Overlapping CNS inflammatory diseases: differentiating features of NMO and MS.

Neuromyelitis optica (NMO) has long been considered as a variant of multiple sclerosis (MS) rather than a distinct disease. This concept changed with the discovery of serum antibodies (Ab) against aquaporin-4 (AQP4), which unequivocally differentiate NMO from MS. Patients who test positive for AQP4-Abs and present with optic neuritis (ON) and transverse myelitis (TM) are diagnosed with NMO and those who show an incomplete phenotype with isolated ON or longitudinally extensive TM (LETM) or less commonly brain/brainstem disease are referred to as NMO spectrum disorders (NMOSD). However, many patients, who have overlapping features of both NMO and MS, test negative for AQP4-Abs and may be difficult to definitively diagnose. This raises important practical issues, since NMO and MS respond differently to immunomodulatory treatment and have different prognoses. Here we review distinct features of AQP4-positive NMO and MS, which might then be useful in the diagnosis of antibody-negative overlap syndromes. We identify discriminators, which are related to demographic data (non-white origin, very late onset), clinical features (limited recovery from ON, bilateral ON, intractable nausea, progressive course of disability), laboratory results (cerebrospinal fluid (CSF) pleocytosis with eosinophils and/or neutrophils, oligoclonal bands, glial fibrillary acidic protein in the CSF) and imaging (LETM, LETM with T1 hypointensity, periependymal brainstem lesions, perivenous white matter lesions, Dawson's fingers, curved or S-shaped U-fibre juxtacortical lesions). We review the value of these discriminators and discuss the compelling need for new diagnostic markers in these two autoimmune demyelinating diseases of the central nervous system

Isolated new onset 'atypical' optic neuritis in the NMO clinic: serum antibodies, prognoses and diagnoses at follow-up.

Severe, recurrent or bilateral optic neuritis (ON) often falls within the neuromyelitis optica spectrum disorders (NMOSD), but the diagnosis can be particularly challenging and has important treatment implications. We report the features, course and outcomes of patients presenting with atypical ON when isolated at onset. We retrospectively analyzed 69 sequential patients referred to a single UK NMO center with isolated ON at onset. Aquaporin-4 antibody (AQP4-Ab) assessment was performed in all patients and IgG1 myelin-oligodenrocyte glycoprotein (MOG-Ab) in AQP4-Ab(neg) patients. 37 AQP4-Ab positive (AQP4-Ab(pos)) and 32 AQP4-Ab negative (AQP4-Ab (neg)) patients (8 with MOG-Ab) were identified. The AQP4-Ab(neg) group included heterogeneous diagnoses: multiple sclerosis (MS), NMO, relapsing isolated ON (RION), monophasic isolated ON and relapsing acute disseminated encephalomyelitis (ADEM)-like syndromes. Compared to AQP4-Ab(neg) patients, AQP4-Ab(pos) patients had a worse residual visual outcome from first attack (median VFSS 4 vs. 0, p = 0.010) and at last assessment (median VFSS 5 versus 2, p = 0.005). However, AQP4-Ab(neg) patients with RION also had poor visual outcome. Up to 35 % of AQP4-Ab(neg) patients developed a LETM and two developed low positivity for AQP4-Ab over time. Eight AQP4-Ab(neg) patients (25 %) were MOG-Ab positive, covering a range of phenotypes excluding MS; the first ON attack was often bilateral and most had relapsing disease with a poor final visual outcome [VFSS 4, range (0-6)]. In conlcusion, AQP4-Ab positivity is confirmed as a predictor of poor visual outcome but AQP4-Ab(neg) RION also had a poor visual outcome. Of those without AQP4-Ab, 25 % had MOG-Ab and another 25 % developed MS; thus, MOG-Ab is associated with AQP4-Ab(neg) non-MS ON

MOG cell-based assay detects non-MS patients with inflammatory neurologic disease

