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Neuroimmunology testing services Neuroimmunology

Quest Diagnostics is your source for neuroimmunological testing with expanded offerings for several autoimmune neurological disorders

Neuroimmunology is the field of autoimmune disorders Table 1 Autoimmune neurological disorders that affect the central (CNS) and range Autoimmune ataxia, Movement disorders in diversity from neuromuscular and movement disorders , to neuro-oncology. Clinical neuroimmunology testing is a rapidly growing field driven by the increasing amount of Myasthenia gravis, Neuromuscular disorders newly discovered neural autoantibodies. Lambert Eaton It is important to test for these antibodies as many Paraneoplastic neurological are associated with treatable neurological . Neuro-oncology Autoantibody-mediated neuroimmunological disorders can syndrome (PNS) arise from tumors, genetic predisposition, or even Autoimmune , such as polyneuropathy disorder and Guillain-Barré function disorders syndrome (GBS) (which can result from the Zika ).

Testing can be useful to exclude an immunological disorder (MS), Demyelinating that may be responsible for the neurological symptoms neuromyelitis optica (NMO) present in a patient. When a patient presents with symptoms suggesting a CNS autoimmune disorder, early identification Guillain-Barré syndrome Peripheral nervous of antibodies can help direct therapy in patients likely to (GBS), peripheral and system (PNS) disorders improve with treatments such as immunotherapy. sensory neuropathies

Table 2 ICD-10 Codes1

ICD Code Symptom Description ICD Code Symptom Description ICD Code Symptom Description

Neuro-oncology Tests (Paraneoplastics) Neuromyelitis Optica Myasthenia Gravis

G62.9 Polyneuropathy, unspecified G36.0 Neuromyelitis optica [Devic] H53.2 Diplopia

Hereditary and idiopathic Myasthenia gravis without G60.9 G35 Multiple sclerosis G70.00 neuropathy, unspecified (acute) exacerbation R42 Dizziness and giddiness Myasthenia gravis with R20.2 of skin G70.01 (acute) exacerbation G95.9 of , unspecified M62.81 Muscle weakness (generalized) M62.81 Muscle weakness (generalized) Other long term (current) Unspecified disturbances Z79.899 Unspecified ptosis of R20.9 drug therapy H02.409 of skin sensation unspecified eyelid R41.3 Other amnesia E78.5 Hyperlipidemia, unspecified Unspecified ptosis of H02.403 bilateral eyelids of central R27.0 Ataxia, unspecified G37.9 nervous system, unspecified H02.402 Unspecified ptosis of left eyelid G60.3 Idiopathic progressive neuropathy M12.9 Arthropathy, unspecified H02.401 Unspecified ptosis of right eyelid R20.0 Anesthesia of skin Acute transverse in G37.3 demyelinating disease of central R53.1 Weakness nervous system R53.83 Other fatigue E03.9 Hypothyroidism, unspecified H46.9 Unspecified Unspecified abnormalities R26.9 of gait and mobility Deficiency of other specified E53.8 Paraneoplastic neuromyopathy B group vitamins G13.0 and neuropathy Neoplasm of unspecified behavior D49.9 of unspecified site

2 Quest Diagnostics | Neuroimmunology Paraneoplastic and other CNS disorders

Paraneoplastic neurological syndromes (PNS) are a set of Paraneoplastic antibodies degenerative autoimmune disorders due to the remote In a majority of PNS, the neurological symptoms appear effects of cancer. Identification of a specific paraneoplastic before the cancer has been identified. Identification antibody can guide the search for an underlying malignancy. of paraneoplastic antibodies can direct the search for an underlying cancer, increasing the likelihood of making Early detection and quick treatment can make a an early diagnosis of the tumor and treating the difference in patient outcomes neurological symptoms. “Patients with disorders of the CNS associated with autoantibodies can now be diagnosed and treated.”2 Other CNS autoantibodies The positive identification of specific antibodies can help Immunotherapy and other treatments have been successful direct therapy to improve patient outcomes, avoid treatment in patients with antibodies against LGI1, CASPR2, VGKC, that may harm the patient, and/or aid in early detection and NMDA (NR1) and GAD65. Early detection may enable treatment of cancer. better outcomes.2

Figure 1 Interpretation of “Paraneoplastic Antibody Evaluation with Reflex to Titer and Western Blot, Basic (Test Code 93876) Panel”

