What is NMOSD? A rare disease commonly misdiagnosed as MS

Neuromyelitis optica spectrum disorder (NMOSD) is a rare, severe inflammatory condition of the central nervous system that predominantly affects the optic nerves and the spinal cord.

The condition will present differently depending on the individual, but it usually manifests with clinical symptoms of optic neuritis (inflammation of the optic nerve) and myelitis (inflammation of the spinal cord).

Patients with NMOSD may therefore have blurry vision; pain upon eye movements; loss of vision; sensory and motor disturbances; weakness, numbness or tingling in an extremity; impaired ambulation; and bladder or bowel disturbances. In extreme circumstances, patients may have blindness in one or both eyes, or be wheelchair bound.

Patients with optic neuritis will often first present at their GP or see an ophthalmologist, while patients with myelitis will usually go straight to A&E, as the symptoms are usually dramatic.

However, since NMOSD is a rare disease, awareness among healthcare professionals and the wider public is generally poor. For this reason, NMOSD is often misdiagnosed as multiple sclerosis (MS), which can cause huge problems for the patient.¹

Why is NMOSD often misdiagnosed as MS?

“NMOSD is often misdiagnosed as MS because there is a clinical or phenotypic overlap, but it’s a lot rarer than classic MS,” explains Professor Friedemann Paul, Professor and Scientific Director of the Experimental and Clinical Research Center (ECRC).

In saying this, Prof. Paul indicates that many of the clinical symptoms of MS and NMOSD are similar. That is, both MS and NMOSD patients are likely to experience vision problems, numbness and tingling, mobility problems and pain.

However, NMOSD and MS are very different diseases, and misdiagnosis can be very problematic for the patient. In fact, wrongly prescribing MS medication to NMOSD patients can make symptoms worse.

How can doctors differentiate between MS and NMOSD?

“For almost 20 years, we have known about a very specific biomarker for NMOSD; this is called aquaporin-4 (APQ4). This water channel protein is found on cells known as astrocytes that surround the blood-brain barrier, and the presence of AQP4 antibodies can be tested for with a blood test,” says Prof. Paul.

MS patients will always test negative for AQP4 antibodies, whereas around 70-80% of NMOSD patients will test positive. This test therefore has high discriminatory power at differentiating between NMOSD and MS.

However, around 20% of NMOSD patients do not have APQ4 antibodies, these patients are known as seronegative patients. In such instances, healthcare professionals should conduct alternative tests to identify so-called ‘red flags’ of NMOSD, in order to make a diagnosis. This is particularly relevant for doctors practising in regions of the world that do not have access to APQ4 tests.

Recently, a subgroup of patients without AQP4 antibodies who show clinical symptoms of NMOSD were shown to harbour serum autoantibodies against myelin oligodendrocyte glycoprotein (MOG). This is now considered a distinct disease from NMOSD named MOGAD (MOG antibody associated disease).²

What are the ‘red flag’ symptoms of NMOSD?

Unfortunately, the rate of misdiagnosis is much higher in seronegative cases. However, there is a set of diagnostic criteria for seronegative patients which can aid doctors in making a diagnosis.³

As it is difficult to differentiate based on symptoms alone, neurologists should conduct MRI scans in order to reveal some of the characteristics that are typical of NMOSD.

“NMOSD patients will often have changes in the optic nerves, which we can see on brain imaging. They will also have areas of damage on the spinal cord that are typically longer or more extensive than we see with MS. Sometimes NMOSD patients will have lesions in certain areas of the brain too, but it’s very different than what we typically see with multiple sclerosis,” explains Dr Mitzi Joi Williams, a neurologist specialising in NMOSD and MS.

Healthcare professionals should also look at the patient’s recovery following an acute episode, as typically, MS patients have a better recovery from episodes than NMOSD patients.

Why is it so important that NMOSD patients receive an accurate and timely diagnosis?