Objective: To optimize sensitivity and disease specificity of a myelin oligodendrocyte glycoprotein (MOG) antibody assay. Methods: Consecutive sera (n 5 1,109) sent for aquaporin-4 (AQP4) antibody testing were screened for MOG antibodies (Abs) by cell-based assays using either full-length human MOG (FL-MOG) or the short-length form (SL-MOG). The Abs were initially detected by Alexa Fluor goat anti-human IgG (H 1 L) and subsequently by Alexa Fluor mouse antibodies to human IgG1. Results: When tested at 1:20 dilution, 40/1,109 sera were positive for AQP4-Abs, 21 for SLMOG, and 180 for FL-MOG. Only one of the 40 AQP4-Ab–positive sera was positive for SLMOG-Abs, but 10 (25%) were positive for FL-MOG-Abs (p 5 0.0069). Of equal concern, 48% (42/88) of sera from controls (patients with epilepsy) were positive by FL-MOG assay. However, using an IgG1-specific secondary antibody, only 65/1,109 (5.8%) sera were positive on FL-MOG, and AQP4-Ab– positive and control sera were negative. IgM reactivity accounted for the remaining anti-human IgG (H 1 L) positivity toward FL-MOG. The clinical diagnoses were obtained in 33 FL-MOG–positive patients, blinded to the antibody data. IgG1-Abs to FL-MOG were associated with optic neuritis (n 5 11), AQP4-seronegative neuromyelitis optica spectrum disorder (n 5 4), and acute disseminated encephalomyelitis (n 5 1). All 7 patients with probable multiple sclerosis (MS) were MOG-IgG1 negative. Conclusions: The limited disease specificity of FL-MOG-Abs identified using Alexa Fluor goat antihuman IgG (H 1 L) is due in part to detection of IgM-Abs. Use of the FL-MOG and restricting to IgG1-Abs substantially improves specificity for non-MS demyelinating diseases. Classification of evidence: This study provides Class II evidence that the presence of serum IgG1- MOG-Abs in AQP4-Ab–negative patients distinguishes non-MS CNS demyelinating disorders from MS (sensitivity 24%, 95% confidence interval [CI] 9%–45%; specificity 100%, 95% CI 88%–100%)

MOG cell-based assay detects non-MS patients with inflammatory neurologic disease

Objective: To optimize sensitivity and disease specificity of a myelin oligodendrocyte glycoprotein (MOG) antibody assay. Methods: Consecutive sera (n 5 1,109) sent for aquaporin-4 (AQP4) antibody testing were screened for MOG antibodies (Abs) by cell-based assays using either full-length human MOG (FL-MOG) or the short-length form (SL-MOG). The Abs were initially detected by Alexa Fluor goat anti-human IgG (H 1 L) and subsequently by Alexa Fluor mouse antibodies to human IgG1. Results: When tested at 1:20 dilution, 40/1,109 sera were positive for AQP4-Abs, 21 for SLMOG, and 180 for FL-MOG. Only one of the 40 AQP4-Ab–positive sera was positive for SLMOG-Abs, but 10 (25%) were positive for FL-MOG-Abs (p 5 0.0069). Of equal concern, 48% (42/88) of sera from controls (patients with epilepsy) were positive by FL-MOG assay. However, using an IgG1-specific secondary antibody, only 65/1,109 (5.8%) sera were positive on FL-MOG, and AQP4-Ab– positive and control sera were negative. IgM reactivity accounted for the remaining anti-human IgG (H 1 L) positivity toward FL-MOG. The clinical diagnoses were obtained in 33 FL-MOG–positive patients, blinded to the antibody data. IgG1-Abs to FL-MOG were associated with optic neuritis (n 5 11), AQP4-seronegative neuromyelitis optica spectrum disorder (n 5 4), and acute disseminated encephalomyelitis (n 5 1). All 7 patients with probable multiple sclerosis (MS) were MOG-IgG1 negative. Conclusions: The limited disease specificity of FL-MOG-Abs identified using Alexa Fluor goat antihuman IgG (H 1 L) is due in part to detection of IgM-Abs. Use of the FL-MOG and restricting to IgG1-Abs substantially improves specificity for non-MS demyelinating diseases. Classification of evidence: This study provides Class II evidence that the presence of serum IgG1- MOG-Abs in AQP4-Ab–negative patients distinguishes non-MS CNS demyelinating disorders from MS (sensitivity 24%, 95% confidence interval [CI] 9%–45%; specificity 100%, 95% CI 88%–100%)

Brain lesion distribution criteria distinguish MS from AQP4-antibody NMOSD and MOG-antibody disease

