed at an additional charge.

 

If IFA pattern suggest NMDA-Receptor antibody and NMDA-Receptor Ab antibody CBA is positive, NMDA-Receptor Ab antibody IF titer assay is performed at an additional charge.

 

If IFA patterns suggest PCA-1, Purkinje Cell Cytoplasmic antibody Type 1 assay is performed at an additional charge.

 

See Dementia Autoimmune Evaluation Algorithm, Spinal Fluid in Special Instructions

Method Name

ANN1C, ANN2C, ANN3C, AGN1C, PCA1C, PCA2C, PCTRC, AMPHC, CRMC, AMPIC, GABIC, NMDIC: Indirect Immunofluorescence Assay (IFA)

AMPCC, GABCC, NMDCC, LG1CC, CS2CC: Cell-Binding Assay (CBA)

GD65C: Immunoprecipitation Assay

VGKCC: Radioimmunoassay Assay (RIA)

WBNC, ABLTC: Western Blot

Reporting Name

Dementia-Autoimmune Evaluation, CSF

Specimen Type

CSF


Necessary Information


Include name, phone number, mailing address, and e-mail address (if applicable) of ordering physician.



Specimen Required


Container/Tube: Sterile vial

Specimen Volume: 4 mL


Specimen Minimum Volume

2 mL

Specimen Stability Information

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

Reject Due To

Hemolysis

Mild OK; Gross reject

Lipemia

Mild OK; Gross reject

Icterus

NA

Other

NA

Clinical Information

The rapid identification of subacute cognitive decline as autoimmune dementia facilitates optimum treatment with immunotherapy and an expedited search for a limited stage of cancer in some patients. Traditionally, neurologists have been reluctant to consider a diagnosis of an autoimmune cognitive disorder in the absence of delirium. However, some recent case series and clinical-serologic observations have suggested a growing appreciation for autoimmune neurologic disorders presenting with features of a rapidly progressive dementia rather than delirium. These disorders can affect all age groups.

 

Unfortunately, these potentially reversible conditions may be misdiagnosed as being progressive neurodegenerative (currently irreversible) disorders, with devastating consequences for the patient. In the evaluation of a patient with cognitive decline, clinicians should consider the possibility of an autoimmune etiology on their list of differential diagnoses. The importance of not overlooking this possibility rests in the experience that these patients have a potentially immunotherapy-responsive, reversible disorder. The development and widespread availability of neural antibody marker testing has changed this perspective so that other presenting symptoms such as personality change, executive dysfunction, and psychiatric symptoms are increasingly recognized in an autoimmune context.

 

Clues that are helpful in identifying patients with an autoimmune dementia can be summarized within a triad of: 1) suspicious clinical features (a subacute onset of symptoms, a rapidly progressive course, and fluctuating symptoms) and radiological findings, 2) the detection of cerebral spinal fluid (CSF) or serological biomarkers of autoimmunity and 3) a response to immunotherapy.

 

Detection of neural autoantibodies in serum or CSF serves 2 purposes; to inform the physician of a likely autoimmune etiology, and to raise suspicion for a paraneoplastic cause. The neurological associations of neural autoantibodies tend to be diverse and multifocal, although certain syndromic associations may apply. For example, neuronal voltage-gated potassium channel (VGKC) antibodies were initially considered to be specific for autoimmune limbic encephalitis or disorders of peripheral nervous hyperexcitability, but over time other presentations have been reported, including rapidly progressive course of cognitive decline mimicking frontotemporal dementia and Creutzfeldt-Jakob disease.

 

Since neurological presentations are often multifocal and diverse, comprehensive antibody testing is usually more informative than testing for 1 or 2 selected antibodies. Some of the antibodies are highly predictive of an unsuspected underlying cancer. For example; small-cell lung carcinoma (antineuronal nuclear antibody-type 1, ANNA-1; collapsin response-mediator protein-5 neuronal, CRMP-5-IgG), ovarian teratoma (N-methyl-D-aspartate receptor, NMDA-R), and thymoma (CRMP-5 IgG).

 

Also, a profile of seropositivity for multiple autoantibodies may be informative for cancer type. For example, in a patient presenting with a rapidly progressive dementia who has muscle acetylcholine receptor (AChR) binding, alpha 3 ganglionic AChR, and CRMP 5 IgG, the findings should raise a high suspicion for thymoma. If an associated tumor is found, its resection or ablation optimizes the neurological outcome.

 

Antibody testing on CSF is additionally helpful particularly when serum testing is negative. However, simultaneous testing on serum and CSF is recommended for some (such as NMDA-R antibody testing, since CSF is usually more informative).

