On the differential diagnosis of panoptic neuromyelitis (NMOSD) and MOGAD

Written by: Liao Yizhu, Director of the Department of Peripheral Neurology, Neurological Center, Taipei Veterans General Hospital

Evolution from Multiple Sclerosis (MS) and Neuromyelitis Panoptica (NMOSD) to MOG Antibody-Related Diseases (MOGAD): Precision Diagnosis

With the evolution of medical technology, the differential diagnosis of neurological diseases has become more sophisticated.

MS (Multiple sclerosis) and NMOSD (neuromyelitis optica spectrum disorder) are both immune diseases of the central nervous system, which means that the immune system attacks the protective layer of nerve fibers (myelin sheath) and glial cells, resulting in various neurological symptoms. Such as vision loss, myelitis, brainstem syndrome, cerebellar coordination dysfunction, etc.

In the past, NMOSD was considered a variant of MS due to the similarity of symptoms between the two, and the prognosis of NMOSD was poor and ineffective with traditional MS treatments. Until 2004, Professor Lennon discovered that AQP4 antibody can be detected in human blood, which has a high degree of specificity and sensitivity for the diagnosis of NMOSD, and can accurately distinguish between MS and NMOSD, and the NMO diagnostic criteria proposed by Professor Wingerchunk in 2006 and the IPND NMOSD diagnostic criteria published in 2015 include the detection of AQP4 antibodies in the diagnostic conditions.

Similarly, MOGAD (Myelin oligodendrocyte glycoprotein antibody-associated disease). The diagnosis also depends on MOG antibody detection, and a new detection technology can be used to summarize a group of patients with clinical symptoms similar to NMOSD, but negative AQP4 antibody, but positive MOG antibody, forming a new disease classification of MOGAD. The incidence of MOGAD accounts for about 10% of all patients with pan-optic neuromyelitis, and the average age of onset is younger than that of traditional AQP4 antibody-positive neuromyelitis optica, and the male-to-female ratio is 1:1, which is different from MS and NMOSD, which is mostly female, and the response and prognosis of clinical treatment of MOGAD patients are also better than those of AQP4 antibody-positive neuromyelitis optica.

Table, multiple sclerosis (MS), panoptic neuromyelitis (NMOSD) and MOG antibody-related disease (MOGAD).

	MOGAD	AQP4 Ab (+)-NMOSD	MS
Gender (Female: Male) Sex (F:M)	≒1:1	≒9:1	≒2:1
phenotype Phenotype	Optic neuritis (ON) Acute diffuse encephalomyelitis (ADEM) Transverse myelitis (TM) Cerebral cortical encephalitis	Transverse Myelitis (TM), Optic Neuritis (ON), Area Postrema Syndrome	Transverse myelitis (TM), optic neuritis (ON), brainstem/cerebellar syndrome
Onset brain MRI findings Brain MRI at attack	Unclear borders, large lesions in the brainstem or cerebellar region between the white matter and the deep gray matter	unclear borders, lesions near the third and fourth ventricles, lesions near ependymus,	Sharply demarcated, oval lesions, close to periventricles, T1WI hypointense lesions, may have ring-enhancing signals after contrast injection
MRI of the spinal cord at onset Spine MRI at attack	Longitudinal extensive transverse myelitis (LETM) and central lesions of the spinal cord	Longitudinal extensive transverse myelitis (LETM) and central lesions of the spinal cord	Less than three segments, short-segmented myelitis
MRI development MRI evolution	T2WI lesions have regressed markedly, and asymptomatic lesions are rare	T2WI lesions are persistent, and asymptomatic lesions are rare	T2WI lesions are persistent, and asymptomatic lesions are common
CSF oligoclonal band positive	≒15%	≒15%	≒85%
False-positive antibody test results False positive	False positives may occur in both cell-based assays and ELISA/IFA assays (< 1:100 low antibody titer)	Cell based assay has high specificity and sensitivity, ELISA/IFA assays can be falsely negative and false-positive	not applicable
Secondary progression Secondary progressive phase	not	not	be

MS, AQP4 Ab (+)-NMOSD, MOGAD: precision therapy

Whether the initial differential diagnosis can clearly distinguish between these three disorders is the most important key to successful treatment.

