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Test Code DMS1 Dementia, Autoimmune Evaluation, Serum

Useful For

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

-Rapid onset and progression

-Fluctuating course

-Psychiatric accompaniments (psychosis, hallucinations)

-Movement disorder (myoclonus, tremor, dyskinesias)


-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
ADMSI Dementia, Interpretation, S No Yes
VGKC Neuronal (V-G) K+ Channel Ab, S No Yes
GD65S GAD65 Ab Assay, S Yes Yes
ANN1S Anti-Neuronal Nuclear Ab, Type 1 No Yes
ANN2S Anti-Neuronal Nuclear Ab, Type 2 No Yes
ANN3S Anti-Neuronal Nuclear Ab, Type 3 No Yes
AGN1S Anti-Glial Nuclear Ab, Type 1 No Yes
PCAB2 Purkinje Cell Cytoplasmic Ab Type 2 No Yes
PCATR Purkinje Cell Cytoplasmic Ab Type Tr No Yes
AMPHS Amphiphysin Ab, S No Yes
CCN N-Type Calcium Channel Ab No Yes
CCPQ P/Q-Type Calcium Channel Ab No Yes
ARBI ACh Receptor (Muscle) Binding Ab No Yes
GANG AChR Ganglionic Neuronal Ab, S No Yes

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
WBN Paraneoplastic Autoantibody WBlot,S No No
CRMWS CRMP-5-IgG Western Blot, S Yes No
ABLOT Amphiphysin Western Blot, S No No
AMPIS AMPA-R Ab IF Titer Assay, S No No
GABIS GABA-B-R Ab IF Titer Assay, S No No
NMDIS NMDA-R Ab IF Titer Assay, S No No
PCABP 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, Serum in Special Instructions

Method Name

ANN1S, ANN2S, ANN3S, AGN1S, PCAB2, PCATR, AMPHS, CRMS, PCABP, NMDIS, AMPIS, GABIS: Indirect Immunofluorescence Assay (IFA)

VGKC, CCN, CCPQ, GANG, GD65S, ARBI: Radioimmunoassay (RIA)

WBN, ABLOT: Western Blot

AMPCS, GABCS, NMDCS, LG1CS, CS2CS: Cell Binding Assay (CBA)

NMOTS: Flow Cytometry

Reporting Name

Dementia Autoimmune Eval, S

Specimen Type


Necessary Information

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

Specimen Required


Preferred: Red top

Acceptable: Serum gel

Specimen Volume: 4 mL

Specimen Minimum Volume

2 mL

Specimen Stability Information

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

Reject Due To


Mild OK; Gross reject


Mild OK; Gross OK





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 a 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, those 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 of serum and CSF is recommended for NMDA-R antibody, because CSF is usually more informative.

Reference Values


Antineuronal Nuclear Ab, Type 1 (ANNA-1)


Antineuronal Nuclear Ab, Type 2 (ANNA-2)


Antineuronal Nuclear Ab, Type 3 (ANNA-3)


Anti-Glial/Neuronal Nuclear Ab, Type 1 (AGNA-1)




Purkinje Cell Cytoplasmic Ab, Type1 (PCA-1)


Purkinje Cell Cytoplasmic Ab, Type 2 (PCA-2)


Purkinje Cell Cytoplasmic Ab, Type Tr (PCA-Tr)


Amphiphysin Antibody






Paraneoplastic Western Blot


CRMP-5-IgG Western Blot


Amphiphysin Western Blot




Glutamic Acid Decarboxylase (GAD65) Antibody

≤0.02 nmol/L



N-Type Calcium Channel Antibody

≤0.03 nmol/L

P/Q-Type Calcium Channel Antibody

≤0.02 nmol/L

AChR Ganglionic Neuronal Antibody

≤0.02 nmol/L

Neuronal VGKC Autoantibody

≤0.02 nmol/L



ACh Receptor (Muscle) Binding Antibody

≤0.02 nmol/L


N-Methyl-D-aspartate receptor (NMDA-R) CBA


IFA: <1:120

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


IFA: <1:120

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


IFA: <1:120

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


LGI1-IgG CBA: Negative

CASPR2-IgG CBA: Negative


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).


Negative results do not exclude autoimmune dementia or cancer.


This test 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.

