Testing for Neuromyelitis Optica
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Published: April 2010Print Record of Viewing
Dr. Pittock reviews neuromyelitis optica (NMO), a severe, inflammatory demyelinating disease of the central nervous system that predominantly affects women and disproportionately affects African-Americans and Asians. He discusses how an NMO-specific biomarker can be used to differentiate between multiple sclerosis and NMO.
Presenter: Sean Pittock, MD
- Associate Professor in the Department of Neurology
- Co-Director of the Clinical Neuroimmunology Laboratory
- Consultant in the Division of Clinical Biochemistry and Immunology at Mayo Clinic
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Our presenter for this program is Dr. Sean Pittock, Associate Professor in the Department of Neurology and Co-Director of the Clinical Neuroimmunology Laboratory at Mayo Clinic. Dr. Pittock reviews neuromyelitis optica (NMO), a severe, inflammatory demyelinating disease of the central nervous system that predominantly affects women and disproportionately affects African Americans and Asians. He will discuss how an NMO-specific biomarker can be used to differentiate between multiple sclerosis and NMO.
I first of all would like to outline this talk. The first thing that I am going to try and do is talk to you about what is neuromyelitis optica. Secondly, I will then explain what NMO-IgG, a novel biomarker is. Then I will discuss with you the evolving spectrum of neuromyelitis optica. And lastly, I will discuss when a physician should consider ordering NMO-IgG.
Testing for Neuromyelitis Optica
These are the available tests for NMO-IgG. We generally recommend that NMO-IgG be tested in serum rather than spinal fluid.
So, what is neuromyelitis optica? Neuromyelitis optica is a severe, inflammatory demyelinating disease of the central nervous system. Traditionally, neuromyelitis optica has been considered under the term Devic disease and in Asian countries has been considered under the term optic spinal multiple sclerosis. Neuromyelitis optica is a relapsing disease. It is really quite different to what Devic first described. Devic described a monophasic illness, whereas neuromyelitis optica is a relapsing illness. Neuromyelitis optica has a predilection for the optic nerves and spinal cord. It causes optic neuritis when impacting the optic nerve, and transverse myelitis when affecting the spinal cord. In order to have a diagnosis of neuromyelitis optica, by the criteria set forth by Dean Wingerchuck in the late 1990's, patients must have the presence of optic neuritis and myelitis. However, more recently, we have become to realize that there is a broader spectrum of neuromyelitis optica that now includes relapsing optic neuritis, in which case transverse myelitis may not occur, and relapsing transverse myelitis, in which case optic neuritis may not occur. When a patient presents with neuromyelitis optica, the brain MRI is generally normal.
Traditionally, it was considered that the brain MRI should remain normal; however, we have recognized that as the disease progresses the majority of patients with NMO develop brain lesions. Though in adults, brain symptoms are uncommon. As you can see on the right hand side of this slide, this is a T1 postcontrast image, coronal section, which shows you the optic chiasm enhancing. When patients with neuromyelitis optica present with an optic neuritis, they can present with it affecting the right optic nerve, the left optic nerve, sometimes patients will present with bilateral simultaneous optic neuritis, and occasionally, patients will present with sequential optic neuritis, in other words, it starts in the right eye and then moves to the left eye. The other area that is commonly involved in neuromyelitis optica is the spinal cord.
Here you can see a sagittal image, T-2 weighted, MRI of the cervical spine. And, you can see a long area of signal abnormality extending from the cervical medullary junction all the way down the cervical cord, over many segments. Transverse myelitis and neuromyelitis optica is longitudinally extensive. It usually extends greater than 3 vertebral segments. This is extremely unusual for multiple sclerosis in which the lesions are generally short, usually less than 1 vertebral segment. If a patient presents with a longitudinal extensive transverse myelitis, the physician should consider neuromyelitis optica in the differential diagnosis.
For many years, neuromyelitis optica has been considered under the umbrella term of multiple sclerosis. Multiple sclerosis is the most common neurological disorder affecting young people. Most NMO patients that I see are initially misdiagnosed with multiple sclerosis. It is important to recognize that neuromyelitis optica is typically more debilitating than MS. Most disability in MS relates to the progressive phase of the disease, rather than relating to the attacks that occur in the early phase or the relapsing remitting phase.
