prior authorization review panel mco policy submission a ... · anti-vgcc iii. aetna considers the...

Prior Authorization Review Panel MCO Policy Submission

A separate copy of this form must accompany each policy submitted for review. Policies submitted without this form will not be considered for review.

Plan: Aetna Better Health Submission Date:09/01/2019

Policy Number: 0340 Effective Date: Revision Date: 06/03/2016

Policy Name: Antibody Tests for Neurologic Diseases

Type of Submission – Check all that apply:

New Policy Revised Policy* Annual Review – No Revisions Statewide PDL

*All revisions to the policy must be highlighted using track changes throughout the document.

Please provide any clarifying information for the policy below:

CPB 0340 Antibody Tests for Neurologic Diseases

Clinical content was last revised on 06/03/2016 . Additional non-clinical updates were made by Corporate since the last PARP submission, as documented below.

Update History since the last PARP Submission:

06/18/2019-This CPB has been updated with additional background information and references.

Name of Authorized Individual (Please type or print):

Dr. Bernard Lewin, M.D.

Signature of Authorized Individual:

Revised July 22, 2019

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(https://www.aetna.com/)

Antibody Tests for Neurologic Diseases

Clinical Policy Bulletins Medical Clinical Policy Bulletins

Policy History

Last Revi

ew

06/18/2019

Effective: 08/03/1999

Next Review:

03/26/2020

Review

Histor

y

Number: 0340

Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB.

I. Aetna considers antibody tests medically necessary for the diagnosis and

treatment of paraneoplastic neurologic disorders when all of the following

are met:

A. The member displays clinical features of the paraneoplastic neurologic

disease in question, and

B. The result of the test will directly impact the treatment being delivered to the

member, and

C. After history, physical examination, and completion of conventional

diagnostic studies, a definitive diagnosis remains uncertain, and one of

the following antibodies is suspected:

Anti-AChR

Anti-amphiphysin

Anti-bipolar cells of the retina

Anti-CV2/CRMP5

Anti-Hu (ANNA-1)

Anti-Ri (ANNA-2) Anti-Tr

Anti-VGCC

Anti-VGKC

Anti-Yo (APCA-1)

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http://www.aetna.com/cpb/medical/data/300_399/0340.html 08/27/2019

http://www.aetna.com/cpb/medical/data/300_399/0340.html

https://www.aetna.com/

Anti-Ma (MA1, MA2) (Anti-Ta)

Anti-recoverin

Anti-nAChR

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II. Aetna considers antibody tests medically necessary for the diagnosis and

treatment of neurologic diseases when all of the following are met:

A. The member displays clinical features of the neurologic disease in

question, and

B. The result of the test will directly impact the treatment being delivered to the

member, and

C. After history, physical examination, and completion of conventional

diagnostic studies, a definitive diagnosis remains uncertain, and one of

the following antibodies is suspected:

Anti-AChR

Anti-asialo-GM1

Anti-GM1

Anti-GM2

Anti-GAD

Anti-GD1a

Anti-GD1b

Anti-GQ1b

Anti-GT1a

Anti-La

Anti-MAG

Anti-MUSK

Anti-Ro

Anti-SGPG

Anti-sulfatide

Anti-VGCC

III. Aetna considers the LEMS antibody test to detect antibodies to the P/Q

VGCC medically necessary in confirming the diagnosis of Lambert-Eaton

myasthenic syndrome when the clinical features and electrophysiology

studies are inconclusive in diagnosing Lambert-Eaton myasthenic

syndrome.

IV. Aetna considers neuromyelitis optica (NMO)-IgG autoantibody (aquaporin-4

(AQP4) receptor antibody) medically necessary for evaluating persons with

optic neuritis and for distinguishing neuromyelitis optica from multiple

sclerosis.

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V. Aetna considers antibody tests for screening of neurologic

diseases experimental and investigational. These tests are only considered

medically necessary when ordered selectively for evaluating persons with

signs and symptoms of specific immune-mediated neuromuscular

conditions.

VI. Aetna considers auto-antibodies (Abs) (e.g., glycine receptor Abs (GlyR-Ab),

myelin oligodendrocyte glycoprotein (MOG)-Ab, N-methyl-D-aspartate

receptor (NMDAR)-Ab, and voltage-gated potassium channel (VGKC)

-complex Abs) testing for the diagnosis of childhood-acquired demyelinating

syndromes experimental and investigational.

See also

CPB 0285 - Plasmapheresis/Plasma Exchange/Therapeutic

Apheresis (../200_299/0285.html)

and CPB 0206 - Parenteral Immunoglobulins (../200_299/0206.html).

Background

Autoantibodies to nervous system components have been detected in patients with

neurologic symptoms such as paresthesias, weakness, and twitching. Many

autoantibodies have been discovered and characterized; however, research is

ongoing in the field of neuroimmunology and there remains a paucity of clinical

trials in the peer-reviewed medical literature describing their usefulness in clinical

practice. In a review on the use of autoantibodies as predictors of disease, Scofield

(2004) stated that long-term large studies of outcome are needed to assess the use

of assaying autoantibodies for prediction of disease. A review of laboratory testing

in peripheral nerve disease indicated that the use of antibody assays should be

very selective and should not be used as "screening" studies. Antibody testing

often produces results that can be confusing; thus, a stepwise and directed

approach to the evaluation of peripheral neuropathy utilizing clinical examination

and electrodiagnostic testing can increase the yield of finding a treatable cause

(Chang, 2002).

