Neuroimmunology testing services

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Elizabeth Russell
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1 Neuroimmunology testing services

2 Neuroimmunology Quest Diagnostics is your source for neuroimmunological testing with expanded offerings for several autoimmune neurological disorders Neuroimmunology is the field of autoimmune disorders that affect the central nervous system (CNS) and range in diversity from neuromuscular and movement disorders to neuro-oncology. Clinical neuroimmunology testing is a rapidly growing field driven by the increasing amount of newly discovered neural autoantibodies. It is important to test for these antibodies as many are associated with treatable neurological diseases. Autoantibody-mediated neuroimmunological disorders can arise from tumors, genetic predisposition, or even infections such as polyneuropathy disorder and Guillain-Barré syndrome (GBS) (which can result from the Zika virus). Testing can be useful to exclude an immunological disorder that may be responsible for the neurological symptoms present in a patient. When a patient presents with symptoms suggesting a CNS autoimmune disorder, early identification of antibodies can help direct therapy in patients likely to improve with treatments such as immunotherapy. Table 1 Movement disorders Neuromuscular disorders Neuro-oncology Brain function disorders Demyelinating Autoimmune neurological disorders Peripheral nervous system (PNS) disorders Autoimmune ataxia, epilepsy, chorea Myasthenia gravis, Lambert Eaton Paraneoplastic neurological syndrome (PNS) Autoimmune dementia, encephalopathy Multiple sclerosis (MS), neuromyelitis optica (NMO) Guillain-Barré syndrome (GBS), peripheral and sensory neuropathies Table 2 ICD-10 Codes 1 ICD Code Symptom Description ICD Code Symptom Description ICD Code Symptom Description Neuro-oncology Tests (Paraneoplastics) G62.9 Polyneuropathy, unspecified G60.9 Hereditary and idiopathic neuropathy, unspecified R20.2 Paresthesia of skin M62.81 Muscle weakness (generalized) R20.9 Unspecified disturbances of skin sensation R41.3 Other amnesia R27.0 Ataxia, unspecified G60.3 Idiopathic progressive neuropathy R20.0 Anesthesia of skin R53.83 Other fatigue R26.9 G13.0 D49.9 Unspecified abnormalities of gait and mobility Paraneoplastic neuromyopathy and neuropathy Neoplasm of unspecified behavior of unspecified site Neuromyelitis Optica G36.0 Neuromyelitis optica [Devic] G35 R42 Multiple sclerosis Dizziness and giddiness G95.9 Disease of spinal cord, unspecified Z Other long term (current) drug therapy E78.5 Hyperlipidemia, unspecified G37.9 Demyelinating disease of central nervous system, unspecified M12.9 Arthropathy, unspecified G37.3 Acute transverse myelitis in demyelinating disease of central nervous system H46.9 Unspecified optic neuritis E53.8 Deficiency of other specified B group vitamins Myasthenia Gravis H53.2 Diplopia G70.00 G70.01 Myasthenia gravis without (acute) exacerbation Myasthenia gravis with (acute) exacerbation M62.81 Muscle weakness (generalized) H H Unspecified ptosis of unspecified eyelid Unspecified ptosis of bilateral eyelids H Unspecified ptosis of left eyelid H Unspecified ptosis of right eyelid R53.1 Weakness E03.9 Hypothyroidism, unspecified 2 Quest Diagnostics Neuroimmunology

Paraneoplastic and other CNS disorders Paraneoplastic neurological syndromes (PNS) are a set of degenerative autoimmune disorders due to the remote effects of cancer.

3 Paraneoplastic and other CNS disorders Paraneoplastic neurological syndromes (PNS) are a set of degenerative autoimmune disorders due to the remote effects of cancer. Identification of a specific paraneoplastic antibody can guide the search for an underlying malignancy. Early detection and quick treatment can make a difference in patient outcomes Patients with disorders of the CNS associated with autoantibodies can now be diagnosed and treated. 2 The positive identification of specific antibodies can help direct therapy to improve patient outcomes, avoid treatment that may harm the patient, and/or aid in early detection and treatment of cancer. Paraneoplastic antibodies In a majority of PNS, the neurological symptoms appear before the cancer has been identified. Identification of paraneoplastic antibodies can direct the search for an underlying cancer, increasing the likelihood of making an early diagnosis of the tumor and treating the neurological symptoms. Other CNS autoantibodies Immunotherapy and other treatments have been successful in patients with antibodies against LGI1, CASPR2, VGKC, NMDA (NR1) and GAD65. Early detection may enable better outcomes.2 Quest Diagnostics Neuroimmunology 3