In contrast, however, disability in neuromyelitis optica occurs during the specific attack, in other words, the disability is attack related. It is well know that the current immunomodulated drugs that are used for multiple sclerosis can reduce the likelihood of an attack of MS and reduce the number of lesions that accrue on MRI. However, unfortunately, the immunomodulated medications used in MS are only partially effective and this is because disability in MS is not specifically related to the attacks, but more related to the progressive phase of the illness. In NMO, patients develop disability because of the specific attacks. Therefore, prevention of attacks in NMO, we hope would prevent disability.
Accurate Diagnosis Essential
It is essential that an accurate diagnosis of NMO be made, and that it be made early. Misdiagnosing NMO as MS leads to inappropriate treatment. NMO is treated by immunosuppressant therapies. These therapies include azathioprine or CellCept, also known as mycophenolate mofetil. These medications are generally used in association or combination with prednisone. If these medications are not successful at prevention of attacks, then some patients begin rituximab therapy.
In contrast, multiple sclerosis is treated using immunomodulatory medications such as glatiramer acetate, interferon beta, or, more recently, natalizumab. There is some data to suggest that immunomodulated therapies that are used for MS may, in fact, make NMO worse. Untreated or treated inappropriately, 50% of NMO patients lose functional vision in at least 1 eye or become unable to walk within 5 years. This underscores the importance of making the diagnosis of NMO or an NMO spectrum disorder early, initiating appropriate treatment, preventing attacks and, thus, hopefully preventing longer term disability.
This brings us to NMO-IgG. NMO-IgG is the first ever biomarker that is specific and sensitive for any form of central nervous system inflammatory demyelinating disease. It was discovered at the Mayo Clinic and the findings were published in 2004. NMO-IgG is 99% specific and 70% sensitive for neuromyelitis optica. It does not occur in patients with multiple sclerosis. It is important to note that multiple sclerosis has no specific biomarker.
If you look over on the right hand side of the slide, you can see in the top figure an image of a mouse cerebellum. To this slide, we have applied a patient's serum that contains NMO-IgG. The NMO-IgG fluoresces and, thus, gives you this pattern of staining. Here you can see that the peel linings of the brain are stained, that the white matter of the cerebellum is stained, and then you can also see staining around the little blood vessels that occur in the cerebellum. In the lower figure, you can see staining of the distal tubules in the kidney.
Approximately 1 year after the first paper describing NMO-IgG as a sensitive and specific biomarker for neuromyelitis optica, the target autoantigen of NMO-IgG was discovered and it was discovered to be a water channel, aquaporin-4. Aquaporin-4 not only is located in the distal tubules of the kidney, but is the most abundant water channel in the central nervous system and it is present on the astrocytic foot processes. These are the foot processes that extend out from the astrocyte. This finding has resulted in a seismic shift in how the field thinks about demyelinating diseases. It was surprising that the water channel was located on an astrocyte, rather than the oligodendrocyte, which is the cell that makes myelin. The discovery of NMO-IgG and its target autoantigen, the water channel-aquaporin-4, provided further evidence that NMO was a distinct entity from multiple sclerosis. Recent in vitro and in vivo studies support a pathogenic role for NMO-IgG and, furthermore, are beginning to define the cascade of events that lead to inflammation, demyelination, and ultimate tissue destruction.
The identification of NMO-IgG has also allowed us to recognize a broader spectrum of disease associated with this antibody. As I previously discussed with you, the fact that generally at onset of the disease patients brain MRIs are normal, I stated that contrary to traditional views we have recognized that as the disease progresses, patients commonly develop lesions on their brain scans. A recent study has shown that approximately 60% of NMO patients have brain MRI abnormalities.
Adult NMO Spectrum Disorders
This has allowed us to broaden the definition of what we consider NMO and introduce the concept of an NMO spectrum disorder. Some patients that have brain MRI abnormalities have abnormalities that we consider to be NMO typical. In this slide, you can see the orange dots. These dots represent aquaporin-4, the water channel, which is the target of NMO-IgG.
This water channel is highly expressed in these regions. It is of interest that some patients with neuromyelitis optica have MRI abnormalities that localize to these aquaporin-4-rich sites. Here you can see flair signal abnormality around the floor of the fourth ventricle, in the thalamus, and hypothalamus. And, in this slide, on coronal section, again you can see the high flair signal abnormality again around the floor of the fourth ventricle in the brain stem.
