Anti-Aquaporin-4 IgG (Blood)

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Auckland Te Toka Tumai

Test Guide

Anti-Aquaporin-4 IgG (Blood)

Testing Laboratory

Auckland Te Toka Tumai | Auckland Hospital

Department

Immunology

Delphic Registration Code (Alpha Code)

NMO

Test Code (Numeric Code)

8559

Laboratory Handling

Phlebotomy

Serum

Transport

Ambient (8 - 24 °C) within 48 hours; Chilled (4 - 8 °C) if longer than 48 hours

Registration

NMO

Sample Stability

Up to 48 hours: 8 - 24 °C; Up to 14 days: 4 - 8 °C; Up to 6 months: -30 °C; Indefinite at - 80 °C

Synonyms

Neuromyelitis Optica Spectrum Disorder
Anti-NMO / NMO-IgG
AQP4-IgG

Turnaround Time

2 days

Tested daily: Monday to Friday excluding Public Holidays; Specimen must be in the department available for analysis by 1030 hours, otherwise testing will be deferred to the next working day.

This test may be vetted by the laboratory. Please include relevant clinical information on the request form to ensure appropriate tests are approved. See the 'Clinical Information' section below for more information on the indications for testing.

Specimen Type

Serum

Specimen Requirements

Tube/Container Type:

Preferred

SST II (Gold Cap)

Acceptable

Plain (Red Top)

Preferred Sample Volume (ml)

3.5

Minimum Sample Volume (ml)

Paediatric Specimen Requirements

Tube/Container Type:

Preferred

SST II (Gold Cap)

Acceptable

Plain(Microtainer)
SST(Microtainer)

Minimum Sample Volume (ml)

Pre-testing Requirements

All patients referred for NMO antibody testing must have gone through either a Neurology or Ophthalmology review. Testing will be deferred on all specimens where it is unclear if a review has occurred. In this setting, direct discussion for approval of testing with a laboratory-based Clinical Immunologist must occur.

Additional Specimen Information

Paediatric Specimen: 2 mL clotted blood or 1 mL serum

Diagnostic Use

Neuromyelitis optica (NMO) [Devic?s syndrome] is an immune-mediated chronic inflammatory disease of the CNS, first described in the 19 th century and long considered a clinical variant of multiple sclerosis (MS) [1].

Prevalence of the disease is approximately nine times higher in females and estimates of disease frequency are in the order of <1 to 4 per 100,000 in western populations [2-3]. NMO takes either a monophasic (simultaneous optic neuritis and myelitis) or relapsing course [80-90% of cases] with unpredictable attacks of optic neuritis, myelitis or both. The disease has a median onset of 39 years, although cases in both childhood and the elderly have been described [4-5]. Damage caused by recurrent attacks is cumulative with each new attack targeting new areas of myelin. Severely affected individuals can lose vision in both eyes and be wheelchair bound. Most individuals experience a moderate degree of permanent limb weakness from myelitis. NMO-related deaths result from severe ascending cervical myelitis or brainstem involvement leading to respiratory failure [6].

In 2006, Wingerchuk et al [7] proposed the following diagnostic criteria for a diagnosis of NMO:

In addition to a history of at least one episode of optic neuritis and one episode of myelitis plus any two of the following three criteria:

(a) Contiguous spinal cord MRI lesion extending over three or more vertebral segments

(b) Brain MRI not meeting Paty?s diagnostic criteria for MS at disease onset

Trebst et al (2014) [8] have recommended that the 2006 criteria be used to confirm, rather than exclude a diagnosis of NMO on the basis that brain lesions and short spinal cord lesions (individually or combined) may be present in patients with otherwise typical NMO (Aquaporin-4 antibody positive and / or the presence of longitudinal extensive transverse myelitis [LETM]) during late stages of the disease.

Aquaporin-4 (AQP4) antibodies are present in the majority of patients with both classical NMO disease and those with NMO spectrum disorder (NMOSD). The primary target for the autoantibody is the bi-directional water channel richly expressed in the end feet of astrocytes [9]. The pathogenic IgG 1 subclass antibodies are able to promote efficient antibody and complement dependent cell mediated cytotoxicity causing severe astrocyte injury on in vivo animal and human pathological studies [10-11].