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Antibodies to Glycolipid and Glycoprotein-Related Saccharides (MAG, GM1, Asialo-GM1 (Anti-GA1), GD1a, GD1b, GQ1b, MAG-SGPG, Sulfatide) (See Appendix for Complete List)

Gangliosides are a group of glycosphingolipids widely distributed in membrane

components of the nervous system. They possess a common long chain fatty acid,

but exhibit distinctive carbohydrate moieties containing one or more sialic acid

residues. Ganglioside nomenclature is defined by the following scheme: (i) G

refers to ganglio; (ii) M, D, T, and Q refer to the number of sialic acid residues

(mono, di, tri, and quad); and (iii) numbers and lower case letters refer to the

sequence of migration on thin layer chromatography. The gangliosides most

commonly recognized by neuropathy associated autoantibodies are GM1, asialo-

GM1, GD1a, GD1b, and GQ1b.

Chronic immune-mediated polyneuropathies in which the peripheral nerves are

selectively affected include chronic inflammatory demyelinating polyneuropathy

(CIDP), demyelinating polyneuropathy associated with IgM anti-myelin-associated

glycoprotein (anti-MAG)) antibodies or anti-sulfoglucuronyl paragloboside (anti-

SGPG) antibodies, multi-focal motor neuropathy associated with IgM anti-

ganglioside M1 (anti-GM1) or anti-GD1a antibodies, and sensory polyneuropathy

associated with IgM anti-sulfatide antibodies or anti-GD1b or disialosyl ganglioside

antibodies. Some of these autoantibodies also occur as IgM monoclonal

gammopathies in patients with non-malignant monoclonal gammopathies.

Detection of ganglioside M1 (GM1) antibody, usually of the IgM isotype, is

associated with multi-focal motor neuropathy and lower motor neuropathy,

characterized by muscle weakness and atrophy. Multi-focal motor neuropathy may

occur with or without high serum titers of anti-GM1 antibodies. GM1 antibodies are

detected in approximately 50 % of persons with multi-focal motor neuropathy (Tidy,

2007). However, whether the presence of anti-GM1 antibody or its titer has any

bearing on the response to therapy is controversial (Sridharan and Lorenzo, 2002).

GM1 antibodies of the IgG and IgA isotypes may be found in association with

amyotrophic lateral sclerosis (ALS). European Federation of Neurological Societies

(EFNS) guidelines (2006) on amyotrophic lateral sclerosis recommend testing for

anti-GM1, as well as anti-MAG and anti-Hu antibodies (see below) in selected

cases.

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Ganglioside glycolipid antibodies may be associated with different forms or aspects

of Guillain-Barre Syndrome (GBS). Increased titers of IgG anti-GM1 or GD1a

ganglioside antibodies have been associated with GBS and acute motor axonal

neuropathy, and may be useful in persons suspected of having these syndromes.

Antibodies to GM1 and GD1a are mostly associated with axonal variants of GBS.

Antibodies to GT1a are associated with swallowing dysfunction. The GD1b

ganglioside is present in peripheral nerves on the surface of sensory neurons in the

dorsal root ganglion. Antibodies to GD1b are associated with pure sensory GBS.

Increased IgG anti-GQ1b ganglioside antibodies are closely associated with the

Miller-Fisher syndrome, and may be useful in the evaluation of patients suspected

of having this syndrome. Antibodies against GQ1b are found in 85 to 90 % of

patients with the Miller Fisher syndrome, characterized by ataxia, areflexia, and

ophthalmoplegia. In clinical practice, commercially available testing for serum IgG

antibodies to GQ1b is useful for the diagnosis of Miller Fischer syndrome, having a

sensitivity of 85 to 90 %. GQ1b antibodies are also found in GBS patients with

ophthalmoplegia, but not in GBS patients without ophthalmoplegia. Antibodies to

GQ1b may also be present in Bickerstaff encephalitis and the pharyngo-cervical

brachial GBS variant, but not in disorders other than GBS.

Myelin-associated glycoprotein (MAG) is a constituent of peripheral and central

nervous system myelin. High titer IgM antibodies to MAG are associated with

sensorimotor demyelinating peripheral neuropathy, and are associated with multiple

sclerosis, myasthenia gravis, and systemic lupus erythematosus (SLE) (Tidy,

2007).

Antibodies recognizing MAG react with a carbohydrate determinant that is also

present on SGPG. Initial assays for MAG antibody utilized SGPG as the target

antigen. However, some laboratories now perform 2 separate enzyme-linked

immunosorbant assay (ELISA) procedures, one utilizing SGPG as antigen and one

utilizing the entire MAG as antigen, to maximize detection of MAG antibodies.

Researchers are currently examining the cross-reacted relationship of IgM binding

to both SGPG and MAG and their significance in neuropathy (Garces-Sanchez,

2008).

MAG antibodies are usually associated with the presence of an IgM monoclonal

protein; approximately 50 % of patients with IgM monoclonal gammopathies and

associated peripheral neuropathies have detectable MAG antibodies. Detection of

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MAG antibodies may be useful in paraprotein demyelinating neuropathies. EFNS

guidelines (2006) state that a causal relationship between a paraprotein and a

demyelinating neuropathy is highly probable if there is an immunoglobulin M (IgM)

paraprotein (monoclonal gammopathy of uncertain significance [MGUS] or

Waldenstrom's) and there are high titers of anti-MAG or anti-GQ1b antibodies. A

causal relationship is probable in persons with IgM paraprotein (MGUS or

Waldenström's) with high titers of IgM antibodies to other neural antigens (GM1,

GD1a, GD1b, GM2, sulfatide), and slowly progressive predominantly distal

symmetrical sensory neuropathy.

Guidelines from the British Society of Haematology recommend testing for anti-

MAG in persons with Waldenstrom's macroglobulinemia who present with

neurological symptoms (Johnson et al, 2005).

High titers of antibodies to the ganglioside asialo GM1 (anti-GA1) have been

associated with motor or sensorimotor neuropathies. In most cases, these

antibodies cross-react with the structurally related glycolipids GM1 and GD1b,

although specific anti-asialo GM1 antibodies have also been reported (Lopez,

2006). Some individuals with proximal lower motor neuron syndromes (P-LMN) (30

%) have selective serum antibody binding to asialo-GM1 ganglioside; however,

there is no evidence that P-LMN syndromes respond to immunosuppressive

treatment.