Pediatric NMO Spectrum Disorders
Though brain symptoms are unusual in adult patients with neuromyelitis optica, they do occur more frequently in children with neuromyelitis optica. In a recent study that we did at the Mayo Clinic, you can see that in children with neuromyelitis optica spectrum disorders, the vast majority of the children have optic neuritis, either unilateral or bilateral, or transverse myelitis, or both as the presenting clinical syndrome. However, 16% of children presented with brain symptomatology, vomiting in 7%, nausea and Syndrome of Inappropriate ADH production in 2%, encephalopathy in 5%, and double vision in 2%.
On the right hand side of this figure you can see some of the brain MRI abnormalities that were seen in these children. The children that presented with brain symptomatology and were found to have NMO-IgG, subsequently went on to develop either optic neuritis or transverse myelitis.
On the lower figure you can see a diffuse, white matter signal abnormality in both of the hemispheres. This patient presented with an encephalopathy. All 3 patients that presented with encephalopathy as the presenting symptom of an NMO spectrum disorder were initially diagnosed as having acute disseminated encephalomyelitis. The identification of NMO-IgG allowed the patient to be clinically classified as neuromyelitis optica spectrum disorder. The presence of the antibody predicted the development of further attacks of optic neuritis or transverse myelitis.
NMO Graph 1
So I have talked to you about how NMO-IgG can help us make a diagnosis of a neuromyelitis optica spectrum disorder, but what else can the antibody do? We have also found that the antibody can be predictive of the development of future attacks, and this is important because it will impact management.
Here you can see a Kaplan-Meier survival analysis stratified by NMO-IgG status. In this study, Dr. Weinshenker and colleagues looked at the likelihood of developing a further event of either transverse myelitis or optic neuritis if you had had a single event of transverse myelitis. Patients were divided into those that were NMO-IgG positive and those that were NMO-IgG negative. If you had a single episode of longitudinally extensive transverse myelitis and you are NMO-IgG negative, then none of those patients developed another attack or a second event in the follow-up period. However, if a patient had a single episode of longitudinally extensive transverse myelitis and was found to be positive for the NMO-IgG, then 56% of those patients had a second event of either optic neuritis or a further episode of longitudinally extensive transverse myelitis within 1 year.
This study suggests that NMO-IgG, if positive in the setting of a single episode of longitudinally extensive transverse myelitis, is predictive of the development of a further event and, if that event is an optic neuritis, then fulfillment of the criteria for NMO. Thus, if a patient has a longitudinally extensive transverse myelitis and is positive for the antibody, we would recommend initiation of an attack-preventing treatment, an immunosuppressive medication that I have discussed previously.
NMO Graph 2
Similarly, in respect of optic neuritis, patients were divided into those that had an optic neuritis that tested NMO-IgG negative and those that had optic neuritis that tested NMO-IgG positive. Again, if the patient was positive for NMO-IgG, they had a high likelihood of developing another attack of optic neuritis or an attack of longitudinally extensive transverse myelitis in the follow-up period. Identification of NMO-IgG in a patient with optic neuritis or a current optic neuritis, predicts the development of another attack. So, who should we consider ordering NMO-IgG in?
In regards to optic neuritis, there are 2 groups of patients to consider. The first are those that present with a single episode of optic neuritis, and the second are those that present with multiple episodes of optic neuritis.
In regards to the spinal cord disease, there are 2 groups of patients to consider. Those that present with a longitudinally extensive spinal cord lesion, extending over greater than or equal to 3 vertebral segments, similar to the image that I showed on the first slide, or, patients with short spinal cord lesions that are less than 1 vertebral segment.
We recommend that NMO-IgG be tested in patients presenting with longitudinally extensive transverse myelitis for whom no other cause has been found, or patients presenting with multiple episodes of optic neuritis. In our studies we have found that the likelihood of identifying neuromyelitis optica IgG in a patient with a longitudinally extensive transverse myelitis is approximately 30% to 40%. The likelihood of identifying NMO-IgG in patients with recurrent episodes of optic neuritis is approximately 15% to 20%.
We think it is reasonable to consider ordering NMO-IgG in patients with a single episode of optic neuritis or a short spinal cord lesion. However, the prevalence of NMO-IgG in these 2 groups is much, much lower than in the other groups marked in green. Though, the frequency of the antibody in these patients is much lower. If, for example, NMO-IgG were to be identified in a patient with a single episode of optic neuritis than that would predict the development of another attack of optic neuritis, or of a transverse myelitis, and would mean that that patient likely has an NMO spectrum disorder.