4 Neuroimmunology 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 binding antibody positive or equivocal AChR modulating antibody CRMP5 / CV2 Western blot Positive Positive Myasthenia gravis Cerebellar degeneration, encephalomyelitis/limbic encephalitis, sensory neuropathy, chorea, or optic neuritis AMPAR, GABABR, or NMDAR suggested by tissue IFA AMPAR1, AMPAR2, GABABR, NMDAR (CBA) AMPAR1, AMPAR2, or GABABR positive NMDAR Positive Encephalomyelitis or limbic encephalitis Encephalitis with psychiatric manifestations, seizures, dyskinesias, dystonia, and autonomic instability ANNA3 positive by tissue IFA ANNA3 titer >1:40 Encephalomyelitis or sensory neuropathy NMO antibody suggested by tissue IFA pattern Aquaporin 4 (NMO) Positive Neuromyelitis optica PCA2 positive by tissue IFA PCA2 titer >1:40 Encephalomyelitis, cerebellar degeneration Striated muscle antibody positive Striated muscle antibody titer >1:40 Myasthenia gravis or thymoma AGNA/SOX1, amphiphysin, ANNA1, ANNA2, CRMP5/CV2, GAD65, PCA1, PCA2, or PCA-Tr (DNER) positive, indeterminate, or suggested by IFA Western blot, Quantitative Positive gachr, VGCC (N-type), VGCC (P/Q-type), or VGKC positive This figure was developed by Quest Diagnostics based on references 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

5 Table 3 Para antibodies and associated cancers and clinical significance Associated neurologic syndrome Associated tumor or cancer type Autoantibody target Autonomic neuropathy Brainstem encephalitis/ opsoclonus-myoclonus Cerebellar degeneration LE / Encephalomyelitis LEMS Myasthenia gravis Neuromyelitis optica Neuromyotonia Sensory neuropathy Stiff person Other Breast cancer Hodgkin's lymphoma Lung cancer Ovarian cancer Prostate cancer Renal cell cancer SCLC Testicular tumor Thymoma Other AChR AGNA/SOX1 AMPAR Amphiphysin ANNA1 (Hu) ANNA2 (Ri) ANNA3ª Aquaporin 4 (NMO) gynecological tumors CRMP5/CV2 b GABABR c gachr d GAD65 gastrointestinal, lymphoid, melanoma, bladder pancreatic, 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 d f Case report Cortical and neuropsychiatric presentation Teratoma b Chorea, optic neuritis c Tumor e Encephalitis with psychiatric manifestations, seizures, dyskinesias, dystonia, and autonomic instability g Morvan syndrome Quest Diagnostics Neuroimmunology 5

Neuroimmunology AQP4 autoantibody for neuromyelitis optica (NMO) When the syndrome is severe, and multiple sclerosis (MS) is ruled out, could it be neuromyelitis optica?

6 Neuroimmunology AQP4 autoantibody for neuromyelitis optica (NMO) When the syndrome is severe, and multiple sclerosis (MS) is ruled out, could it be neuromyelitis optica? NMO is a rare and severe disease syndrome of the CNS that affects the optic nerves and spinal cord. It is primarily characterized by optic neuritis (ON) and transverse myelitis (TM) and the prognosis is serious. Because the symptoms are similar to MS, especially early in the disease course, NMO can be misdiagnosed as MS. NMO is known to progress rapidly. Within five years 50% of patients lose functional vision in one eye or become unable to walk independently. 14 It is important to distinguish between the two and provide the appropriate treatment as well as understand the prognosis. Most relapses of NMO worsen over several days and then slowly improve in the weeks or months after the maximum clinical deficit is reached. Recovery is usually incomplete, and most patients follow a course of early incremental disability due to frequent and severe relapses. 15 Current evidence suggests that conventional immunomodulatory treatments for MS are ineffective for NMO. 16 Finding NMO early can make a difference. Consider NMO in the following patients with ON or TM (or both) and an MRI without typical lesions: Patients who have MS-like symptoms Patients with a spinal cord lesion extending contiguously over three or more spinal segments Patients with normal brain MRI findings that show non-specific white-matter lesions that do not fulfill the criteria for diagnosis of MS The about 5% of MS patients that have normal brain MRIs, suggesting they do not have MS, may be false-negatives 17 Patients with abnormal MRI and MS-looking lesions that are actually age-related. Some estimate 5% of these patients will have a false-positive diagnosis. A falsepositive diagnosis can be potentially dangerous because it implies unnecessary successive tests and treatments 17 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 reflex to MuSK antibody testing Normal MG