Antibodies Associated with Paraneoplastic Syndromes and Associated Cancers (Anti-Hu, Anti-Yo, Anti-Ri, Anti-VGKC, Anti-VGCC, Anti-CV2, Anti-Ma, Anti-Amphiphysin, Anti-Zic4) (See Appendix for Complete List)

Paraneoplastic neurologic syndromes are a heterogeneous group of neurologic

disorders associated with systemic cancer and caused by mechanisms other than

metastases, metabolic and nutritional deficits, infections, coagulopathy, or side

effects of cancer treatment. These syndromes may affect any part of the nervous

system from cerebral cortex to neuromuscular junction and muscle, either

damaging one area or multiple areas. Although a pathogenic role of paraneoplastic

antibodies has not been proven, their presence indicates the paraneoplastic nature

of a neurologic disorder, and in many cases, can narrow the search for an occult

tumor to a few organs.

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Polyclonal immunoglobulin G (IgG) anti-Hu antibodies (previously called ANNA-1)

are found predominantly in patients with paraneoplastic neurologic syndromes

associated with small-cell carcinoma of the lung. Anti-Hu antibodies are also

expressed in most neuroblastomas and occasional other tumors (including several

types of sarcoma and prostate carcinoma). Anti-Hu antibody reacts with 35- to 42-

kD proteins present in nuclei and cytoplasm of virtually all neurons. The role of Hu

proteins in small-cell lung cancer and the other cancers in which they are

expressed is unclear (Mehdi and Ko, 2002). Some investigators have argued that

detection of anti-Hu antibody is important to determine whether a paraneoplastic

syndrome is immune-mediated and thus, in theory, amenable to

immunosuppressive therapy (Santacroce et al, 2002; Senties-Madrid and Vega-

Boada, 2001). However, the value of immunosuppressive therapy in antibody

associated paraneoplastic syndromes has not been proven in clinical studies.

Although the titer of anti-Hu antibodies has been suggested as a prognostic

indicator of paraneoplastic neurologic syndromes, the clinical course of these

syndromes is unpredictable (Liebeskind, 2001).

Paraneoplastic limbic encephalitis (PLE) is a rare disorder characterized by

personality changes, irritability, depression, seizures, memory loss and sometimes

dementia. The diagnosis is difficult because clinical markers are often lacking and

symptoms usually precede the diagnosis of cancer or mimic other complications.

Limbic encephalitis may be associated with voltage-gated potassium channel

antibodies (VGKC) (53 %). However, responsiveness to treatment is not limited to

patients with VGKC antibodies (Bataller, 2007). Other paraneoplastic

encephalomyelitis antibodies include anti-CV2, anti-Ma1, anti-Ma2 (anti-Ta, anti-

MaTa), and several other atypical antibodies. The targets of such antibodies may

be quite varied, including neuropil and intraneuronal sites. Testicular cancer is

associated with anti-Ma2 antibodies. The Ma2 antigen is selectively expressed in

neurons and the testicular tumor. Ma2 shares homology with Ma1, a gene that is

associated with other paraneoplastic neurologic syndromes, particularly brainstem

and cerebellar dysfunction. Treatment of the tumor is reported to have more effect

on neurologic outcome than the use of immune modulation (Gultekin, 2000).

The diagnosis of Lambert-Eaton myasthenic syndrome (LEMS) is usually made on

clinical grounds and confirmed by electrodiagnostic studies. A serum test for

voltage-gated calcium channel antibodies (VGCC) is commercially available.

Treatment involves removing the cancer associated with the disease. If cancer is

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not found, immunosuppressive medications and acetylcholinesterase inhibitors are

used with moderate success. Patients with idiopathic LEMS should be screened

every 6 months with chest imaging for cancer (Mareska, 2004).

Anti-Yo antibodies (also called Purkinje cell antibody type 1 or PCA-1) primarily

occur in patients with paraneoplastic cerebellar degeneration (PCD) who have

breast cancer or tumors of the ovary, endometrium, and fallopian tube. The target

antigens of anti-Yo antibodies are the cdr proteins that are expressed by Purkinje

cells and ovarian and breast cancers. A cytotoxic T cell response against cdr2 has

also been identified in these patients.

Anti-CV2 antibodies, directed against a cytoplasmic antigen in some glial cells, and

against peripheral nerve antigens, have been associated with several syndromes,

including cerebellar degeneration, limbic encephalitis, encephalomyelitis, peripheral

neuropathy, and optic neuritis. The most common tumors are SCLC, thymoma,

and uterine sarcoma.

Opsoclonus is a disorder of ocular motility characterized by spontaneous,

arrhythmic, conjugate saccades occurring in all directions of gaze without a

saccadic interval. Although opsoclonus can be paraneoplastic in origin, it can also

result from viral infections, post-streptococcal pharyngitis, metabolic disorders,

metastases, and intra-cranial hemorrhage. The most frequent tumor associated

with opsoclonus myoclonus in adults is small cell lung cancer. In women, however,

the detection of anti-Ri (anti-neuronal nuclear autoantibody type 2, or ANNA-2)

usually indicates the presence of breast cancer, although other tumors have been

reported (e.g., gynecologic, lung, bladder). The target antigens of anti-Ri

antibodies are the Nova proteins.