Receiving a timely diagnosis is extremely important to reduce the risk of long-term disability and death. This is because around half of patients will become wheelchair bound and/or blind, and around a third of patients will die within five years of their first attack without the correct treatment.⁴

“Unlike multiple sclerosis, NMOSD is not a progressive disease, but the associated problems are accumulated every time someone has an acute episode. So, every acute episode can cause very severe damage, and people have poorer recovery from their episodes than we typically see with MS,” says Dr Williams.

“At present, there is no cure for NMOSD. But luckily, we now have therapies that can decrease the number and severity of relapses so that we can prevent disability if we catch it early on,” adds Dr Williams.

What treatments are available for NMOSD patients?

To manage acute attacks when a patient presents with optic neuritis, myelitis or brainstem symptoms, healthcare professionals should immediately implement high dose intravenous methylprednisolone.

If patients do not respond well to corticosteroids, healthcare professionals should consider plasmapheresis or immunoadsorption as a second-line treatment.

“We know that the likelihood of recovery depends on the time lag between onset of symptoms and the implementation of treatment. The faster, the better,” says Prof Paul.

In the long-term, patients namely rely on B cell depleting therapies. AQP4 antibodies are produced by CD19+ expressing B cell lymphocytes, which trigger an escalating autoimmune reaction.

Depletion of CD19+ B cells is therefore thought to remove important contributors to autoimmune reactions, including inflammation, lesion formation or astrocyte damage.

“We have widely used rituximab as a B cell depleting agent for many years in many countries. Classic immunosuppressants such as azathioprine, mycophenolate mofetil and prednisone are also widely used. But since 2019, we have had approvals of three new drugs,” explains Prof Paul.

“One drug that targets B cells or plasma cells is inebilizumab, an anti-CD19 monoclonal antibody. This drug is somewhat similar to rituximab which is anti-CD20. We also have a second monoclonal called eculizumab, a complement targeting antibody, and a third called satralizumab, which works by targeting the IL-6 receptor.”

Some of these B-cell depletion therapies, such as inebilizumab, are administered once every six months (following the initial loading dose of two infusions given two weeks apart). These newer treatments can therefore free up time for patients and allow them to continue with day-to-day activities without interruption due to frequent hospital appointments.

However, Prof. Paul expects many NMOSD patients receiving treatment will remain on one of the older drugs for the time being. “But as time advances, newly diagnosed patients will, in many cases, be put on one of these three new drugs,” he says.

Can NMOSD be prevented or cured?

While there is no cure for NMOSD, these newer therapies have been shown to be effective in reducing relapses.

As with any autoimmune disease, there are also certain steps people can take to reduce the risk, as Prof Paul explains: “Upholding certain lifestyle-related measures, such as eating a healthy diet, supplementing Vitamin D, quitting – or never starting – smoking, and maintaining a healthy weight can all help to lower the risk of autoimmune diseases,” says Prof Paul.

How does NMOSD impact on the patient in terms of quality of life?

The consequences of NMOSD extend beyond clinical impact. The disease has physical, functional and psychological effects, and can therefore significantly impact a patient’s quality of life. According to an NMOSD information pack by Horizon Therapeutics:⁵

75% of patients experience pain
40% experience depression due to pain severity
55% report fatigue
54-57% have some form of cognitive impairment
60% report significant impact on work, physical activities and ability to accomplish things all or most of the time
Sexual disfunction and bladder and bowel problems are also common.

NMOSD is nine times more likely to affect women compared to men. Since the median age of disease onset is 40, many patients will experience their first symptom at the peak of their career and when their children are still young.

Not only does NMOSD take a toll on the individual, but it can also have an impact on the family and friends, who often have to step in to provide care.

“I had a 25-year-old who, unfortunately, had a delayed diagnosis, and within six months was blind. Now, she can’t get to her appointments on her own and her mother cares for her full-time. She’s had an extreme loss of livelihood,” explains Dr Williams.

NMOSD can therefore take a mental and financial toll on the patient, as they are often no longer able to work, or may have to pay for their healthcare, depending on where they live.