Clinical Reference

1. McKeon A, Lennon, VA, Pittock, SJ: Immunotherapy Responsive Dementias and Encephalopathies. Continuum Lifelong Learning 2010;16(2):80-101

2. Flanagan EP, McKeon A, Lennon VA, et al: Autoimmune dementia: clinical course and predictors of immunotherapy response. Mayo Clin Proc Oct;85(10):881-897

3. Geschwind MD, Tan KM, Lennon VA, et al: Voltage-gated potassium channel autoimmunity mimicking Creutzfeldt-Jakob disease. Arch Neurol 2008 Oct;65(10):1341-1346

4. Lancaster E, Martinez-Hernandez E, Dalmau J: Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology 2011;77(2):179-189

5. Klein CJ, Lennon VA, Aston PA, et al: Insights from LGI1 and CASPR2 potassium channel complex autoantibody subtyping. JAMA Neurol 2013;70(2):229-234

Method Description

Indirect Immunofluorescence Assay (IFA):

Before testing, the 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-recombinant human GAD65 is used as antigen 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 nontransfected 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 AG. Stocker W. et al: Differenzierte Autoantikorper-Diagnostik mit BIOCHIP-Mosaiken. U Conrad, K. (Hrsg) 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 (AcGFP) and AQP4-M1. After 36 hours, a mixed population of cells (transfected expressing AQP4 on the surface and AcGFP in the cytoplasm and nontransfected lacking AQP4 and AcGFP) are lifted and resuspended in live cell binding buffer. Patient serum is then added to cells at a 1 in 5 screening dilution. After incubation and washing, the cells are resuspended in secondary antibody (AlexaFluor 647–conjugated goat antihuman IgG; 1:2000 in LCBB), held on ice, washed, fixed with 4% paraformaldehyde, and analyzed by flow cytometry (BD FACSCanto; Becton, Dickinson and Co). Two populations are gated on the basis of AcGFP 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 non-specifically-bound IgG. The IgG binding index is 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 serum 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 1:5 dilution, but negative at 1:10 dilution, the endpoint will be reported as 5.

Day(s) and Time(s) Performed


Monday through Friday; 11:30 a.m. and 8:00 p.m.; Saturday and Sunday 8:00 a.m.


AMPCS, GABCS, NMDCS, LG1CS, CS2CS: Monday through Friday; 6 a.m.

Paraneoplastic autoantibody Western blot confirmation, CRMP-5-IgG Western blot, Amphiphysin Western blot: Monday, Wednesday, Friday; 8 a.m.

ARBI: Monday through Friday 11:00 a.m., 6:00 p.m., and 10:00 p.m.; Saturday 6:00 a.m.; Sunday 6:00 a.m. and 10:00 a.m.

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

GD65S: Monday to Friday; 6:00 a.m. and 4:00 p.m.

Analytic Time

4 days if negative/ 7 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-ACh receptor (muscle) binding antibody

83519-AChR ganglionic neuronal antibody

83519-Neuronal VGKC autoantibody

83519-N-type calcium channel antibody

83519-P/Q-type calcium channel antibody














86255- CS2CS


86255-PCA-1 (if appropriate)

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)

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
DMS1 Dementia Autoimmune Eval, S In Process


Result ID Test Result Name Result LOINC Value
61516 NMDA-R Ab CBA, S No LOINC Needed
61518 AMPA-R Ab CBA, S 82980-4
61519 GABA-B-R Ab CBA, S 82977-0
34255 Dementia, Interpretation, S 69048-7
64279 LGI1-IgG CBA, S In Process
64281 CASPR2-IgG CBA, S In Process
89080 AGNA-1, S 53709-2
81722 Amphiphysin Ab, S 33927-5
80150 ANNA-1, S 13997-2
80776 ANNA-2, S 43188-2
83137 ANNA-3, S 33924-2
8338 ACh Receptor (Muscle) Binding Ab 11034-6
81184 N-Type Calcium Channel Ab 33979-6
81185 P/Q-Type Calcium Channel Ab 33980-4
83077 CRMP-5-IgG, S 35386-2
84321 AChR Ganglionic Neuronal Ab, S 42233-7
81596 GAD65 Ab Assay, S 30347-9
83138 PCA-2, S 33925-9
83076 PCA-Tr, S 33926-7
89165 Neuronal (V-G) K+ Channel Ab, S 41871-5
36349 Reflex Added No LOINC Needed


If not ordering electronically, complete, print, and send a Neurology Specialty Testing Client Test Request (T732) with the specimen (