In a cross-sectional study, Pranzatelli et al (2002) examined paraneoplastic

antibodies in 59 children with opsoclonus-myoclonus-ataxia, 86 % of them were

moderately or severely symptomatic, and 68 % of them had relapsed at the time of

testing. This total number of patients includes 18 children with low-stage

neuroblastoma (tested after tumor resection), 6 of them had never been treated

with immunosuppressants. All were sero-negative for anti-Hu, anti-Ri (IgG

autoantibody ANNA-2), and anti-Yo (antibodies against a Purkinje cell cytoplasmic

antigen, called Yo), the 3 paraneoplastic antibodies most associated with

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opsoclonus-myoclonus or ataxia in adults. The findings of this study suggested that

anti-Hu, anti-Ri, and anti-Yo do not explain relapses in pediatric opsoclonus-

myoclonus-ataxia.

Paraneoplastic optic neuritis has been described in a few reports, usually in

association with paraneoplastic encephalomyelitis or retinitis and small cell lung

cancer. Some of these patients harbor antibodies to the 62kDa collapsin-

responsive mediator protein-5 (CRMP-5, also called anti-CV2). However, the small

number of patients, the extensive number of accompanying symptoms, and the

frequent co-occurrence of other antibodies suggest low specificity and sensitivity of

CRMP-5 antibodies as markers of paraneoplastic optic neuritis or retinitis

associated with small cell lung cancer.

Anti-Ro/SSA and anti-La/SSB antibodies, which are directed against two

extractable nuclear antigens, have been detected with high frequency in patients

with Sjögren's syndrome. They also have diagnostic usefulness in patients with

SLE. Indications for ordering an anti-Ro/SSA antibody test include: women with

SLE who have become pregnant; women who have a history of giving birth to a

child with heart block or myocarditis; patients with a history of unexplained

photosensitive skin eruptions; patients suspected of having a systemic connective

tissue disease in whom the screening ANA test is negative; patients with symptoms

of xerostomia, keratoconjunctivitis sicca and/or salivary and lacrimal gland

enlargement; and patients with unexplained small vessel vasculitis or atypical

multiple sclerosis.

Retinal antibodies have been associated with small cell carcinoma of the lung (Tidy,

2007).

In patients with neurologic symptoms of unknown cause, detection of Zic4

antibodies has been associated with cerebellar degeneration and small-cell lung

cancer (SCLC) and often associates with anti-Hu or CRMP5 antibodies (Bataller,

2004). However, there is insufficient evidence on the clinical usefulness of

measuring Zic4 antibodies in the peer-reviewed medical literature.

Stiff-Person Syndrome

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Stiff-person syndrome (formerly called stiff-man syndrome) is an uncommon

disorder characterized by progressive muscle stiffness, rigidity, and spasm

involving the axial muscles. The muscle spasms are triggered by different stimuli

and may lead to limb deformities and fracture. Electrophysiological studies show

continuous discharges of motor unit potentials, which improve during sleep or

general anesthesia. Paraneoplastic stiff-person syndrome usually occurs in

patients with breast cancer and small cell lung cancer (SCLC). Paraneoplastic

muscle rigidity in association with myoclonus has also been described in patients

with SCLC and progressive encephalomyelitis. The serum of patients with

paraneoplastic stiff-person syndrome often contains antibodies against a protein

called amphiphysin. In contrast, patients with stiff-person syndrome who do not

have cancer (but who usually develop diabetes and other symptoms of

endocrinopathy) have antibodies against glutamic acid decarboxylase (GAD). Both

GAD and amphiphysin are nonintrinsic membrane proteins that are concentrated in

nerve terminals, where a pool of both proteins is associated with the cytoplasmic

surface of synaptic vesicles.

To better understand GADAb and SPS, Murinson et al (2004) studied a population

of patients with clinically suspected SPS. A total of 576 patients with suspected

SPS underwent ICC. Of these, 286 underwent RIA for GADAb; 116 were GADAb-

positive by one or both tests. Ninety-six percent of those positive by ICC had RIA

values several standard deviations above normal. RIA did not correlate with age or

illness duration. Marked elevations of RIA for GADAb were characteristic of ICC-

confirmed SPS, and modest elevations were not. The findings of this study

indicated that patients with clinically suspected SPS almost always have either very

high GADAb or undetectable GADAb. An additional important observation was that

the specificity of RIA for GAD-positive SPS is sharply dependent on the diagnostic

cut-off value. The authors noted that until a universal standard for GAD65 RIA is

adopted, interpretation will depend on knowing the particularities of each testing

laboratory.

In an editorial, Chang and Lang (2004) stated that "the data from the Murinson, et

al. do not imply a pathogenic role because they found no correlation between age

or duration of illness and GADAbs and no change over the course of the disease in

individuals. Thus, there is no value in monitoring the antibody titer during the

course of disease .... Although the exact role of GADAbs in the pathogenesis of

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SPS still remains elusive, Murinson, et al. have established the reliability of RIA in

measuring these antibodies. Nevertheless, clinical criteria remain the benchmark

for the diagnosis of SPS".

Myasthenia Gravis (MuSk, AChR Antibodies)

Myasthenia gravis (MG), an autoimmune disorder, is caused by the failure of

neuromuscular transmission, which results from the binding of autoantibodies to

proteins involved in signaling at the neuromuscular junction. These proteins

include the nicotinic acetylcholine receptors (AChRs) or, less frequently, a muscle-

specific tyrosine kinase (MuSK) involved in AChRs clustering. Chan and Liu (2005)

noted that diagnosis of MG relies on clinical as well as investigatory evidences.

Among the usual investigatory tools, the Tensilon (edrophonium chloride) test has

been given the credit as a test of high sensitivity (80 to 85 %). Antibodies to AChRs

are found in about 80 % of persons with myasthenia gravis (Tidy, 2007).