Ongoing support and management

Because NMOSD is a chronic condition, patients will require ongoing support and management. This should take a multidisciplinary approach, according to Dr Williams, and healthcare professionals should consider talking to the patient about “wellness, diet, exercise, mindfulness and yoga, as well as traditional therapies and mental health services.”

Exercise and other forms of rehabilitation can be an important way to recover from the physical symptoms of NMOSD, adds Dr Williams. “If people have muscle weakness, they will often benefit from targeted exercise programmes to deal with their specific symptoms. Physical therapy can be extremely helpful for these patients, but the goal is always for them to continue some type of programme at home if they’re not in physical therapy indefinitely.”

“I’m also a big advocate of yoga to help with things like muscle tension, as well as anxiety and mindfulness to boost overall wellbeing,” she said.

However, this type of ongoing support is rarely offered to newly diagnosed NMOSD patients, and many can be left feeling completely alone following a diagnosis. This is what prompted Sumaira Ahmed, a patient with NMOSD, to create the Sumaira Foundation, a global non-profit that works to raise awareness of NMOSD and MOGAD.

Patient case study: Sumaira’s story

Sumaira experienced her first NMOSD symptoms in June 2014 when she lost vision in her right eye. She went to A&E where she spent 14 hours before the clinical team ordered an MRI.

The MRI showed that Sumaira had inflammation in the optic nerves and in the brain. She was admitted and spent three days on intravenous steroids.

When she was discharged, she was told she had an idiopathic case of optic neuritis, with an 18% chance of developing multiple sclerosis later in life. She was also severely deficient in Vitamin D and was given supplements.

Sumaira was told her vision would return within three months to a year, but was told to return to the hospital if her symptoms worsened.

Six weeks later, not long after her 25^th birthday, Sumaira’s symptoms deteriorated. She had numbness and tingling in her hands and feet, and was rushed to the hospital.

There, the doctors performed further MRIs and a lumbar puncture and diagnosed Sumaira with probable NMOSD. The doctors struggled to make a definitive diagnosis for months following Sumaira’s second presentation as she was testing (and continues to test) negative for AQP4. She is among the 20% of NMOSD patients who are seronegative.

To be sure of the diagnosis, the doctors conducted a myriad of tests to exclude other autoimmune diseases. After spending nine days in the hospital, Sumaira was discharged.

“I am very lucky in the sense that I was diagnosed within six weeks of my first symptoms. It’s almost unheard of to receive a diagnosis that quickly. Receiving a diagnosis early has meant that my symptoms have remained well-managed. I do have permanent vision loss in a quadrant of my right eye and I get bad nerve pain, but my bladder issues are well-managed and I don’t feel debilitated. Do I feel excellent? No. But all things considered, and seeing how other people in this community are affected by the disease, I consider myself to be incredibly lucky and very high functioning. I am the perfect example of how early detection can not only save a life, but also save your quality of life,” Sumaira said.

However, despite Sumaira’s early diagnosis and ongoing medical treatment, she felt that there was little support available to help her process her new diagnosis.

“I remember leaving the hospital when I was diagnosed after nine days of being there, freshly turned 25, newly diagnosed with a rare disease. I had half of the vision that I had, I couldn’t feel my hands or my feet, and I was discharged. The only thing I was told was which medication to take and when. I wasn’t given any idea of my prognosis or what to expect. I wasn’t directed to any support or advocacy groups. Everyone told me not to Google NMOSD but I did, and it told me that I had a maximum of five years to live. So here I was at 25, thinking I wouldn’t even make it to 30, yet I was given no mental health or wellbeing support whatsoever.

“I am very fortunate that I have family, friends and colleagues who have supported me through this whole process. But the reality is, when you have a rare disease, it is so isolating no matter how much support you have. You feel less alone when you have community support from people who know and understand the disease, which is what I was desperately seeking,” she said.