Patient with suspected paraneoplastic neurological syndrome

Paraneoplastic Antibody Evaluation with Reflex to Titer and Western Blot, Basic Reflex tests

AChR modulating Positive Myasthenia gravis antibody AChR binding antibody positive or equivocal Cerebellar degeneration, CRMP5 / CV2 /limbic Positive Western blot , sensory neuropathy, chorea, or optic neuritis

AMPAR1, AMPAR2, or Encephalomyelitis or AMPAR, GABABR, GABABR positive AMPAR1, AMPAR2, or NMDAR suggested GABABR, NMDAR (CBA) by tissue IFA Encephalitis with psychiatric manifestations, , , NMDAR Positive , and autonomic instability

Encephalomyelitis or ANNA3 positive by tissue IFA ANNA3 titer >1:40 sensory neuropathy

NMO antibody suggested by Aquaporin 4 (NMO) Positive Neuromyelitis optica tissue IFA pattern

Encephalomyelitis, PCA2 positive by tissue IFA PCA2 titer >1:40 cerebellar degeneration

Striated muscle Striated muscle >1:40 Myasthenia gravis or thymoma antibody positive antibody titer

AGNA/SOX1, amphiphysin, This figure was developed by Quest Diagnostics based on ANNA1, ANNA2, references 3 – 13. It is provided for informational purposes CRMP5/CV2, GAD65, PCA1, Western blot, only and is not intended as medical advice. A physician’s test Positive PCA2, or PCA-Tr (DNER) quantitative selection and interpretation, diagnosis, and patient positive, indeterminate, or management decisions should be based on his/her education, suggested by IFA clinical expertise, and assessment of the patient.

gAChR, VGCC (N-type), VGCC (P/Q-type), or VGKC positive Quest Diagnostics | Neuroimmunology 3 Neuroimmunology

Figure 2 Interpretation of “Paraneoplastic Antibody Evaluation, CSF, Basic (Test Code 94536) Panel”

Patient with suspected paraneoplastic neurological syndrome

Paraneoplastic Antibody Evaluation, CSF, Basic

Reflex tests

AMPAR1, AMPAR2, GABABR, AMPAR1, AMPAR2, NMDAR1, CASPR2, LGI1 GABABR, NMDAR1, AMPAR1, AMPAR2, or Encephalomyelitis or limbic encephalitis suggested by tissue IFA CASPR2, LGI1 (CBA) GABABR titer >1:10

Encephalitis with psychiatric Titer for positive Positive (any test) NMDAR1 titer >1:10 manifestations, seizures, dyskinesias, antibody dystonia, and autonomic instability

CASPR2 or LGI1 titer Limbic encephalitis, neuromyotonia, >1:10 or Morvan syndrome

ANNA3 positive by ANNA3 titer >1:10 Encephalomyelitis or sensory neuropathy tissue IFA

NMO antibody suggested by Aquaporin 4 (NMO), Aquaporin 4 (NMO), Positive >1:10 Neuromyelitis tissue IFA pattern CBA titer optica

PCA2 positive by tissue IFA PCA2 titer >1:10 Encephalomyelitis, cerebellar degeneration

AGNA/SOX1, amphiphysin, ANNA1, ANNA2, CRMP5/CV2, GAD65, PCA1, Western line blot, Positive (signal Refer to table for interpretation or PCA-Tr (DNER) positive, quantitative intensity >11) indeterminate, or suggested by IFA

VGKC, LGI1, CASPR2 antibody Neuronal (V-G) K+ suggested by tissue IFA >20 pmol/L Refer to table for interpretation pattern Channel Ab, CSF

This figure was developed by Quest Diagnostics based on references 8, 12, 23, and 24. It is provided for informational purposes only and is not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.

4 Quest Diagnostics | Neuroimmunology Table 3 Para antibodies and associated cancers and clinical significance

Associated neurologic syndrome Associated tumor or cancer type

Autoantibody target neuropathy Autonomic encephalitis/Brainstem - Cerebellar degeneration Encephalomyelitis / LE LEMS gravisMyasthenia optica Neuromyelitis Neuromyotonia Sensory neuropathy Stiff person Other cancer Breast lymphoma Hodgkin's Lung cancer Ovarian cancer Prostate cancer cancer cell Renal SCLC tumor Testicular Thymoma Other AChR • ° AGNA/SOX1 • • • • • ° AMPAR • • • • • • Amphiphysin • • • ° • ° ANNA1 (Hu) • • • • • ° gynecological ANNA2 (Ri) • • ° • ° tumors ANNA3ª • • • Aquaporin 4 (NMO) • • • CRMP5/CV2 • • • • •b ° ° GABABR • •c ° gastrointestinal, lymphoid, gAChR d • • • • • • • ° • melanoma, bladder