IMPORTANCE: Neuromyelitis optica spectrum disorders (NMOSD) can present with very similar clinical features to multiple sclerosis (MS), but the international diagnostic imaging criteria for MS are not necessarily helpful in distinguishing these two diseases. OBJECTIVE: This multicentre study tested previously reported criteria of '(1) at least 1 lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe; or (2) the presence of a subcortical U-fibre lesion or (3) a Dawson's finger-type lesion' in an independent cohort of relapsing-remitting multiple sclerosis (RRMS) and AQP4-ab NMOSD patients and also assessed their value in myelin oligodendrocyte glycoprotein (MOG)-ab positive and ab-negative NMOSD. DESIGN: Brain MRI scans were anonymised and scored on the criteria by 2 of 3 independent raters. In case of disagreement, the final opinion was made by the third rater. PARTICIPANTS: 112 patients with NMOSD (31 AQP4-ab-positive, 21 MOG-ab-positive, 16 ab-negative) or MS (44) were selected from 3 centres (Oxford, Strasbourg and Liverpool) for the presence of brain lesions. RESULTS: MRI brain lesion distribution criteria were able to distinguish RRMS with a sensitivity of 90.9% and with a specificity of 87.1% against AQP4-ab NMOSD, 95.2% against MOG-ab NMOSD and 87.5% in the heterogenous ab-negative NMOSD cohort. Over the whole NMOSD group, the specificity was 89.7%. CONCLUSIONS: This study suggests that the brain MRI criteria for differentiating RRMS from NMOSD are sensitive and specific for all phenotypes

Brain lesion distribution criteria distinguish MS from AQP4-antibody NMOSD and MOG-antibody disease

IMPORTANCE: Neuromyelitis optica spectrum disorders (NMOSD) can present with very similar clinical features to multiple sclerosis (MS), but the international diagnostic imaging criteria for MS are not necessarily helpful in distinguishing these two diseases. OBJECTIVE: This multicentre study tested previously reported criteria of '(1) at least 1 lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe; or (2) the presence of a subcortical U-fibre lesion or (3) a Dawson's finger-type lesion' in an independent cohort of relapsing-remitting multiple sclerosis (RRMS) and AQP4-ab NMOSD patients and also assessed their value in myelin oligodendrocyte glycoprotein (MOG)-ab positive and ab-negative NMOSD. DESIGN: Brain MRI scans were anonymised and scored on the criteria by 2 of 3 independent raters. In case of disagreement, the final opinion was made by the third rater. PARTICIPANTS: 112 patients with NMOSD (31 AQP4-ab-positive, 21 MOG-ab-positive, 16 ab-negative) or MS (44) were selected from 3 centres (Oxford, Strasbourg and Liverpool) for the presence of brain lesions. RESULTS: MRI brain lesion distribution criteria were able to distinguish RRMS with a sensitivity of 90.9% and with a specificity of 87.1% against AQP4-ab NMOSD, 95.2% against MOG-ab NMOSD and 87.5% in the heterogenous ab-negative NMOSD cohort. Over the whole NMOSD group, the specificity was 89.7%. CONCLUSIONS: This study suggests that the brain MRI criteria for differentiating RRMS from NMOSD are sensitive and specific for all phenotypes

The role of pontine lesion location in differentiating multiple sclerosis from vascular risk factor-related small vessel disease

BACKGROUND:Differentiating multiple sclerosis (MS) from vascular risk factor (VRF)-small vessel disease (SVD) can be challenging. OBJECTIVE AND METHODS:In order to determine whether or not pontine lesion location is a useful discriminator of MS and VRF-SVD, we classified pontine lesions on brain magnetic resonance imaging (MRI) as central or peripheral in 93 MS cases without VRF, 108 MS patients with VRF and 43 non-MS cases with VRF. RESULTS:MS without VRF were more likely to have peripheral pons lesions (31.2%, 29/93) than non-MS with VRF (0%, 0/43) (Exp(B) = 29.8; 95% confidence interval (CI) = (1.98, 448.3); p = 0.014) but there were no significant differences regarding central pons lesions between MS without VRF (5.4%, 5/93) and non-MS with VRF patients (16.3%, 7/43) (Exp(B) = 0.89; 95% CI = (0.2, 3.94); p = 0.87). The presence of peripheral pons lesions discriminated between MS and VRF-SVD with 100% (95% CI = (91.8, 100)) specificity. The proportion of peripheral pons lesions in MS with VRF (30.5%, 33/108) was similar to that seen in MS without VRF (31.2%, 29/93, p = 0.99). Central lesions occurred in similar frequency in MS with VRF (8.3%, 9/108) and non-MS with VRF (16.3%, 7/43, p = 0.15). CONCLUSION:Peripheral pons lesion location is a good discriminator of MS from vascular lesions