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Subspecialties Neuro-ophthalmology, Professional Development, Health Economics and Policy, Education and Training

Mystery (Mis)Diagnosis

Neuromyelitis optica spectrum disorder (NMOSD) is a rare disease, making up only around one percent of all demyelinating diseases. It manifests with severe attacks of optic neuritis – inflammation of the optic nerve, or of myelitis - inflammation of the spinal cord. Patients complain of vision loss, pain with eye movement, scotomas, and a couple of other vision related problems. Likewise for myelitis attacks, there are complaints of paralysis, motor problems, bladder and bowel disturbances, and more. The problem is that, until quite recently, many of these patients were misdiagnosed with MS.

In many countries, when a patient presents with NMOSD symptoms – eye pain and vision loss – the first port of call often is an ophthalmologist and not a neurologist. Right now, few ophthalmologists are familiar with the condition, so many of these patients are misdiagnosed. And the consequences are drastic. Around 50 percent of untreated NMOSD patients become blind and need wheelchairs; around a third are likely to die within five years of their first attack (1, 2).

First of many

I’m a board certified neurologist, and have been working in the field of neuroimmunology for almost 20 years. I first became acquainted with the condition 18 years ago; indeed, my first NMOSD patient was a sufficiently striking experience that I was driven into the NMOSD field. Prior to this patient, I hadn’t heard much about the condition either. She was referred to our outpatient clinic with a long myelitis lesion – essentially severe inflammation of almost the entire spinal cord – but she had been diagnosed with MS. Thankfully, the team at the referring hospital rightfully felt that it was not a typical MS diagnosis (because of the long cord inflammation). Around the same time (2004), a seminal publication from the Mayo Clinic in Minnesota, USA, and Vanda A. Lennon described the discovery of aquaporin-4 (AQP4) autoantibodies as a specific biomarker of NMOSD. We rapidly devised an assay for these autoantibodies, and sent our patients’ serum in for testing. It came back positive. For me, it was a very inspiring experience; we were able to provide this patient with a definitive diagnosis of NMOSD. Since then, she has been part of our cohort; more importantly, she is being treated and is doing well. With my newly found interest and more patients being referred, we started to build up a cohort of patients. 

Today, we run a big outpatient clinic for neuroimmunology, with approximately 1,500–2,000 multiple sclerosis (MS) patients per year and a neuromyelitis optica spectrum disorder (NMOSD) cohort of more than 100 participants – by far the largest cohort in Germany, and one of the biggest in the world.

Managing the misdiagnosis maelstrom 

As you’ve probably guessed, the biggest unmet need in this field is a lack of awareness – there needs to be more information and education for ophthalmologists on this condition. The key point: when a patient presents with signs and symptoms of optic neuritis, it is not necessarily MS or an isolated attack of optic neuritis; rather, it can be a first symptom of NMOSD. Being aware of the potential for misdiagnosis can lead to direct referral to a neurologist or selection of appropriate antibody testing.

Awareness is all the more important thanks to a dramatic change in the therapeutic landscape for NMOSD. Historically, we had empirical treatments, such as broad immunosuppressants, which may work on empiric grounds, but not in randomized control trials. But over the past two to three years, three pivotal drug trials have led to the approval of three different drugs – eculizumab, inebilizumab, and satralizumab – each with a different mechanism of action. And they all work pretty well in seropositive and AQP4 positive NMOSD, with a reduction in attack rates of between roughly 65 and 95 percent. 

Inebilizumab has been approved in the US and has received a positive Committee for Medicinal Products for Human Use (CHMP) opinion by the European Medicines Agency; it will be available in Germany from July 2022. The advantage of inebilizumab is that it was investigated in by far our largest NMOSD trial (in terms of the sample size against a placebo), using a very rigorous design relating to the adjudication of attacks of relapses. And this point is key because reduction of attack rates is the most important therapeutic goal.

The main target for therapeutics is AQP4 pathogenesis, and these three drugs all target different aspects of the immune biology of the disease – eculizumab acts more on the downstream complement system; inebilizumab acts as an anti-CD19 agent; and further upstream you have IL-6-targeting satralizumab, which impedes interactions with T and B cells and other immune system interactions with astrocytes. 