7 Immunological testing for myasthenia gravis (MG) Myasthenia gravis panel 2 with reflex quantitative AChR binding, blocking, modulating antibodies with reflex to MuSK antibody testing Normal MG Myasthenia gravis (MG) is an autoimmune disorder characterized by muscle weakness that ranges from mild weakness of specific muscle groups to severe weakness of multiple muscle groups. MG affects approximately 20 per 100, patients and arises from antibody-mediated synaptic dysfunction of the transmission of nerve impulses to muscle fibers at the neuromuscular junction. This disruption involves either acetylcholine receptors (AChR) or muscle-specific kinase receptors (MuSK) that ultimately inhibit muscle contraction. Onset of symptoms is generally gradual, but can sometimes be acute following viral infection or pregnancy. Figure 2 AChR ACh AChR Ab Muscle Diagram of the neuromuscular junction showing motor neurons transmitting acetylcholine (ACh) to receptors in the muscle tissue. (Left) ACh freely binds with the acetylcholine receptors (AChR). (Right) ACh is blocked from binding to the receptors by AChR antibodies. What are the symptoms of MG? 19,20 Weakness and fatigue of skeletal muscles, ranging from mild to severe weakness of multiple muscle groups. 90% have ptosis or diplopia with pupillary involvement MuSK antibody-positive patients experience more pronounced bulbar weakness and may have tongue and facial atrophy AChR-positive patients Limb weakness, ptosis, diplopia, dysarthria, dysphagia MuSK-positive patients Bulbar weakness is predominant, and can include ptosis, diplopia, dysarthria, facial weakness, difficulty chewing or swallowing; other signs and symptoms may vary Performing AChR antibody quantification may be important as AChR antibody levels are directly proportional to disease severity in the population, but the absolute level does not necessarily correspond to disease severity in individual patients. Binding antibodies were present in 82% of patients with moderate / severe generalized disease; 69% of patients with mild, generalized disease; and 59% of patients with ocular myasthenia. 18 MuSK Seventy percent of seronegative 19 AChR patients have antibodies to MuSK. Overall, MuSK antibodies are seen in 5% to 10% of all MG patients. MuSK antibody-positive MG patients are also less likely to respond to acetylcholinesterase inhibitors (AChE), and symptoms may worsen with certain medications. 20 It is important that MuSK antibody-positive MG patients are identified, as one-third of patients experience a life-threatening respiratory crisis, and longterm immunosuppression is the sole treatment. 21 Patients who test positive for MuSK antibodies are much less likely to have thymomas. Quest Diagnostics Neuroimmunology 7