pancreatic, GAD65 • • • • • • • thymic cancer NMDAR •e °f •f PCA1 (Yo) • • ° PCA2ª • • • PCA-Tr (DNER) • ° Striated muscle • ° VGCC, N-type • ° VGCC, P/Q-type • • ° VGKC • • •g • •

° indicates tumor type(s) most frequently associated with the antibody; LE, limbic encephalitis; LEMS, Lambert-Eaton myasthenia gravis, SCLC, small-cell lung cancer. a Case report d Cortical and neuropsychiatric presentation f Teratoma b Chorea, optic neuritis e Encephalitis with psychiatric manifestations, seizures, g Morvan syndrome c Tumor dyskinesias, dystonia, and autonomic instability

Quest Diagnostics | Neuroimmunology 5 Neuroimmunology

AQP4 autoantibody for neuromyelitis optica (NMO)

When the syndrome is severe, and multiple sclerosis Finding NMO early can make a difference. Consider NMO (MS) is ruled out, could it be neuromyelitis optica? in the following patients with ON or TM (or both) and an NMO is a rare and severe disease syndrome of the CNS MRI without “typical” lesions: that affects the optic nerves and spinal cord. It is primarily • Patients who have MS-like symptoms characterized by optic neuritis (ON) and transverse myelitis • Patients with a spinal cord lesion extending contiguously (TM) —and the prognosis is serious. Because the symptoms over three or more spinal segments are similar to MS, especially early in the disease course, NMO can be misdiagnosed as MS. NMO is known to progress • Patients with normal brain MRI findings that show rapidly. Within five years 50% of patients lose functional vision non-specific white-matter lesions that do not fulfill the in one eye or become unable to walk independently.14 It is criteria for diagnosis of MS important to distinguish between the two and provide the • The about 5% of MS patients that have “normal” appropriate treatment as well as understand the prognosis. brain MRIs, suggesting they do not have MS, may be 17 • Most relapses of NMO worsen over several days and then false-negatives slowly improve in the weeks or months after the maximum • Patients with abnormal MRI and MS-looking lesions that clinical deficit is reached. Recovery is usually incomplete, are actually age-related. Some estimate 5% of these and most patients follow a course of early incremental patients will have a false-positive diagnosis. A false- disability due to frequent and severe relapses.15 positive diagnosis can be potentially dangerous because 17 • Current evidence suggests that conventional it implies unnecessary successive tests and treatments immunomodulatory treatments for MS are ineffective for NMO.16 Methodology Aquaporin 4 antibody is detected by indirect immunofluorescence on HEK293 cells that express recombinant aquaporin 4.

Multiple sclerosis Patients with MS have multiple abnormal changes in areas of the brain. Symptoms can initially be mild but typically lead to relapsing or progressive incapacitating of neuromotor dysfunction.

6 Quest Diagnostics | Neuroimmunology Immunological testing for myasthenia gravis (MG)

Myasthenia gravis panel 2 with reflex — quantitative AChR binding, blocking, modulating antibodies with Normal MG reflex to MuSK antibody testing Myasthenia gravis (MG) is an autoimmune disorder characterized by muscle weakness that ranges from mild weakness of specific muscle groups to severe weakness ACh AChR Ab of multiple muscle groups. MG affects approximately 20 AChR per 100,00018 patients and arises from antibody-mediated synaptic dysfunction of the transmission of nerve impulses to muscle fibers at the neuromuscular junction. This Muscle disruption involves either acetylcholine receptors (AChR) or muscle-specific kinase receptors (MuSK) that ultimately Figure 2 Diagram of the neuromuscular junction showing motor inhibit muscle contraction. Onset of symptoms is generally transmitting acetylcholine (ACh) to receptors in gradual, but can sometimes be acute following viral the muscle tissue. (Left) ACh freely binds with the ace- or pregnancy. tylcholine receptors (AChR). (Right) ACh is blocked from binding to the receptors by AChR antibodies.

