Diagnosis

The diagnostic criteria are a series of requirements that patients must fulfill in order for a physician to confidently make a diagnosis of NMO spectrum disorder (NMOSD), the new term that is being applied to anyone who has a similar disease to what used to be known as NMO. Some people with limited symptoms, for example recurrent transverse myelitis, didn’t satisfy the previous criteria for NMO that required having both optic neuritis and myelitis even though they had a positive test for aquaporin-4 antibodies. Clinical studies showed that such patients behaved the same as did other patients who satisfied the previous full criteria for NMO. Patients with limited forms of NMO, as well as patients with brain lesions not previously felt to be diagnostic for NMO, can now be diagnosed with NMOSD when they meet the new specified criteria. In the new criteria, patients are divided into those with and without aquaporin-4 antibodies. In those with the antibodies, only a single symptom complex is necessary to support the diagnosis from among a group of symptoms that are known to occur with neuromyelitis optica. In those without aquaporin-4 antibodies, similar symptoms are required, but because of greater diagnostic uncertainty in that group, at least two symptoms are required as are some additional MRI findings that are typical of NMOSD in certain circumstances.

Many different types of individuals use diagnostic criteria. Doctors use them as a guide so they can make a confident diagnosis of NMOSD and exclude other disorders and to teach new physicians about what constitutes NMOSD. Clinical researchers use them to clearly define people with NMOSD and compare them to people who have other diseases, such as Multiple Sclerosis (MS). This is critical to detect differences between the groups that can then be studied and to advance our scientific understanding of what causes NMOSD to occur in the first place, why attacks happen, genetic or environmental influences, etc. Diagnostic criteria are also used by drug companies to design clinical trials of new therapies. The criteria ensure that they are testing those therapies on the appropriate groups of people in order to decide if they work.

The criteria were developed by an International Panel of NMO Diagnosis (IPND) which consisted of 18 physician and scientist experts from nine different countries, brought together by The Guthy – Jackson Charitable Foundation. The members were from North and South America, Europe, Asia and Australia and all are experts in NMOSD issues. They met in person several times over two years. They developed the criteria by reviewing the entire medical literature pertinent to NMO/NMOSD diagnosis, followed by discussion in subgroups and as a full panel, and finally by analysis of hypothetical case examples to generate consensus on minimal requirements for diagnosis. The panel analyzed imaging studies (e.g. MRI) and laboratory testing methods (e.g. aquaporin-4 antibody) to recommend how these should be incorporated into the diagnosis. The panel also identified “red flags” that could warn clinicians about potential for making an incorrect diagnosis in certain circumstances known to commonly mislead neurologists who might not be highly experienced in diagnosis of NMOSD.

Diagnostic criteria lead to a best working diagnosis, but clinical followup of patients and careful consideration of other potential diagnoses is always necessary, especially when a disease is not behaving as expected in terms of symptoms or response to therapy. No diagnostic criteria are perfect. We hope to institute a systematic study evaluating how accurate these diagnostic criteria prove to be under the auspices of The Guthy-Jackson Foundation, and no doubt clinicians around the world will be doing so as well, either as part of this consortium or through independent research studies.

Scientific advances have made the 2006 criteria inadequate for diagnosing patients with NMO/NMOSD. For example, many patients with NMOSD have attacks of hiccups or nausea and vomiting or they have brain MRI lesions that follow distinct patterns. These individuals are not captured by 2006 NMO criteria. We also knew that most patients who presented with a first attack of optic neuritis or longitudinally extensive transverse myelitis and who had a positive NMO-IgG (aquaporin-4 antibody) test would go on to develop all of the NMO criteria later on. The revised criteria allow them to be diagnosed at the time of the first attack.

In contrast to the requirements to diagnose NMO that included having BOTH optic neuritis and myelitis, NMOSD includes patients who have limited versions of NMO symptoms (e.g. recurrent optic neuritis, but not myelitis, with aquaporin-4 antibodies; a single myelitis with aquaporin-4 antibodies) or patients who have certain brain syndromes that are typical for NMO that were previously not considered sufficient for a diagnosis (e.g. persistent unexplained vomiting with aquaporin-4 antibodies).

The IPND criteria represent agreement amongst an international group of experienced doctors and researchers and are meant for worldwide use. The panel members felt that it was very important for doctors to be able to diagnose NMOSD in the same way regardless of where they practiced and even if they could not easily access the aquaporin-4 antibody test. Uniformity of terminology and internationally accepted standards for diagnosis will improve the care of NMOSD around the world and facilitate cooperative research studies.

It is likely that compared to using previous NMO criteria, the incidence and prevalence of NMOSD will roughly double the number of patients with NMO-like illness. We will not be sure of the exact effect until the criteria are widely utilized.

The IPND members concluded that as of 2015, the clinical symptoms and course, MRI findings, most immunological data, and the treatment of patients with NMOSD (2007 definition) are not known to be conclusively different from those with NMO. The NMOSD term recognizes the much broader spectrum of disease than just optic neuritis and transverse myelitis.

Devic was a doctor whose report from 1894 is strongly associated with this disease. He still deserves credit as inspiring future research on this condition. However, Devic did not identify specific criteria, and would likely have said that he didn’t appreciate the spectrum of this disease and how further research would evolve. Medicine is often complicated unnecessarily by differing terminology that is used differently by doctors and patients in different parts of the world to refer to the same disease. A very confusing terminology was “opticospinal MS” that was used in some parts of Asia; it could either refer to MS with prominent optic nerve and spinal cord symptoms or to what was referred to as neuromyelitis optica in Western countries. The International Panel concluded that opticospinal MS, while important from a historical perspective, was confusing, and should be dropped as a diagnostic term in favor of NMOSD. To be sure patients are accurately and appropriately diagnosed and treated, we should all adopt the preferred terminology and criteria as recommended by the International Panel, namely NMO spectrum disorder (NMOSD).

For people who are already diagnosed with NMO or NMOSD based on previous criteria, nothing will change except that they all will now be formally diagnosed with NMOSD. We expect that the new criteria will allow future NMOSD patients to be diagnosed at an earlier disease stage, which should result in earlier treatment.

The new criteria will include more patients who likely have this disease than previously, and hopefully, will do so without compromising on accuracy, although further study will need to be undertaken to be sure that accuracy remains at a level that we expect. Diagnosis will be possibly earlier, even after the first symptom, if aquaporin-4 antibodies are detected. Earlier diagnosis and earlier institution of appropriate therapy should translate into better outcomes.

Clinical researchers and industry (drug companies) may use these criteria when designing research studies and they will need to describe the clinical and MRI characteristics of people who they believe have (or do not have) NMOSD. Because the new criteria will likely result in more people being diagnosed with NMOSD, more individuals will likely have opportunities to participate in clinical trials and other clinical research. They may also be eligible for clinical studies at an earlier stage in the disease, for example, after a single clinical attack if they have aquaporin-4 antibodies.