8 Table 4 Test ordering information 22 Test Code Test Name Neuro-oncology Tests Turnaround Time (TAT) Paraneoplastic Antibody Evaluation, Serum, Basic 7 14 days Neuromyelitis Optica Specimen Requirements Serum; Frozen; 6 ml preferred (3.5 ml minimum) CPT Codes ( 10), ( 5) AQP-4 Antibody (ELISA) 6 8 days 2 ml serum (0.5 ml minimum) AQP-4 Antibody (Cell Based Assay) 7 days Myasthenia Gravis Myasthenia Gravis Panel 2 with Reflex to MuSK Antibody AChR Binding, Blocking, Modulating Antibody 0.5 ml (0.3 ml minimum) serum collected in a red-top tube (no gel) or CSF collected in a sterile, screwcap container 4 7 days 3 ml serum (0.7 ml minimum) ( 3) without reflex ( 4) with MuSK reflex 206 AChR Binding Antibody 1 2 days 1 ml serum (0.5 ml minimum) AChR Blocking Antibody 3 5 days 1 ml serum (0.5 ml minimum) AChR Modulating Antibody 5 days 1 ml serum (0.5 ml minimum) MuSK Antibody 4 7 days 2 ml serum (0.5 ml minimum) Anti-Striated Muscle Antibody with Reflex to Titer 5 days 0.5 ml serum (0.1 ml minimum) Multiple Sclerosis Myasthenia Gravis Panel 1 AChR Binding, Anti-Striated Muscle Antibody w/reflex Myasthenia Gravis Panel 2 AChR Binding, Blocking, Modulating Antibody Myasthenia Gravis Panel 3 AChR Binding, Blocking, Modulating Antibody, Anti-Striated Muscle Antibody w/reflex Multiple Sclerosis Panel Myelin Basic Protein; Oligoclonal Bands IgG Multiple Sclerosis Panel 1 Albumin IgG, Oligoclonal Bands, and IgG Synthesis Rate / Index Multiple Sclerosis Panel 2 Albumin IgG, IgG Synthesis Rate/Index Myelin Basic Protein, and Oligoclonal Bands 5 days 2 ml serum (0.4 ml minimum) 5 days 2 ml serum (0.7 ml minimum) ( 3) 5 days 2 ml serum (0.8 ml minimum) 4 6 days 2.2 ml CSF and 1 ml serum Minimum Volume: 1 ml CSF and 0.5 ml serum (86256 with titer reflex) 83519, (86256 with titer reflex) ( 3), (86256 with titer reflex) 83873, days 3 ml CSF and 2 ml serum 82040, 82042, ( 2), days 4 ml CSF and 2 ml serum 82040, 82042, ( 2), 83873, MY.QUEST ( ) or visit QuestDiagnostics.com/NeuroImmunology References 1. This list of commonly submitted diagnoses is intended to assist ordering physicians in providing ICD-10-CM codes. This is not a comprehensive list and an ICD-10-CM book should be used as the official reference. Diagnoses must always be documented in the patient s medical record. The ultimate responsibility belongs to the ordering physician to correctly assign the patient s diagnosis based on the patient s history, symptoms, and medical condition. 2. Vincent A, Bien CG, Irani SR, Waters P. Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol 2011; 10: Arino H, Hoftberger R, Gresa-Arribas N, et al. JAMA Neurol. 2015;72: Dalmau J, Gleichman AJ, Hughes EG, et al. Lancet Neurol. 2008;7: Graus F, Vincent A, Pozo-Rosich P, et al. J Neuroimmunol. 2005;165: Hoftberger R, van Sonderen A, Leypoldt F, et al. Neurology. 2015;84: McKeon A, Lennon VA, Lachance DH, et al. Arch Neurol. 2009;66: Pittock SJ, Lennon VA. Arch Neurol. 2008;65: Pittock SJ, Lucchinetti CF, Lennon VA. Ann Neurol. 2003;53: Pittock SJ, Lucchinetti CF, Parisi JE, et al. Ann Neurol. 2005;58: Romi F, Skeie GO, Aarli JA, et al. J Neurol. 2000;247: Titulaer MJ, Soffietti R, Dalmau J, et al. Eur J Neurol. 2011;18:19-e Yu Z, Kryzer TJ, Griesmann GE, et al. Ann Neurol. 2001;49: Wingerchuk DM, et al. The Spectrum of neuromyelitis optica. Lancet, Wingerchuk DM, et al. The clinical course of neuromyelitis optica (Devic s syndrome). Neurology, Matiello, et al. NMO-IgG predicts the outcome of recurrent optic neuritis, Neurology, Whiting P, et al. Accuracy of magnetic resonance imaging for the diagnosis of multiple sclerosis: systematic review, BMJ, Haven TR, Astill ME, Pasi BM. An Algorithm for Acetylcholine Receptor Antibody Testing in Patients with Suspected Myasthenia Gravis. Clinical Chemistry. 2010; 56(6): Yuebing Li. Myasthenia Gravis. Cleveland Clinic Center for Continuing Education Website. clevelandclinicmeded.com/ medicalpubs/diseasemanagement/ neurology/ myasthenia-gravis/. Published February Accessed April 7, Shah AK. Myasthenia Gravis Workup. Medscape. com/article/ workup. Updated March 23, Accessed April 7, Huijbers MG, Zhang W, Klooster R, et al. MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4. Proc Natl Acad Sci US. 2013; 110(51): The CPT code provided herein is based on AMA guidelines and is provided for informational purposes only. CPT coding is the sole responsibility of the billing party. Any questions regarding coding should be directed to the payer being billed. 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 Quest Diagnostics Incorporated. All rights reserved. Models used for illustrative purposes. SB /2016

Neuroimmunology testing services

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