The rapidly expanding clinical spectrum of patients with seropositive AQP4-IgG required the development of new diagnostic criteria that would capture the clinical experience of physicians and provide a codification for future translational and clinical research. The International Panel for NMO Diagnosis (IPND) was convened in 2011 and tasked with developing new diagnostic criteria based on clinical, laboratory, and neuroimaging data (8). In recognition of accumulating data that the clinical behavior, treatment, and pathology of AQP4-IgG–seropositive patients with incomplete or atypical presentations of NMO are not different from patients fulfilling previous diagnostic criteria (20), the term NMOSD was chosen as a new diagnostic moniker. Because approximately 25% of patients meeting previous NMO criteria were seronegative for AQP4-IgG, separate diagnostic criteria for seronegative NMOSD were formulated using a mixture of clinical and radiologic criteria. The result was the generation of 2 new diagnoses: NMOSD with AQP4-IgG and NMOSD with negative or unknown AQP4-IgG.
The diagnosis of NMOSD with AQP4-IgG requires one of 6 core clinical characteristics and a positive test for AQP4-IgG. The core clinical presentations are distinguished by their neuro-anatomic locations: optic nerve, spinal cord, area postrema (dorsal medulla), diencephalon, brainstem, and cerebrum. Involvement of the optic nerves and spinal cord manifests as ON or TM. ON typically presents as acute vision or visual field loss in one or both eyes, whereas TM may present with a variety of motor, sensory, or sphincter problems. TM is commonly longitudinally extensive (3 or more vertebral segments) (Fig. 1A), involving the central cord (Fig. 1B) with contrast enhancement (Fig. 1B'). Optic nerve lesions are typically gadolinium enhancing and extensive (Fig. 1C) and often involve the prechiasmatic optic nerve and optic chiasm (Fig. 1D). An area postrema syndrome (incidence: 16%–43%) (19,21,22) is characterized by intractable hiccups or nausea/vomiting occurring for 7 consecutive days without, or 2 days with, an accompanying MRI lesion in the dorsal medulla (Fig. 1E). Acute brainstem symptoms include ocular motor, motor, sensory, or cerebellar dysfunction associated with parenchymal (Fig. 1F) or ependymal lesions (Fig. 1G) that may or may not be contiguous with spinal cord injury (Fig. 1A). Diencephalic syndromes include hypersomnolence, narcolepsy, anorexia, hypothermia, hyponatremia, and behavioral changes associated with a MRI lesion in the thalamus, hypothalamus, or third ventricular region (Fig. 1H, J). Cerebral syndromes include hemiparesis, hemisensory loss, encephalopathy, postchiasmal visual field loss, and cortical vision loss that are often associated with large, confluent subcortical or deep white matter lesions (Fig. 1I, J).
A diagnosis of NMOSD without AQP4-IgG requires additional clinical and radiologic criteria that are not mandated for seropositive patients. Patients with NMOSD who do not have detectable AQP4-IgG must have a minimum of 2 core clinical presentations, and 1 presentation must be ON, TM, or an area postrema syndrome. The clinical presentation may be simultaneous or sequential. Additional radiologic criteria are required based on the type of core presentation. For ON, the brain MRI should be normal if the optic nerve lesion is not extensive (half the length of the optic nerve) or involving the optic chiasm. For TM, spinal cord MRI should demonstrate a central medullary lesion or focal atrophy involving 3 contiguous segments. Area postrema syndromes require a dorsal medulla lesion, and acute brainstem syndromes should demonstrate periependymal lesions. These additional radiologic criteria were deemed necessary to provide additional specificity for NMOSD in the absence of AQP4-IgG. Because patients may convert to a positive AQP4-IgG serostatus over time, repeat serologic testing is recommended in relapsing seronegative patients before immunosuppressive or B-cell ablative therapies are initiated. Rarely, AQP4-IgG has been detected only in CSF (26,27). Therefore, routine CSF testing of AQP4-IgG–seronegative patients is generally not recommended. Additional CSF features such as extensive pleocytosis (>50 leukocytes/μL), presence of neutrophils or eosinophils (>5/μL), absence of oligoclonal bands, or elevation of glial fibrillary acidic protein are considered supportive but not confirmatory evidence of NMOSD (2,28,29).
Because the diagnosis of NMOSD without AQP4-IgG may be difficult, the 2015 IPND criteria highlight multiple “red flags” that should caution clinicians against a NMOSD diagnosis. Clinical red flags include progressive disease course, hyperacute onset (<4 hours to symptom nadir), presence of CSF oligoclonal bands, partial TM, chronic infection, or clinical features suggestive of cancer or sarcoidosis (8). Radiologic red flags include brain MRI findings suggestive of MS, persistent contrast enhancement, (>3 months) short and predominantly peripheral spinal cord lesions, and diffuse, indistinct T2-weighted lesions (8).