Vincent and Leite (2005) noted that some of the 20 % of patients with MG who do

not have antibodies to AChRs have antibodies to MuSK, but a full understanding of

their frequency, the associated clinical phenotype and the mechanisms of action of

the antibodies has not yet been achieved. Moreover, some patients do not respond

well to conventional corticosteroid therapy. These researchers reported that MuSK

antibodies are found in a variable proportion of AChR antibody negative MG

patients who are often, but not exclusively, young adult females, with bulbar, neck,

or respiratory muscle weakness. The thymus histology is normal or only very mildly

abnormal. Surprisingly, limb or intercostal muscle biopsies exhibit no reduction in

AChR numbers or complement deposition. However, patients without AChR or

MuSK antibodies appear to be similar to those with AChR antibodies and may have

low-affinity AChR antibodies. A variety of treatments, often intended to enable

corticosteroid doses to be reduced, have been used in all types of MG with some

success, but they have not been subjected to randomized clinical trials. The

authors noted that MuSK antibodies define a form of MG that can be difficult to

diagnose, can be life threatening and may require additional treatments. An

improved AChR antibody assay may be helpful in patients without AChR or MuSK

antibodies. Randomized clinical studies of drugs in other neuroimmunological

diseases may help to guide the treatment of MG.

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Romi et al (2005) examined MG severity and long-term prognosis in seronegative

MG compared with seropositive MG, and reviewed specifically at anti-AChR

antibody negative and anti-MuSK antibody negative patients. A total of 17

consecutive sero-negative non-thymomatous MG patients and 34 age- and sex-

matched contemporary sero-positive non-thymomatous MG controls were included

in a retrospective follow-up study for a total period of 40 years. Clinical criteria

were assessed each year, and muscle antibodies were assayed. There was no

difference in MG severity between sero-negative and sero-positive MG. However,

when thymectomized patients were excluded from the study at the year of

thymectomy, sero-positive MG patients had more severe course than sero-negative

(p < 0.001). One sero-positive patient died from MG related respiratory

insufficiency. The need for thymectomy in sero-negative MG was lower than in sero-

positive MG. None of the sero-negative patients had MuSK antibodies. The findings

of this study showed that the presence of AChR antibodies in MG patients correlates

with a more severe MG. The authors noted that with proper treatment, especially

early thymectomy for seropositive MG, the outcome and long-term prognosis is good

in patients with and without AChR antibodies.

Lee et al (2006) stated that several reports from Western countries suggest

differences in the clinical features of patients with MuSK antibody-positive and

MuSK antibody-negative sero-negative MG. These investigators performed the first

survey in Korea of MuSK antibodies, studying 23 patients with AChR-antibody sero-

negative MG. MuSK antibodies were present in 4 (26.7 %) of 15 generalized sero-

negative MG patients and none of 8 ocular sero-negative MG patients. All 4 MuSK

positive patients were females, with pharyngeal and respiratory muscle weakness,

and required immunosuppressive treatment. However, overall disease severity and

age at onset was similar to that of MuSK-negative MG and treatment responses

were equally good.

In the appropriate clinical setting (lack of AChR-Ab and typical clinical features

listed below), MuSK testing can clarify the diagnosis and perhaps direct treatment.

However, the initial management of clinically apparent myasthenia should be the

same for patients with or without AChR antibodies; this would change only if future

studies find additional therapeutic differences related to MuSK status.

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Although some differences between MuSK-positive and MuSK-negative MG have

been found, the initial management of clinically apparent MG should be the same

for patients with or without MuSK antibodies; this would change only if future

studies show significant therapeutic differences related to MuSK status.

GALOP Autoantibody

A peripheral neuropathy syndrome described by Pestronk (1994) is the gait

disorder, autoantibody, late-age onset, polyneuropathy (GALOP) syndrome that

resembles anti-MAG neuropathies with distal sensory loss, ataxia, and

demyelinating features on nerve conduction velosity testing. High titer IgM

antibodies bind to a central nervous system myelin antigen preparation that

copurifies with MAG. GALOP syndrome appears to be immune-mediated.

However, there is insufficient evidence on the clinical usefulness of measuring the

GALOP autoantibody for the diagnosis and treatment of GALOP syndrome in the

peer-reviewed medical literature.

Finally, it has been estimated that up to 1/3 of peripheral neuropathies are

idiopathic. These neuropathies are classified by their clinical syndrome, which

include sensory axonal polyneuropathy with large and small fiber involvement,

small-fiber sensory neuropathy, large-fiber sensory neuropathy, sensorimotor

neuropathy, and autonomic neuropathy (Shy-Drager syndrome). Treatment is

usually symptomatic, although some patients may respond to a trial of

immunotherapy. More research into their causes as well as the development of

better diagnostic tests and treatments are needed (Chang, 2002).

Dermatomyositis/Polymyositis

Several serological abnormalities (e.g., formation of specific autoantibodies) have

been identified in patients with dermatomyositis (DM) and polymyositis

(PM), however their routine use has not yet been established. As a group, these

antibodies have been termed myositis-specific antibodies (MSAs) and include

antibodies to EJ, Jo-1, Ku, Mi-2, OJ, PL-7, PL-12, signal recognition protein (SRP),

and U2 small nuclear ribonucleoprotein (snRNP). Pappu and Seetharaman (2009)

stated that anti-nuclear antibody assay findings are positive in 1/3 of patients

with PM and in only 15 % of patients with inclusion body myositis, and about 4 % of

patients with PM have antibodies to SRPs. Miller (2009) noted that

electromyography (EMG) and tissue biopsies of skin and/or muscle are important

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facets of the evaluation of patients with possible DM or PM. Abnormalities in EMG

may support the diagnosis of DM or PM but are not diagnostic. Moreover, skin

biopsy (e.g., findings of Gottron's sign, the shawl sign, and erythroderma) can

provide confirmation of the diagnosis of DM. In addition, muscle biopsy is the

definitive test for PM, in which skin lesions are not seen.

Although MSA may offer valuable information regarding prognosis and potential

future patterns of organ involvement, there is no reliable evidence that detection of

these antibodies influences clinical management. Furthermore, while there is some

limited evidence on the association between the presence of MSA with cancer-

associated myositis (CAM), the available literature on this association is limited.