Reference Values

Anti-neuronal Nuclear Ab, Type 1 (ANNA-1), CSF: <1:2     

Anti-neuronal Nuclear Ab, Type 2 (ANNA-2), CSF: <1:2                             

Anti-neuronal Nuclear Ab, Type 3 (ANNA-3), CSF: <1:2

Purkinje Cell Cytoplasmic Ab, Type1 (PCA-1), CSF: <1:2

Purkinje Cell Cytoplasmic Ab, Type 2 (PCA-2), CSF: <1:2         

Purkinje Cell Cytoplasmic Ab, Type Tr (PCA-Tr), CSF: <1:2     

Amphiphysin Ab, CSF: <1:2                                                                       

CRMP-5-IgG Ab, CSF: <1:2

Paraneoplastic Western Blot, CSF: Negative

CRMP-5-IgG Western Blot, CSF: Negative

Amphiphysin Western Blot, CSF: Negative                                                          

Glutamic Acid Decarboxylase-65 (GAD65), CSF: ≤0.02 nmol/L

Neuronal Voltage-Gated Potassium Channel-Complex Autoantibody, Spinal Fluid: ≤0.02 nmol/L

N-Methyl-D-aspartate receptor (NMDA-R), CSF

CBA: Negative

IFA: <1:2

2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl) propanoic acid receptor (AMPA-R), CSF

CBA: Negative

IFA: <1:2

Gamma-Amino Butyric acid-type B receptor (GABA-B-R), CSF

CBA: Negative

IFA: <1:2                     

Anti-Glial/Neuronal Nuclear Ab, Type 1 (AGNA-1), CSF: <1:2

Neuromyelitis Optica (NMO)/Aquaporin-4-IgG FACS Assay, CSF

Negative

LGI1-IgG CBA, CSF: Negative

CASPR2-IgG CBA, CSF: Negative   

Interpretation

Antibodies specific for neuronal, glial, or muscle proteins are valuable serological markers of autoimmune epilepsy and of a patient's immune response to cancer. These autoantibodies are not found in healthy subjects, and are usually accompanied by subacute neurological symptoms and signs. It is not uncommon for more than 1 of the following autoantibodies to be detected in patients with autoimmune dementia:

-Plasma membrane antibodies (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). These autoantibodies are all potential effectors of dysfunction.

-Neuronal nuclear autoantibody type 1 (ANNA-1) or type 3 (ANNA-3).

-Neuronal or muscle cytoplasmic antibodies (amphiphysin, Purkinje cell antibody-type 2 [PCA-2], collapsin response-mediator protein-5 neuronal [CRMP-5-IgG], or glutamic acid decarboxylase [GAD65] antibody).

Cautions

Negative results do not exclude autoimmune dementia or cancer.

 

This evaluation does not detect Ma1 or Ma2 antibodies (alias: MaTa). Ma2 antibody has been described in patients with brainstem and limbic encephalitis in the context of testicular germ cell neoplasms. Scrotal ultrasound is advisable in men who present with unexplained subacute encephalitis.

Method Description

Indirect Immunofluorescence Assay (IFA):

Before testing, patient's serum is preabsorbed with liver powder to remove nonorgan-specific autoantibodies. After applying to a composite substrate of frozen mouse tissues (brain, kidney, and gut) and washing, fluorescein-conjugated goat-antihuman IgG is applied to detect the distribution and pattern of patient IgG binding.(Pittock SJ, Kryzer TJ, Lennon VA: Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol 2004; 56:715-719)

 

Radioimmunoassay (RIA):

Goat-antihuman IgG and IgM is used as precipitant in all assays. Cation channel protein antigens are solubilized from neuronal or muscle membrane, in nonionic detergent, and complexed with a selective high-affinity ligand labeled with (125)I.(125)I-labelled recombinant human GAD65 antigen is used to confirm GAD65 autoantibody (when suspected from immunofluorescent staining pattern).(Griesmann GE, Kryzer TJ, Lennon VA: Autoantibody profiles of myasthenia gravis and Lambert-Eaton myasthenic syndrome. In Manual of Clinical and Laboratory Immunology, Sixth edition. Edited by NR Rose, RG Hamilton, et al. Washington, DC, ASM Press, 2002, pp 1005-1012; Walikonis JE, Lennon VA: Radioimmunoassay for glutamic acid decarboxylase [GAD65] autoantibodies as a diagnostic aid for stiff-man syndrome and a correlate of susceptibility to type 1 diabetes mellitus. Mayo Clin Proc 1998; 73[12]:1161-1166)

 

Western Blot (WB):

WB is performed when IFA screening for ANNA-1 is not interpretable due to interfering autoantibodies. A mixture of neuronal antigens extracted aqueously from adult rat cerebellum is denatured, reduced, and separated by electrophoresis on 10% polyacrylamide gel. Full-length recombinant human CRMP-5 antigen is used to confirm CRMP-5-IgG.(Yu Z, Kryzer TJ, Griesmann GE, et al: CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann Neurol 2001; 49[2]:145-154)

 

Cell Binding Assay (CBA):

Patient serum is applied to a composite slide containing transfected and non-transfected HEK-293 cells. After incubation and washing, fluorescein-conjugated goat-antihuman IgG is applied to detect the presence of patient IgG binding.(Package insert: EUROIMMUN US. Morris Plains, New Jersey; Stocker W, Teegen B, Meyer W, et al: Differenzierte Autoantikorper-Diagnostik mit BIOCHIP-Mosaiken. Morris Autoantikorper. Pabst-Verlag;1998:78-99)

 

NMO-IgG Fluorescence-Activated Cell Sorting Assay (FACS):