NMOSD patients include those with isolated LETM, monophasic or recurrent isolated optic neuritis and various types of brainstem encephalopathies. Brainstem manifestations frequently include intractable hiccups or vomiting, symptomatic narcolepsy and neuro-endocrine dysfunction [12-13]. In children, in addition to those presentations outlined, seizures are a frequent finding [5, 14-15].

MRI is the most important imaging technique in the differential diagnosis of NMO. Imaging of the entire CNS should always be performed irrespective of presenting symptoms. Predominantly central longitudinally spinal cord lesions, usually extending over three or more vertebral segments are typical of NMO. Lesions typically (but not exclusively) show contrast enhancement for a period of weeks to months after symptom onset [16].

Unlike in MS, AQP4 positive NMO is more frequently associated with other autoimmune diseases, specifically, coeliac disease, myasthenia gravis, SLE and Sjogren?s syndrome. Therefore, presence of autoantibodies found in these disorders does not exclude the possibility of concomitant NMO disease [17-19]. If NMO disease is part of a differential diagnosis, this should prompt an active search for clinical manifestations and, if found, be treated as such.

There is currently no cure for NMO. Treatment goals are:

1. Remission and improvement of relapse ?associated symptoms

2. Long-term stabilisation of disease course by means of relapse prevention

3. Symptomatic therapy of residual symptoms

In the setting of an acute disease attack, corticosteroids (usually methylprednisone) are applied on five consecutive days in combination with a proton pump inhibitor and thrombosis prophylaxis. In an unchanging or worsening condition, therapeutic plasma exchange (5-7 cycles) has been shown to have clinical benefit [20].

With respect to long-term treatment of NMO, following diagnosis, long-term immunosuppressive treatment should be initiated. This also applies to AQP4 seronegative patients with a severe first relapse and incomplete remission. Following a review of clinical cases the NEMOS group recommend the following staged therapies [8]:

First line therapy

Azathioprine and / or Rituximab with IVIg in those patients and notably children with a contra-indication to immunosuppression

Second line therapy

Mycophenolate, Mofetil, Mitoxantrone, Methotrexate

Third line therapy

Tocilizumab

Combination therapies (a) steroids plus cyclosporine A or methotrexate or azathioprine (b) immunosuppression plus intermittent plasma exchange (c) Rituximab with methotrexate or IV Ig.

The Euroimmun indirect IFA biochip method (cell-based assay) uses HEK293 cells transfected with recombinant full length human AQP4 as the coating antigen. This assay has been shown to have higher levels of sensitivity and specificity than other IFA systems, ELISA?s and RIPA assays [21-23].

Reference Intervals

Units: Units

Age Range Either Sex

All < 10

Age Range	Either Sex
All	< 10

Test Method

IFA - manual
Manual processing and manual LED microscopy visual evaluation

Limitations / Interference

Grossly haemolysed, icteric, and/or high lipaemic serum specimens.

Uncertainty of Measurement

Not applicable for this assay.

References

Jarius S, Wildemann B. The history of Neuromyelitis optica. J Neuroinflammation (2013) 10:8
Wingerchuk DM. Neuromyelitis optica: effect of gender. J Neurol Sci (2009) 286: 18-23
3. Asgari N, Lillevang ST, Skejoe HPB, Falah M, Stenager E, Kyvik KO. A population based study of neuromyelitis optica in Caucasians. Neurology (2011) 76: 1589-95

4. Wingerchuk DM, Lennon VA, Lucchinetti CF, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol (2007) 6: 805-15

5. Lotze TE, Northrop JL, Hutton GJ, Ross B, Schiffman JS, Hunter JV. Spectrum of paediatric neuromyelitis optica. Paediatrics (2008) 122: e1039-47

6. Wingerchuk DM, Hogancamp WF, O?Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic?s syndrome). Neurology (1999) 53: 1107-14

7. Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology (2006) 66: 1485-89

8. Trebst C, Jarius S, Berthele A, et al . Update on the diagnosis and treatment of neuromyelitis optica: Recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurology (2014) 261: 1-16

9. Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med (2005) 202: 473-77

10. Ratelade J, Asavapanumas N, Ritchie AM, Wemlinger S, Bennett JL, Verkman AS. Involvement of antibody-dependent cell-mediated cytotoxicity in inflammatory demyelination in a mouse model of neuromyelitis optica. Acta Neuropathol (2013) 126: 699-709

11. Bradl M, Misu T, Takahashi T et al. Neuromyelitis optica: Pathogenicity of patient immunoglobulin in vivo. Ann Neurol (2009) 66: 630-43

12. Apiwattanakul M, Popescu BF, Matiello M et al . Intractable vomiting as the initial presentation of neuromyelitis optica. Ann Neurol (2010) 68: 757-61

13. Popescu BF, Lennon VA, Parisi JE et al . Neuromyelitis optica unique area postrema lesions: nausea, vomiting and pathogenic implications. Neurology (2011) 76: 1229-37

14. Banwell B, Tenembaum S, Lennon VA et al . Neuromyelitis optica-IgG in childhood inflammatory demyelinating CNS disorders. Neurology (2008) 70: 344-52

15. McKeon A, Lennon VA, Lotze TE et al . CNS aquaporin-4 autoimmunity in children. Neurology (2008) 71: 93-100

16. Filippi M, Rocca MA. MR imaging of Devic?s neuromyelitis optica. Neurol Sci (2004) 25 suppl 4: S371-73

17. Bergamaschi R, Jarius S, Robotti M, Pichiecchio A, Wildemann B, Meola G. Two cases of benign neuromyelitis optica in patients with coeliac disease. J Neurol (2009) 256: 2097-99

18. Kay CSK, Scola RH, Lorenzoni PJ, Jarius S, Arruda WO, Werneck LC. NMO IgG positive neuromyelitis optica in a patient with myasthenia gravis but no thymectomy. J Neurol Sci (2008) 278: 148-150

19. Wandinger K-P, Stangel M, Witte T et al . Antibodies against aquaporin-4 in patients with neuro-psychiatric systemic lupus erythematosus and primary Sjogren?s syndrome. Arthritis Rheum (2010) 62: 1198-1200

20. Merle H, Olindo S, Jeannin S et al. Treatment of optic neuritis by plasma exchange (add-on) in neuromyelitis optica. Arch Opthalmol (2012) 130: 858-62

21. Jarius S, Wildemann B. AQP4 antibodies in neuromyelitis optica: diagnostic and pathogenic relevance. Nat Rev Neurol (2010) 6: 383-92

22. McKeon A, Fryer JP, Apiwattanakul M et al . Diagnosis of neuromyelitis spectrum disorders: comparative sensitivities and specificities of immunohistochemical and immunoprecipitation assays. Arch Neurol (2009) 66: 1134-38

23. Jarius s, Paul F, Franciotta D et al . Mechanisms of disease: aquaporin-4 antibodies in neuromyelitis optica. Nat Clin Pract Neurol (2008) 4: 202-14

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Acceptable

Preferred Sample Volume (ml)

Minimum Sample Volume (ml)

Paediatric Specimen Requirements

Tube/Container Type:

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Acceptable

Minimum Sample Volume (ml)

Pre-testing Requirements

Additional Specimen Information

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Uncertainty of Measurement

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Anti-Aquaporin-4 IgG (Blood)

Overview

Testing Laboratory

Department

Delphic Registration Code (Alpha Code)

Test Code (Numeric Code)

Laboratory Handling

Phlebotomy

Transport

Registration

Sample Stability

Synonyms

Turnaround Time

Specimen

Specimen Type

Specimen Requirements

Tube/Container Type:

Preferred

Acceptable

Preferred Sample Volume (ml)

Minimum Sample Volume (ml)

Paediatric Specimen Requirements

Tube/Container Type:

Preferred

Acceptable

Minimum Sample Volume (ml)

Pre-testing Requirements

Additional Specimen Information

Referral

Aliquot Instructions

Sample Type

Minimum Volume (ml)

Transport to Lab

Clinical Information/Test Method

Diagnostic Use

Reference Intervals

Test Method

Limitations / Interference

Uncertainty of Measurement

Additional Information

Resources

Contact Information

Contact Information

Enquiry Form

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