Moving on from NMOSD, there are other studies focused on myelin oligodendrocyte glycoprotein associated disease (MOGAD) – another rare disease that has phenotypic overlap with both MS and NMOSD. The most frequent manifestation of MOGAD is optic neuritis and, despite the phenotypic similarities, MOGAD patients do not test positive for the AQP4 antibody, and response to AQP4 targeting therapeutics has not been thoroughly investigated.

From a clinical perspective, the biggest challenge is guiding and managing the patient through the healthcare system, and finding the right drug at the right moment for the right patient, which is not trivial. For example, should a patient who has been doing well on the off-label immunosuppressant azathioprine, now be switched to one of the three new approved on-label drugs, or should they stay on azathioprine, and deal with any side effects that may arise? From a research standpoint, the biggest challenge is developing efficacious symptomatic therapies because this has not been sufficiently addressed by clinical trials with immunotherapies. Yes, we have done well to produce therapies to reduce the attack rates, but we also need drugs to target debilitating symptoms, such as pain, fatigue, cognitive problems, and bladder and bowel problems.

The research continues

Our group has two major themes of research. First, we are investigating subclinical tissue damage caused in NMOSD (in other words, any damage beyond the clinically overt attacks that cause optic neuritis and myelitis). To do this, we use MRI and OCT to measure retina damage and observe any progressive tissue loss in the CNS – and try to understand if this has any clinical impact on patients. The second theme is around immune tolerance, where we have one project exploring regulatory T-cells with a view to engineering T-cell therapies for individual patients with NMOSD. 

With colleagues at Moorfields Eye Hospital in London, UK, and in collaboration with the International Multiple Sclerosis Visual System Consortium we’re also looking at the use of AI algorithms to discriminate, with high accuracy, an NMOSD scan from an MS scan or a scan from a patient with another condition. Evidence gained here could be particularly valuable when a patient presents with first symptoms, as – depending on the country they’re in – results of an antibody test may take two to three weeks, or antibody testing might not be available at all. Within this timeframe, you need to make therapeutic decisions for the acute attack management, but also for preventative immunotherapy. An AI algorithm that helps with differential diagnosis at a very early stage of the disease would be extremely useful. We hope to publish data on this topic soon.

Finally, one strange aspect of NMOSD is that it affects more women than men. “Not that strange!” you may say, if you know this is the case for most autoimmune diseases; however, in NMOSD, it’s a 9:1 ratio – and that is really extraordinary. We don’t know exactly why, but it is likely related to sex hormones. We’ve just started a research project on this aspect as well.

Two critical take-home messages

First, simply be aware of NMOSD (and MOGAD) when diagnosing. Second, you may have heard the phrase “time is brain” for stroke patients, but we say, “time is retina.” Of course, we’re not talking on the same time-scale as stroke – where minutes to hours without treatment can affect patient outcomes; however, we do know that, the earlier we begin optic neuritis acute attack management, the better the functional and visual outcomes down the road. When confronted with suspicion of optic neuritis, it is so important that you, as ophthalmologists, take immediate action to diagnose optic neuritis, and then either refer the patient to the neurologist or start immediate corticosteroid or plasma exchange intervention to prevent irreversible vision loss.

To find out more about therapeutic advantages of the new NMOSD treatment, read Bruce Cree’s article.

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  1. S Huda et al., “Neuromyelitis optica spectrum disorders,” Clin Med, 19, 169 (2019). PMID: 30872305.
  2. DM Wingerchuk et al., “The clinical course of neuromyelitis optica (Devic’s syndrome),” 53, 1107 (1999). PMID: 10496275.
  3. VA Lennon et al., “A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis,” Lancet, 364, 2106 (2004). PMID: 15589308.
  4. S Jarius et al., “Neuromyelitis optica,” Nat Rev Dis Primers, 6, 85 (2020). PMID: 33093467.
  5. JS Graves et al., “Leveraging visual outcome measures to advance therapy development in neuroimmunologic disorders,” Neurol Neuroimmunol Neuroinflamm, 9, e1126 (2021). PMID: 34955459.
  6. FC Oertel et al., “Retinal optical coherence tomography in neuromyelitis optica,” Neurol Neuroimmunol Neuroinflamm, 8, e1068 (2021). PMID: 34526385.
About the Author
Friedemann Paul

Professor of Clinical Neuroimmunology, Charité-University Medicine Berlin, Germany

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