Chinoy et al (2007) stated that these antibody tests are not foolproof, and do not

replace the need for intensive surveillance for cancer in persons with new onset

myositis. The authors concluded that before these results can be applied clinically,

confirmation in a large independent trial with prospective follow-up is needed.

Kalluri et al (2009) stated that the anti-synthetase syndrome consists of interstitial

lung disease (ILD), arthritis, myositis, fever, mechanic's hands, and Raynaud

phenomenon in the presence of an anti-synthetase autoantibody, most commonly

anti-Jo-1. It is believed that all the anti-synthetases are associated with a similar

clinical profile, but definitive data in this diverse group are lacking. These

researchers examined the clinical profile of anti-PL-12, an anti-synthetase

autoantibody directed against alanyl-transfer RNA synthetase. A total of 31

subjects with anti-PL-12 autoantibody were identified from the databases at the

Medical University of South Carolina, the University of Pittsburgh Medical Center,

Johns Hopkins Medical Center, and Brigham and Women's Hospital. The medical

charts were reviewed and the following data were recorded: demographic

information; pulmonary and rheumatological symptoms; connective tissue disease

(CTD) diagnoses; serological autoantibody findings; CT scan results; BAL findings;

pulmonary function test results; lung histopathology; and treatment interventions.

The median age at symptom onset was 51 years; 81 % were women and 52 %

were African American; 90 % of anti-PL-12-positive patients had ILD, 65 % of

whom presented initially to a pulmonologist; 90 % of anti-PL-12-positive patients

had an underlying CTD. Polymyositis and DM were the most common underlying

diagnoses. Raynaud phenomenon occurred in 65 % of patients, fever in 45 % of

patients, and mechanic's hands in 16 % of patients. Test results for the presence

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of antinuclear antibody were positive in 48 % of cases. The authors concluded that

anti-PL-12 is strongly associated with the presence of ILD, but less so with myositis

and arthritis.

Derfuss and Meinl (2012) stated that identification of auto-antigens in demyelinating

diseases is essential for the understanding of the pathogenesis. Immune

responses against these antigens could be used as biomarkers for diagnosis,

prognosis and treatment responses. Knowledge of antigen-specific immune

responses in individual patients is also a prerequisite for antigen-based therapies.

A proportion of patients with demyelinating disease have antibodies to aquaporin 4

(AQP4) or myelin oligodendrocyte glycoprotein (MOG). Patients with anti-AQP4

have the distinct clinical presentation of neuromyelitis optica (NMO), and these

patients often also harbor other autoimmune responses. In contrast, anti-MOG is

seen in patients with different disease entities such as childhood multiple sclerosis

(MS), acute demyelinating encephalomyelitis (ADEM), anti-AQP4 negative NMO,

and optic neuritis, but hardly in adult MS. A number of new candidate auto-

antigens have been identified and await validation. Antigen-based therapies are

mainly aimed at tolerizing T-cell responses against myelin basic protein (MBP) and

have shown only modest or no clinical benefit so far. The authors concluded that

currently, only few patients with demyelinating diseases can be characterized

based on their auto-antibody profile. The most prominent antigens in this respect

are MOG and AQP4. Moreover, they stated that further research has to focus on

the validation of newly discovered antigens as biomarkers.

Reindl et al (2013) noted that MOG has been identified as a target of demyelinating

auto-antibodies in animal models of inflammatory demyelinating diseases of the

central nervous system (CNS), such as MS. Numerous studies have aimed to

establish a role for MOG antibodies in patients with MS, although the results have

been controversial. Cell-based immunoassays using MOG expressed in

mammalian cells have demonstrated the presence of high-titer MOG antibodies in

pediatric patients with ADEM, MS, AQP4-seronegative NMO, or isolated optic

neuritis (ON) or transverse myelitis (TM), but only rarely in adults with these

disorders. These studies indicated that MOG antibodies could be associated with a

broad spectrum of acquired human CNS demyelinating diseases. The authors

discussed the current literature on MOG antibodies, their potential clinical

relevance, and their role in the pathogenesis of MOG antibody-associated

demyelinating disorders.

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Hacohen and colleagues (2014) noted that auto-antibodies to glial, myelin and

neuronal antigens have been reported in a range of central demyelination

syndromes and autoimmune encephalopathies in children, but there has not been a

systematic evaluation across the range of CNS autoantibodies in childhood-

acquired demyelinating syndromes (ADS). Children under the age of 16 years with

first-episode ADS were identified from a national prospective surveillance study;

serum from 65 patients had been sent for a variety of diagnostic tests. Antibodies

to astrocyte, myelin and neuronal antigens were tested or re-tested in all samples.

A total of 15 patients (23 %) were positive for at least 1 antibody (Ab): AQP4-Ab

was detected in 3 (2 presenting with NMO and 1 with isolated ON); MOG-Ab was

detected in 7 (2 with ADEM, 2 with ON, 1 with TM and 2 with clinically isolated

syndrome [CIS]). N-Methyl-D-Aspartate receptor (NMDAR)-Ab was found in 2 (1

presenting with ADEM and 1 with ON). Voltage-gated potassium channel (VGKC)

-complex antibodies were positive in 3 (1 presenting with ADEM, 1 with ON and 1

with CIS). Glycine receptor antibody (GlyR-Ab) was detected in 1 patient with TM.

All patients were negative for the VGKC-complex-associated proteins LGI1,

CASPR2 and contactin-2. The authors concluded that a range of CNS-directed

autoantibodies were found in association with childhood ADS. Moreover, they

stated that although these antibodies are clinically relevant when associated with

the specific neurological syndromes that have been described, further studies are

needed to evaluate their roles and clinical relevance in demyelinating diseases.