What are the symptoms of MG?19,20 Performing AChR antibody quantification may be important as AChR antibody levels are directly proportional to disease • Weakness and fatigue of skeletal muscles, ranging from severity in the population, but the absolute level does not mild to severe weakness of multiple muscle groups. necessarily correspond to disease severity in individual 90% have ptosis or diplopia with pupillary involvement patients. Binding antibodies were present in 82% of patients • MuSK antibody-positive patients experience more with moderate / severe generalized disease; 69% of patients pronounced bulbar weakness and may have tongue and with mild, generalized disease; and 59% of patients with facial atrophy ocular myasthenia.18

AChR-positive patients MuSK

• Limb weakness, ptosis, diplopia, dysarthria, dysphagia Seventy percent of seronegative19 AChR patients have antibodies to MuSK. Overall, MuSK antibodies are seen in MuSK-positive patients 5% to 10% of all MG patients. MuSK antibody-positive MG patients are also less likely to respond to acetylcholinesterase • Bulbar weakness is predominant, and can include inhibitors (AChE), and symptoms may worsen with certain ptosis, diplopia, dysarthria, facial weakness, difficulty medications.20 It is important that MuSK antibody-positive chewing or swallowing; other MG patients are identified, as one-third of patients may vary experience a life-threatening respiratory crisis, and long- term immunosuppression is the sole treatment.21 Patients who test positive for MuSK antibodies are much less likely to have thymomas.

Quest Diagnostics | Neuroimmunology 7 Table 4 Test ordering information22

Turnaround Test Code Test Name Specimen Requirements CPT Codes Time (TAT) Neuro-oncology Tests Serum; Frozen; 93876 Paraneoplastic Antibody Evaluation, Serum, Basic 7 – 14 days 86255 (×10), 83519 (×5) 6 mL preferred (3.5 mL minimum) Paraneoplastic Antibody Evaluation with Reflex to Titer 3.8 mL CSF collected in a sterile 94536 7 – 14 days 86255 (x10), 86341 and WB, Basic, CSF leak-proof container Neuromyelitis Optica

90382 AQP-4 Antibody (ELISA) 6 – 8 days 2 mL serum (0.5 mL minimum) 83516

0.5 mL (0.3 mL minimum) serum collected in a red-top tube 93893 AQP-4 Antibody (Cell Based Assay) 7 days 86255 (no gel) or CSF collected in a sterile, screwcap container Myasthenia Gravis Myasthenia Gravis Panel 2 with Reflex to MuSK Antibody 83519 (×3) without reflex 93859 4 – 7 days 3 mL serum (0.7 mL minimum) AChR Binding, Blocking, Modulating Antibody 83519 (×4) with MuSK reflex

206 AChR Binding Antibody 1 – 2 days 1 mL serum (0.5 mL minimum) 83519

34459 AChR Blocking Antibody 3 – 5 days 1 mL serum (0.5 mL minimum) 83519

26474 AChR Modulating Antibody 5 days 1 mL serum (0.5 mL minimum) 83519

18842 MuSK Antibody 4 – 7 days 2 mL serum (0.5 mL minimum) 83519

86255 266 Anti-Striated Muscle Antibody with Reflex to Titer 5 days 0.5 mL serum (0.1 mL minimum) (86256 with titer reflex) Myasthenia Gravis Panel 1 83519, 86255 7550 5 days 2 mL serum (0.4 mL minimum) AChR Binding, Anti-Striated Muscle Antibody w/Reflex (86256 with titer reflex) Myasthenia Gravis Panel 2 10104 5 days 2 mL serum (0.7 mL minimum) 83519 (×3) AChR Binding, Blocking, Modulating Antibody

Myasthenia Gravis Panel 3 83519 (×3), 86255 10211 AChR Binding, Blocking, Modulating Antibody, 5 days 2 mL serum (0.8 mL minimum) Anti-Striated Muscle Antibody w/Reflex (86256 with titer reflex) Multiple Sclerosis 2.2 mL CSF and 1 mL serum Multiple Sclerosis Panel 17728 4 – 6 days 83873, 83916 Basic Protein; Oligoclonal Bands IgG Minimum Volume: 1 mL CSF and 0.5 mL serum Multiple Sclerosis Panel 1 37581 3 – 5 days 3 mL CSF and 2 mL serum 82040, 82042, 82784 (×2),83916 Albumin IgG, Oligoclonal Bands, and IgG Synthesis Rate / Index