Following Sumaira’s experience, she decided to create The Sumaira Foundation – a global non-profit that is dedicated to generating global awareness of NMOSD and MOGAD. The Sumaira Foundation creates communities of support for patients and their caregivers, advocating on behalf of patients globally and supporting research to find a cure.

Since its creation eight years ago, the Foundation has raised $500,000 for research and shared over 140 patient stories in multiple languages. It has 40 patient and caregiver ambassadors working across five continents.

During the pandemic, the Sumaira Foundation began to offer virtual support groups. These meetings reached people across the globe, including in the US, the UK, South Africa and Germany, with the hope of expanding to other countries in the near future.

The Foundation has also hosted various webinars and podcasts on a variety of relevant health topics, which have enabled patients to listen to and interact with leading medical experts as they give advice on how to cope with a chronic disease diagnosis.

“What I’d love to create in the future, if we can make it happen, is a 24-hour hotline, so that patients have access to support whenever they need it,” Sumaira says.

Improving outcomes and quality of life for NMOSD patients

It seems one of the main challenges when it comes to NMOSD is poor awareness of the disease. Until NMOSD becomes better recognised, patients will continue to receive delayed or incorrect diagnoses, which hugely increases the risk of poor patient outcomes, including blindness, paralysis and death.

“It is very important that the right referral is made,” says Prof Paul. “If a patient presents with visual symptoms, he or she should be immediately referred to a neurologist with some expertise in neuroinflammation. Likewise, if a patient presents in A&E, they should be immediately referred to neurology. If there is no classic MS presentation, APQ4 testing should be ordered.”

Another challenge is improving patient support so that it is readily available and easily accessible to all those diagnosed with NMOSD. As Sumaira highlights, it is often extremely difficult for NMOSD patients to access support and long term management strategies, which are integral to improving quality of life.

As with all chronic disease, NMOSD can have a huge impact on wellbeing and quality of life, and healthcare professionals must ensure they signpost newly diagnosed patients to support groups, to ensure they have a community of people around them who know and understand the disease.

Dr. Mitzi Joi Williams is a Board-Certified neurologist and Fellowship trained Multiple Sclerosis Specialist.
Prof. Friedemann Paul is a professor of Clinical Neuroimmunology and head of the neuroimmunology outpatient clinic at the Experimental and Clinical Research Centre (ECRC).
Sumaira Ahmed is a patient with NMOSD and the founder/executive Director of The Sumaira Foundation.

References

Narayan R, Simpson A, Fritsche K, et al. MOG antibody disease: A review of MOG antibody seropositive neuromyelitis optica spectrum disorder. Mult Scler Relat Disord. 2018;25:66-72. doi:10.1016/j.msard.2018.07.025 Available at: https://pubmed.ncbi.nlm.nih.gov/30048919/. Accessed September 2022.
Ji Q, Dong H et al., Clinical Characteristics and Outcomes of Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder With Brainstem Lesions as Heralding Prodrome. Frontiers in Neurology. Multiple Sclerosis and Neuroimmunology. Available at: https://www.frontiersin.org/articles/10.3389/fneur.2022.836337/full. Accessed September 2022.
Wingerchuk D, Bennett J et al., International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Published July 2015, 85 (2) 177-189. Available at: https://n.neurology.org/content/neurology/85/2/177.full.pdf. Accessed September 2022.
Huda S, Whittam D, Bhojak M, Chamberlain J, Noonan C, Jacob A. Neuromyelitis optica spectrum disorders. Clin Med (Lond). 2019;19(2):169-176. doi:10.7861/clinmedicine.19-2-169. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454358/. Accessed September 2022
Horizon Therapeutics. What is NMOSD? Published 2022. Available at: https://www.horizontherapeutics.com/PDFs/NMOSD-Fact-Sheet.pdf

Lauren Nicolle

Lauren is a qualified journalist who writes primarily across the health and social care sectors. She is passionate about exposing the injustices faced by people with a learning disability, with a particular focus on equal access to healthcare.

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