A comparative evaluation of different NeuroMyelitis Optica Spectrum Disorder sets criteria

Background Three different sets of criteria have been proposed for the diagnosis of neuromyelitis optica spectrum disorders (NMOSD). OBJECTIVE To compare the specificity, sensitivity and diagnostic accuracy of the three different sets of NMOSD criteria, in patients presenting with inflammatory disorders of the central nervous system suggestive of NMOSD. Methods From 236 suspected NMOSD referred for serum AQP4-IgG testing between 2012 and 2014, the three sets of NMOSD criteria (1999, 2006 NMO criteria and 2015 International Panel for NMO Diagnosis criteria) were applied and compared to the final diagnosis. Results Seventy-six patients fulfilled at least one set of criteria and 28 patients fulfilled all NMOSD set of criteria. The final diagnosis was NMOSD in 66 cases, MS according to the MacDonald 2010 in 85 cases and another diagnosis in 85 cases. 2006 NMO criteria has the highest specificity (99%) and 2015 IPND NMOSD criteria, the highest sensitivity (97%). For the 1999, 2006 and 2015 IPND NMOSD criteria, the accuracy was respectively 82%, 87% and 97%. Our study highlights the limitations of the first set of criteria, that include optico-spinal form of MS. The accuracy of NMO/SD diagnostic criteria improved from 1999 to 2015. It confirms the increased performance of the last set of criteria which covers a larger spectrum of clinical presentation. This study raises some the concern to classify patients with seronegative transverse myelitis or optic neuritis, and MOG-antibody associated disease.


Introduction
Since 1999, three different sets of diagnostic criteria have been proposed, mainly to distinguish NMO from multiple sclerosis (MS) and other CNS inflammatory disorders. Initially, NMO diagnosis was based 3 essentially on a probabilistic combination of clinical signs, brain or spinal cord MRI and CSF analysis. 1 The identification of aquaporin-4 immunoglobulin G antibody (AQP4-IgG) 2

Methods Study objective:
The main objective of this observational retrospective study was to compare the diagnostic value of 3 different sets of NMOSD criteria, as indexed by specificity, sensitivity, and accuracy in patients with clinical symptoms suggestive of NMOSD.

Study Population
We evaluated the data of 756 patients (from Lyon, Paris, Strasbourg) referred to the Lyon lab for serum AQP4-IgG testing because of central nervous system inflammatory disorders suspected of being NMOSD (called NMO until 2007) by the treating clinician, between 2012 and 2014. Medical records were available for 520 patients. Incomplete files were excluded from the analysis. Finally, we evaluate 236 files for which all the clinical, imaging and biological information necessary to evaluate the 3 sets of NMOSD criteria were available. For each patients, the presence of the following core clinical characteristics was determined: optic neuritis, myelitis, area postrema syndrome, brainstem syndrome, diencephalic and encephalic syndrome. Brain, spinal cord and orbital MRI were reviewed when available, as well as cerebrospinal fluid (CSF) analyses. All samples were tested for AQP4-IgG using the same technique based on live cell-based assay. When available, MOG-IgG serostatus was 4 collected. 8 Data collection: Clinical, imaging and biological data were collected center by center in 2017 and reviewed by 3 neurologists, expert in NMOSD, from the three participating referral centers. The treating neurologist was defined as the neurologist of the center evaluated and the two evaluating neurologists were defined as external neurologist at the evaluated center.

Statistical analysis:
Statistical analyses were performed with R software (3.6.0 version). The performance of NMOSD criteria with regard to clinical diagnosis was expressed as sensitivity, specificity, positive predictive value, negative predictive value and accuracy.

Ethical concern
According to the French legislation regarding observational studies, patients were informed of the study, but did not have to provide a formal and written informed consent to have their anonymized data collected. Data confidentiality and safety were ensured in keeping with the recommendations of the French Commission Nationale Informatique et Libertés, which also provided approval.

Results
The clinical, imaging, CSF characteristics and AQP4-IgG sero-status of the 236 files analyzed are detailed in Table 1. The final diagnosis was NMOSD in 66 cases, MS in 85 cases. Another diagnosis was made for the 85 other cases ( Table 2). Ten patients fulfilled the 2006 but not the 1999 NMOSD criteria. They had clinical signs outside of the optic nerve or spinal cord (6 in area postrema, 5 in brainstem, 1 located in diencephalon). Brain MRI showed "MS like" lesions (n = 3) "ADEM like" (n = 1), brainstem abnormalities (n = 1) and area postrema abnormalities (n = 2). Eight patients were tested positive for AQP4-IgG. The diagnosis of NMOSD was made in all of these 10 cases (Table 3). All limited forms were tested positive for AQP4-IgG. Five of the seven patients with negative AQP4-IgG had at least clinical and radiological area postrema and /or brainstem syndrome. In one case the MRI lesion extended from cervical cord to area postrema ( Fig. 2A, patient 52) and in one other case tumefactive brain lesion was observed in addition to brainstem lesion. (Fig. 2B and 2C patient 48).
6 Among these 30 patients, five (16.6%) had a final diagnosis other than NMOSD. One had extended brain lesion and LETM with a final diagnosis of endovascular lymphoma (Fig. 3). Two patients were

Value of the three different sets of NMOSD criteria
The specificity of the criteria was highest ( 99%) in 2006 NMO criteria. The specificity was similar in the first and the last set of criteria (96% in 1999, and in 2015 IPND criteria). The sensitivity was highest ( 97%) in 2015 IPND NMOSD criteria and the accuracy significantly increased from the first to the last NMOSD criteria (from 82-97%) ( Table 3).

Discussion
The accuracy of the NMO sets criteria increases with the successive version of criteria with a significant improvement of the sensitivity from 1999 to 2015 IPND criteria while the specificity remains similar. NMOSD from MS there is still matter of concern in the patients with MS like lesions. The appearance of "MS like" brain lesions during the evolution of the disease is particularly worrying in the limited form.
Despite the fact that IPND 2015 allowed an early diagnosis, some patients with NMO related disorder, with either isolated or recurrent TM and ON but tested negative for AQP4-IgG are still not classified.
As found in our study, some of these patients are tested positive for MOG-IgG, highlighting the current need to establish a clear definition of MOGAD (MOG -Auto Antibody disease) and its link with NMOSD.

Ethical Approval and Consent to participate
According to the French legislation regarding observational studies, patients were informed of the study, but did not have to provide a formal and written informed consent to have their anonymized data collected. Data confidentiality and safety were ensured in keeping with the recommendations of the French Commission Nationale Informatique et Libertés, which also provided approval.