Furthermore, an UpToDate review on “Differential diagnosis of acute central

nervous system demyelination in children” (Lotze, 2014) states that “Differential

diagnostic considerations for acute central nervous system demyelination in

children include acute disseminated encephalomyelitis (ADEM), multiple sclerosis

(MS), optic neuritis, transverse myelitis, neuromyelitis optica (Devic disease), and

various infectious, metabolic, and rheumatologic conditions. Most of these

conditions are thought to be caused by immune system dysregulation triggered by

an infectious agent in a genetically susceptible host. With the possible exception of

the NMO-IgG autoantibody found in neuromyelitis optica, there are no disease-

specific biomarkers for these conditions, making it difficult to distinguish among

them at the time of the initial presentation. However, certain clinical features,

laboratory results, and imaging findings can usually lead to the correct diagnosis”.

Aquaporin-4 Autoantibodies

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Approximately 75 percent of patients with neuromyelitis optica (NMO) express

antibodies to the aquaporin-4 (AQP4) receptor. Diagnosis of NMO requires the

presence of longitudinally extensive acute myelitis (lesions extending over 3 or

more vertebral segments) and optic neuritis. While absence of antibodies to the

AQP4 receptor does not rule out the diagnosis of NMO, presence of this antibody is

diagnostic for NMO.

Waschbisch et al (2013) stated that recurrent optic neuritis is frequently observed in

multiple sclerosis (MS) and is a typical finding in NMO. Patients that lack further

evidence of demyelinating disease are diagnosed with RION (recurrent isolated

optic neuritis) or CRION (chronic relapsing inflammatory neuropathy) if they require

immunosuppressive therapy to prevent further relapses. The etiology and disease

course of this rare condition are not well-defined. These investigators studied a

series of 10 patients who presented with recurrent episodes of isolated optic

neuritis (ON, n = 57) and were followed over a median of 3.5 years. Visual acuity

was severely reduced at the nadir of the disease (20/200 to 20/800). All patients

had MRI non-diagnostic for MS/NMO and were aquaporin-4 antibody negative. Six

patients fulfilled the CRION criteria. In 2 of these a single ON followed by a long

disease-free interval preceded development of CRION for years, suggesting the

conversion of an initially "benign" isolated ON into the chronic relapsing course.

Cerebrospinal fluid (CSF) analysis revealed mild pleocytosis in 5 patients, identical

oligoclonal bands in serum and CSF were observed in 2 patients, while the others

remained negative. The authors concluded that recurrent ON is a disease entity

that requires aggressive glucocorticoid and eventually long-term

immunosuppressive therapy to prevent substantial visual impairment.

Petzold and Plant (2014) noted that CRION is an entity that was described in 2003.

Early recognition of patients suffering from CRION is relevant because of the

associated risk for blindness if treated inappropriately. These researchers

performed a systematic literature review, irrespective of language, on CRION.

They retrieved 22 case series and single reports describing 122 patients with

CRION between 2003 and 2013. They reviewed the epidemiology, diagnostic work-

up, differential diagnosis, and treatment (acute, intermediate, and long-term) in view

of the collective data. These data suggested that CRION is a distinct nosological

entity, which is sero-negative for anti-aquaporin-4 autoantibodies and recognized by

and managed through its dependency on immuno-suppression.

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Sakalauskaite-Juodeikiene et al (2018) stated that NMO is frequently associated

with AQP4 autoantibodies (AQP4-Ab); however, studies of NMO in Lithuania are

lacking. These researchers examined positivity for AQP4-Ab in patients presenting

with inflammatory demyelinating CNS diseases other than typical MS in Lithuania.

Data were collected from the 2 largest University hospitals in Lithuania. During the

study period, there were 121 newly diagnosed typical MS cases, which were

included in the MS registry database. After excluding these typical MS cases,

these investigators analyzed the remaining 29 cases of other CNS inflammatory

demyelinating diseases, including atypical MS (n = 14), acute transverse myelitis

(TM; n = 8), acute disseminated encephalomyelitis (ADEM; n = 3), clinically isolated

syndrome (CIS; n = 2), atypical optic neuritis (ON; n = 1), and NMO (n = 1). These

researchers assessed positivity for AQP4-Ab for the 29 patients and evaluated

clinical, laboratory, and instrumental differences between AQP4-Ab sero-positive

and AQP4-Ab sero-negative patient groups. AQP4-Ab test was positive for 3 (10.3

%) patients in this study, with initial diagnoses of atypical MS (n = 2) and ADEM (n

= 1); 1 patient was AQP4-Ab negative despite being previously clinically diagnosed

with NMO. There were no significant clinical, laboratory, or instrumental differences

between the groups of AQP4-Ab positive (3 [10.3 %]) and negative (26 [89.7 %])

patients. The authors concluded that AQP4-Ab test was positive for 1/10 of

patients with CNS inflammatory demyelinating diseases other than typical MS in

this study. They stated that AQP4-Ab testing is highly recommended for patients

presenting with not only TM and ON but also an atypical course of MS and ADEM.

Multi-Analyte Assays with Algorithmic Analyses (MAAAs)

Multi-analyte assays with algorithmic analyses (MAAAs) are laboratory

measurements that use a mathematic formula to analyze multiple markers that may

be associated with a particular disease state and are designed to evaluate disease

activity or an individual’s risk for disease. The laboratory performs an algorithmic

analysis using the results of the assays and sometimes other individual information,

such as gender and age and converts the information into a numeric score, which is

conveyed on a laboratory report. Generally, MAAAs are exclusive to a single

laboratory that owns the algorithm; MAAAs are suggested to assess risk, to

diagnose or monitor disease activity of conditions such as epilepsy, as well as

autoimmune connective tissue disease (CTD) and hepatitis C.