Because the pathogenesis of the three diseases is different, if NMOSD is treated with MS drugs, not only can the disease be controlled, but it may even cause the disease to worsen.

The goal of acute treatment of these three diseases is to control symptoms as soon as possible, reduce inflammation, and reduce the damage to the nervous system caused by acute attacks, so steroid pulse therapy is a common treatment for all three diseases, but AQP4 Ab (+)-NMOSD and MOGAD are used in patients with severe blindness due to optic neuritis or paralysis due to longitudinal extensive transverse myelitis (LETM). In addition to steroid pulse therapy, plasmapheresis or intravenous immunoglobulin may be administered.

The goal of long-term treatment for all three diseases is to reduce the risk of recurrence. Patients with MS can choose appropriate immunomodulatory drugs according to the individual conditions of the patients to improve the course of the disease (disease modifying therapy), while AQP4 Ab (+)-NMOSD requires long-term use of immunosuppressive drugs, such as oral steroids, immunosuppressants, biologics of monoclonal antibodies… Wait. Because MOGAD has just become a single disease isolated from pan-optic neuromyelitis, the treatment development is not as complete as AQP4 Ab (+)-NMOSD, and there is no standard treatment recommendation. The three newly launched monoclonal antibody biologics have been fully validated in phase III double-blind clinical trials for the treatment of AQP4 Ab (+)-NMOSD, but the therapeutic effect on MOGAD patients needs to be further studied.

It is recommended that AQP4 antibody be detected with a cell-based assay in sync with MOG antibody

Since the health insurance benefits are tested for AQP4 antibody by immunofluorescence assay (IFA), the clinical routine practice usually takes the AQP4 antibody provided by the health insurance first, and if it is positive, it can be directly diagnosed with AQP4 Ab(+)-NMOSD; If it is negative, the patient will be asked to send a cell-based assay (CBA) test for AQP4 antibody at his own expense, and if the AQP4-Ab is still negative, the patient will be asked to send the MOG antibody test at his own expense.

However, patients with NMOSD or MOGAD are very concerned about the speed of initiation of acute treatment, so once the diagnosis is made, high-dose steroids and plasmapheresis therapy will be started as soon as possible, and the antibody concentration in the body will drop significantly after plasmapheresis, and then the AQP4 Ab or MOG Ab may not be accurate enough to make a correct diagnosis. Therefore, my personal approach is to test these two antibodies simultaneously when the patient has an acute attack, once the patient is suspected to have NMOSD or MOGAD, and because CBA has higher sensitivity and specificity than IFA, and the IPND NMOSD diagnostic criteria also use the CBA test as a diagnostic recommendation, my personal approach prefers to directly use the CBA assay to detect AQP4 Ab and use live cell-based flow cytometry to detect MOG Ab.

AQP4 antibody tests, whether IFA or CBA, rarely show false positives, so a positive AQP4 antibody test result can confirm the diagnosis without further sequence dilution or quantitative testing. However, the detection method of MOG antibody has always been not specific enough, and there may be doubts about false positives, so the platform selected for MOG Ab test is a very important part of accurate diagnosis. The MOGAD diagnostic criteria published in Lancet Neurology in 2023 can be used as evidence of positive MOG antibody detected by live cell-based combined flow cytometry, or positive cell based assay diluted to 1:100.

According to two other Lancet studies, MOG antibody detection using live cell-based combined flow cytometry can be used to achieve higher accuracy and sensitivity. However, at present, there is no relevant technology and equipment introduced in China, so it is necessary to send the specimen to the laboratory attached to the Mayo Clinic in the United States for testing.

To test AQP4 Ab and MOG Ab, the vast majority of patients can be tested with serum, except for a small number of double-negative patients (negative AQP-4 antibody, negative MOG antibody), but the clinical manifestations are still highly suspected to be MOGAD patients, you can try to test CSF MOG Ab, the proportion of such patients in clinical is very low, only about 5% of MOGAD patients will show negative serum MOG Ab but cerebrospinal fluid MOG Ab positive, so only a few special cases will recommend sending CSF MOG for testing Ab。

References:

1. Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD Panel proposed criteria Lancet Neurol. 2023: 22(3):268-282.

2. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015:85(2):177-89.

3. Evaluation of aquaporin‐4 antibody assays. Clinical and Experimental Neuroimmunology., 2014: 5(3), 290-303.