Multiple Sclerosis Panel 2 82040, 82042, 82784 (×2), 7085 Albumin IgG, IgG Synthesis Rate/Index Myelin Basic Protein, 4 – 6 days 4 mL CSF and 2 mL serum and Oligoclonal Bands 83873, 83916

1.866.MY.QUEST (1.866.697.8378) or visit QuestDiagnostics.com/NeuroImmunology

References 1. This list of commonly submitted 4. Dalmau J, Gleichman AJ, Hughes EG, et 14. Wingerchuk DM, et al. The Spectrum of / myasthenia-gravis/. diagnoses is intended to assist ordering al. Lancet Neurol. 2008;7:1091-1098. neuromyelitis optica. Lancet, 2007. Published February 2014. Accessed April physicians in providing ICD-10-CM 5. Graus F, Vincent A, Pozo-Rosich P, et al. J 15. Wingerchuk DM, et al. The clinical 7, 2016. codes. This is not a comprehensive Neuroimmunol. 2005;165:166-171. course of neuromyelitis optica (Devic’s 20. Shah AK. Myasthenia Gravis Workup. list and an ICD-10-CM book should 6. Hoftberger R, van Sonderen A, Leypoldt F, syndrome). Neurology, 1999. Medscape. http://emedicine.medscape. be used as the official reference. et al. Neurology. 2015;84:2403-2412. 16. Matiello, et al. NMO-IgG predicts the com/article/1171206-workup. Updated Diagnoses must always be documented 7. McKeon A, Lennon VA, Lachance DH, et outcome of recurrent optic neuritis, March 23, 2016. Accessed April 7, 2016. in the patient’s medical record. The al. Arch Neurol. 2009;66:735-741. Neurology, 2008. 21. Huijbers MG, Zhang W, Klooster R, et ultimate responsibility belongs to the 8. Pittock SJ, Lennon VA. Arch Neurol. 17. Whiting P, et al. Accuracy of magnetic al. MuSK IgG4 autoantibodies cause ordering physician to correctly assign 2008;65:629-632. resonance imaging for the diagnosis of myasthenia gravis by inhibiting binding the patient’s diagnosis based on the 9. Pittock SJ, Lucchinetti CF, Lennon VA. multiple sclerosis: systematic review, between MuSK and Lrp4. Proc Natl Acad patient’s history, symptoms, and Ann Neurol. 2003;53:580-587. BMJ, 2006. Sci US. 2013; 110(51): 20783-8. medical condition. 10. Pittock SJ, Lucchinetti CF, Parisi JE, et 18. Haven TR, Astill ME, Pasi BM. An 22. The CPT code provided herein is based 2. Vincent A, Bien CG, Irani SR, Waters P. al. Ann Neurol. 2005;58:96-107. Algorithm for Acetylcholine Receptor on AMA guidelines and is provided for Autoantibodies associated with diseases 11. Romi F, Skeie GO, Aarli JA, et al. J Neurol. Antibody Testing in Patients with informational purposes only. CPT coding is of the CNS: new developments and 2000;247:369-375. Suspected Myasthenia Gravis. Clinical the sole responsibility of the billing party. future challenges. Lancet Neurol 2011; 12. Titulaer MJ, Soffietti R, Dalmau J, et al. Chemistry. 2010; 56(6): 1028-1029. Any questions regarding coding should be 10:559-72. Eur J Neurol. 2011;18:19-e13. 19. Yuebing Li. Myasthenia Gravis. directed to the payer being billed. 3. Arino H, Hoftberger R, Gresa-Arribas N, 13. Yu Z, Kryzer TJ, Griesmann GE, et al. Ann Cleveland Clinic Center for Continuing 23. Chan KH, Vernino S, Lennon VA. et al. JAMA Neurol. 2015;72:874-881. Neurol. 2001;49:146-154. Education Website. http://www. Ann Neurol. 2001;50:301-311. clevelandclinicmeded.com/ 24. Irani SR, Alexander S, Waters P, et al. medicalpubs/diseasemanagement/ Brain. 2010;133:2734-2748. QuestDiagnostics.com Quest, Quest Diagnostics, any associated logos, and all associated Quest Diagnostics registered or unregistered trademarks are the property of Quest Diagnostics. All third-party marks — ® and ™ — are the property of their respective owners.© 2016 Quest Diagnostics Incorporated. All rights reserved. Models used for illustrative purposes. SB6137 12/2016