Human embryonic kidney cells (HEK 293) are transfected transiently with a plasmid (pIRES2- Aequorea coerulescens green fluorescent protein [AcGFP]) encoding both green fluorescent protein (GFP) and AQP4-M1. After 36 hours, the mixed population of cells (transfected expressing AQP4 on the surface and GFP in the cytoplasm and nontransfected lacking AQP4 and GFP) are harvested with short exposure to trypsin. Patient CSF is then added to cells at a 1 in 2 screening dilution. After incubation and washing, the cells are resuspended with AlexaFluor 647–conjugated goat-antihuman IgG-gamma specific secondary antibody (Southern Biotech catalog No. 2040-31, 1:2000 in LCBB), held on ice, washed, fixed with 4% paraformaldehyde, and examined with flow cytometry (BD FACSCanto; Becton, Dickinson and Co). Two populations are gated on the basis of GFP expression: positive (high AQP4 expression) and negative (low or no AQP4 expression). The median Alexafluor 647 fluorescence intensity (MFI) for the AcGFP-positive population indicates relative abundance of human IgG potentially bound to AQP4 surface epitopes; MFI for the GFP-negative population indicated nonspecifically-bound IgG. The IgG binding index was calculated as the ratio of the average MFI for duplicate aliquots of each cell population: (MFI GFP positive/MFI GFP negative). We established conservative cutoff IgG binding index values of 2.00 for M1-FACS.

 

If FACS assay is positive at screening dilution, FACS Titer Assay is performed at an additional charge. The patient CSF is titrated to endpoint. The dilution where the IgG binding index is greater than or equal to 2, is considered the endpoint dilution. If a patient is positive at a 1:2 dilution, but negative at 1:4, the endpoint will be reported as 2.

Day(s) and Time(s) Performed

ANNA-1, ANNA-2, ANNA-3, AGNA-1, PCA-1, PCA-2, PCA-Tr, Amphiphysin, CRMP-5-IgG, AMPIC, GABIC, NMDIC: Monday through Friday; 11:30 a.m. and 8:00 p.m.; Saturday and Sunday 8:00 a.m.

AMPCC, GABCC, NMDCC, LG1CC, CS2CC: Monday through Friday; 6:00 a.m.

Paraneoplastic autoantibody Western blot confirmation, CRMP-5-IgG Western blot, Amphiphysin Western blot: Monday, Wednesday, Friday; 6:00 a.m.

GAD65: Monday to Friday; 6:00 a.m. and 4:00 p.m.

VGKC: Monday through Friday 11:00 a.m. and 6:00 p.m.; Saturday 6:00 a.m.; Sunday 6:00 a.m.

Analytic Time

3 days if negative/5 days if positive

Specimen Retention Time

28 days

Performing Laboratory

Mayo Medical Laboratories in Rochester

Test Classification

See Individual Test IDs

CPT Code Information

83519-Neuronal VGKC autoantibody

86255-AGNA-1

86255-Amphiphysin

86255-ANNA-1

86255-ANNA-2

86255-ANNA-3

86255-CRMP-5-IgG

86255-PCA-2

86255-PCA-Tr

86255-AMPAR-Ab

86255-GABAR-Ab

86255-NMDAR-Ab

86341-GAD65

86255-LG1CC

86255- CS2CC

84182-Amphiphysin Western blot (if appropriate)

84182-CRMP-5 Western blot confirmation (if appropriate)

84182-Paraneoplastic autoantibody Western blot confirmation (if appropriate)

86255-NMO/AQP4-IgG FACS (if appropriate)

86255-PCA-1 (if appropriate)

86256-AMPAR-Ab titer (if appropriate)

86256-GABAR-Ab titer (if appropriate)

86256-NMDAR-Ab titer (if appropriate)

86256- NMO/AQP4-IgG FACS titer (if appropriate)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
DMC1 Dementia-Autoimmune Evaluation, CSF In Process

 

Result ID Test Result Name Result LOINC Value
61513 NMDA-R Ab CBA, CSF In Process
61514 AMPA-R Ab CBA, CSF 82987-9
61515 GABA-B-R Ab CBA, CSF 82984-6
34254 Dementia, Interpretation, CSF 69048-7
61729 VGKC-complex Ab IPA, CSF 68913-3
64280 LGI1-IgG CBA, CSF In Process
64282 CASPR2-IgG CBA, CSF In Process
89079 AGNA-1, CSF 53714-2
5906 Amphiphysin Ab, CSF 56531-7
3852 ANNA-1, CSF 24400-4
7472 ANNA-2, CSF 24401-2
21633 ANNA-3, CSF 35144-5
21650 CRMP-5-IgG, CSF 35385-4
21632 PCA-2, CSF 35143-7
21631 PCA-Tr, CSF 51748-2
21702 GAD65 Ab Assay, CSF 53708-4
36429 Reflex Added No LOINC Needed

Forms

If not ordering electronically, complete, print, and send a Neurology Specialty Testing Client Test Request (T732) with the specimen (http://www.mayomedicallaboratories.com/it-mmfiles/neurology-request-form.pdf)