The 2015 IPND criteria represent a substantial departure from previous diagnostic measures. In the near term, the institution of the new NMOSD criteria in clinical practice will facilitate the early identification of AQP4-IgG–seropositive patients. Previous diagnostic criteria had required the simultaneous or sequential presentation of ON and TM. In clinical practice, however, patients with atypical presentations related to cerebral, diencephalic, and brainstem pathology had been reported in association with AQP4-IgG, and their subsequent clinical course often included ON and LETM. The inclusion of these individuals, along with AQP4-IgG–seropositive patients with isolated or recurrent events of ON and TM, under the umbrella of NMOSD will allow rapid adoption of prophylactic therapy and aggressive treatment of acute attacks. As neurologists and ophthalmologists recognize the core clinical symptoms of NMOSD, by presentation or history, serologic testing for AQP4-IgG will expand leading to earlier diagnosis. In addition, the recognition of clinical presentations and neuroimaging typical of NMOSD will foster testing of AQP4-IgG in high-risk monosymptomatic cases of ON or TM. For instance, in monosymptomatic ON, bilateral ON, poor visual recovery (<20/200), severe visual field depression, altitudinal visual field loss, posterior nerve or optic chiasm involvement, extensive visual pathway lesions, or severe and diffuse peripapillary retinal nerve fiber layer loss should prompt AQP4-IgG testing (30–36).
In the long term, the 2015 IPND criteria also will be a guide for evaluating the natural history and treatment response of AQP4-IgG–seronegative patients. Patients with NMO diagnosed by the 2006 Wingerchuk criteria may transition between AQP4-IgG seropositive and seronegative states, indicating that all AQP4-IgG–seronegative cases are not merely phenotypic mimics. Therefore, monitoring the progress of patients meeting criteria for NMOSD without AQP4-IgG will be critical for developing future diagnostic criteria that delineate those patients with seronegative NMOSD at high risk for relapse and those that are responsive to therapy.
Nevertheless, multiple investigations on independent cohorts of patients with AQP4-IgG–seronegative NMO have demonstrated distinct demographics and clinical characteristics (37). AQP4-IgG–seronegative patients are more often Caucasian (38,39); show a lower female/male ratio (38–41); have a shorter disease duration (38); are more frequently monophasic (40,42); exhibit fewer features of concurrent autoimmunity (40,42); and more often present with simultaneous ON and TM (38–40). These distinctions suggest that a significant portion of seronegative patients represent disorders with overlapping phenotypic presentations of ON and TM. Similar demographic and clinical distinctions have been observed among a small fraction of AQP4-IgG–seronegative patients who are seropositive for antibodies against myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) (43,44). The 2015 IPND NMOSD criteria may differentiate some cohorts of patients previously labeled as seronegative NMO and may identify alternative cohorts at higher risk for relapse. Indeed, 2 studies with longer follow-up have revealed that a significant fraction of NMO-seronegative patients have disease recurrence (38,39).
Interestingly, the initial application of the new 2015 IPND NMOSD criteria in clinical practice has demonstrated enhanced diagnostic sensitivity. In adult cohorts, the 2015 IPND NMOSD criteria identified novel AQP4-IgG–seronegative patients (45,46), and, because of the need for only a single core presentation (8), detected AQP4-IgG–seropositive patients significantly faster following symptom onset (45). As a result, patients with NMOSD at risk for future relapse and disability progression are likely to be rapidly identified and treated. Similarly, in a study of pediatric patients with demyelinating disease, 97% of the panel-defined patients with NMOSD were correctly identified by the IPND 2015 NMOSD criteria; however, only 49% were diagnosed by 2006 Wingerchuk NMO criteria. This may be due in part to the distinct presentations of pediatric and adult NMO cases (47) and the new diagnostic criteria for monophasic AQP4-IgG–seropositive patients (8).
Each iteration of diagnostic criteria for NMO has attempted to aid clinicians in the recognition of this relatively rare but devastating CNS inflammatory disorder. Although the gold standard of diagnostic accuracy, lesion histopathology (48,49), remains unobtainable in most cases, the progressive incorporation of new clinical, radiologic, and serologic criteria seems to be improving both diagnostic sensitivity and specificity. Nonetheless, because of the limited sensitivity of the AQP4-IgG serologic assay and the limited specificity of clinical and radiologic presentations, a clear categorization of NMOSD among other demyelinating disorders remains murky.
As noted previously, approximately 20% of AQP4-IgG–seronegative patients are seropositive for MOG-IgG. Multiple immunologic and histopathologic features of MOG-IgG–seropositive NMOSD indicate that this condition is nosologically distinct from AQP4-IgG–seropositive NMOSD despite its overlapping clinical presentation. Patients with MOG-IgG–seropositive NMOSD are typically male and more often have simultaneous ON and TM, monophasic disease, inflammation of the conus, cauda equina, and deep brain nuclei, and improved functional recovery (43,44). The intracerebral microinjection of MOG-IgG–seropositive patient serum into murine brain produces no inflammation or significant CNS injury (52), and brain lesions from a patient with MOG-IgG–seropositive NMOSD revealed MS-type II pathology (53). The combined clinical and experimental data indicate that MOG-IgG–seropositive patients with TM and ON should be classified outside NMOSD and may represent a subgroup of patients with MS or acute disseminated encephalomyelitis.
A molecular classification of demyelinating disorders may ultimately require substantial advances in technology to reach fruition. Improvement in serologic, radiologic, and immunologic assays is likely to be required to reach levels of sensitivity and specificity necessary to delineate closely aligned demyelinating disorders with overlapping clinical presentations and immunopathologies. High throughput analysis of large biologic data sets from affected individuals may hold the key to discovering groups of biomarkers that can define molecular boundaries between NMOSD and phenotypic mimics. Ultimately, a molecular nosology of CNS demyelinating disorders will result in targeted immunotherapy and improved clinical outcomes in patients with NMOSD.
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