Autoimmune Epilepsy Evaluation uses a gene sequencing multi-analyte panel to

analyze 5 antibodies purportedly associated with autoimmune epilepsy. The

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autoantibodies included in the test are: (i) contactin-associated protein-like 2

(CASPR2), (ii) glutamic acid decarboxylase (GAD65), (iii) leucine-rich, glioma

inactivated 1 (LGI1), (iv) NMDA Receptor (NR1), and (v) voltage-gated potassium

channel complex (VGKC).

Antibody Tests for Screening of Neurologic Diseases

Tebo and colleagues (2016) noted that significant progress has been made in

understanding the role and diversity of autoantibodies in the pathogenesis,

diagnosis and management of paraneoplastic syndrome (PNS) and related

autoimmune neurologic diseases. These investigators evaluated the positivity rates

for diverse autoantibody panels to rationalize testing strategies and utilization. The

result patterns for different autoantibody panels for PNS offered at 2 reference

laboratories in the U.S. were retrospectively reviewed for the same period. The

positivity rates were evaluated and compared for specific autoantibodies within

panels offered at both laboratories. For the Hu, Ri, Yo, and amphiphysin antibodies

offered by both laboratories, no significant difference in positivity rates was

observed. The positivity rates for non-classic PNS markers were 0 % [AGNA and

PCCA-Tr], and 0.06 % [ANNA-3 and PCAC-2] while the prevalence of antibodies

associated with neuromuscular autoimmunity varied from 1.40 % to 4.44 %

[Striated muscle, AChR binding, ganglionic AChR, VGCC, P/Q- and N-type

VGCC]. The authors concluded that these data suggested that test utilization could

be substantially improved based on ordering practice geared towards clinical

manifestations and prevalence of autoantibodies. Moreover, they stated that

concerted efforts towards streamlining diagnostic algorithms based on risk, clinical

manifestations, characterization of autoantibodies and their associations as well as

therapeutic strategies are needed.

Appendix

Table 1: Disorders Associated with Antibodies to Glycolipid and Glycoprotein-

Related Saccharides

Sensory-Motor

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Sulfatide

Adapted from: Pestronk, 2008.

Table 2: Antibodies Associated with Paraneoplastic Syndromes and

Associated Cancers

Associated

Gynecological,

encephalitis, opsoclonus-myoclonus

Page 20 of 30

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Anti-

CV2/CRMP5

Paraneoplastic encephalomyelitis, paraneoplastic

cerebellar degeneration, chorea, peripheral

neuropathy

Germ-cell tumors of

testis, lung cancer,

other solid tumors

Anti-Ma

proteins (Ma1,

Ma2)***

Limbic, hypothalamic, brainstem encephalitis

(infrequently paraneoplastic cerebellar

degeneration)

Breast, testicular,

other

Anti-

amphiphysin

Stiff-person syndrome, paraneoplastic

encephalomyelitis

SCLC

Anti-recoverin Cancer-associated retinopathy (CAR)

Partially-characterized paraneoplastic antibodies**

Anti-Zic 4 Paraneoplastic cerebellar degeneration SCLC

mGluR1 Paraneoplastic cerebellar degeneration Hodgkin's lymphoma

ANNA-3 Paraneoplastic sensory neuronopathy,

paraneoplastic encephalomyelitis

SCLC

PCA2 Paraneoplastic encephalomyelitis, paraneoplastic

cerebellar degeneration

SCLC

Anti-bipolar

cells of the

retina

Melanoma-associated retinopathy (MAR) Melanoma

Antibodies that occur with and without cancer association

Anti-VGCC Lambert-Eaton myasthenic syndrome,

paraneoplastic cerebellar dysfunction

SCLC

Anti-AChR Myasthenia gravis Thymoma

Anti-VGKC Neuromyotonia, limbic encephalitis, seizures Thymoma, others

nAChR Subacute pandysautonomia SCLC, others

Key: AChR: acetylcholine receptor; APCA: anti-Purkinje cell antibody; ANNA: anti-

neuronal-nuclear antibody; SCLC: small-cell lung cancer; VGCC: voltage-gated

calcium channel; VGKC: voltage-gated potassium channel; nAChR: ganglionic

nicotinic acetylcholine receptor antibodies.

* Well-characterized antibodies are those directed against antigens whose

molecular identity is known, or that have been identified by several investigators.

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** Partially-characterized antibodies are those whose target antigens are unknown

or require further analysis in groups of individuals serving as controls.

*** Antibodies to Ma2: younger than 45 years, usually men with testicular germ-cell

tumors; older than 45, men or women with lung cancer and less frequently other

tumors. Ma1 antibodies often associated with tumors other than germ-cell

neoplasms and confers a worse prognosis, with more prominent brainstem and

cerebellar dysfunction.

Adapted from: Dalmau and Rosenfeld, 2006; Bataller and Dalmau, 2004.

CPT Codes / HCPCS Codes / ICD-10 Codes

Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":

Other CPT codes related to the CPB:

83516 Immunoassay for analyte other than infectious agent antibody or

infectious agent antigen; qualitative or semiquantitative, multiple step

method [NMO-IgG autoantibody test]

83519 Immunoassay, analyte, quantitative; by radiopharmaceutical technique

(eg, RIA) [LEMS antibody test]

83520 not otherwise specified

84182 Protein, Western Blot, with interpretation and report, blood or other body

fluid, immunological probe for band identification, each

84238 Receptor assay; non-endocrine (specify receptor)

86235 Extractable nuclear antigen, antibody to, any method (e.g., nRNP, SS-A,

SS-B, Sm, RNP, Sc170, J01), each antibody

86255 Fluorescent noninfectious agent antibody; screen, each antibody [LEMS

antibody test]

ICD-10 codes covered if selection criteria are met:

H46.9

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

G36.0

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G37.0

G37.3

G61.0

G61.89

G62.89

Z13.858

Page 23 of 30

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