Some of the questions that need to be answered in rare diseases are the same as in more common pathologies: how do these diseases arise, and how do we recognize them at the earliest possible opportunity?
The real-world dilemma is that the rarer the disease, the less likely research institutions are to fund the studies needed to answer these questions. In addition, less common diseases provide a smaller pool of potential participants for clinical studies. This then dilutes the potency of any clinical findings.
However, for those diagnosed with rare diseases, well-funded, peer-reviewed research can provide hope for a better (and longer) life. Researchers who study rare diseases, such as neuromyelitis optica spectrum disorder (NMOSD), understand this and hence deserve our recognition. Below, we will examine current practices in how we diagnose NMOSD.
The Role of AQP4-Ab
First of all, it should be noted that NMOSD has been redefined in recent years. Holroyd and colleagues explained, “Prior calculations relied on criteria created in 2006, which required both clinical optic neuritis and transverse myelitis. However, updated 2015 criteria require only 1 of 6 core clinical features along with antibodies to aquaporin-4 (AQP4-Ab) positivity, or 2 clinical features if AQP4-Ab seronegative.”
This means that scientists have not been able to track disease prevalence consistently over the last few decades. With the updated definition of NMOSD in 2015, studies have estimated a rise of around 1.5 fold in disease prevalence. The implication here is that the quality of the epidemiological data we have on NMOSD is not on par with those of other diseases.
Read more about NMOSD epidemiology
On the bright side, it is important that clinical definitions of diseases change according to the latest available evidence. The 2015 criteria mean that AQP4-Ab serology status is now a major factor in defining this disease. The other 6 clinical features that can be used to diagnose NMOSD in conjunction with AQP4-Ab positivity relate to different central nervous system (CNS) regions:
- Optic nerve
- Spinal cord
- Area postrema of the dorsal medulla
Can NMOSD be diagnosed in the absence of AQP4-Ab? Yes, but diagnostic requirements are more stringent. Patients would need to report experiencing 2 or more different core clinical characteristics (such as the ones listed above), as well as have supportive magnetic resonance imaging (MRI) evidence that enhances diagnostic specificity.
The reasons that NMOSD diagnosis is today centered around AQP4-Ab serology status are well-documented in the medical literature. It all started with the discovery that selective AQP4-Ab bind to AQP4, leading to a paradigm shift in how we understand NMOSD pathogenesis.
Carnero Contentti and Correale wrote, “Clinical observations also support the hypothesis that AQP4-Ab causes NMOSD and are highly specific. They can be detected in the sera of most patients, and levels of both AQP4-ab and AQP4-ab–producing plasmablasts correlate with disease activity.”
In addition, studies also suggest that the presence of AQP4-Ab is useful in predicting future relapses. However, it should be noted that scientists have yet to determine a serum level threshold of AQP4-Ab that warrants closer monitoring. This is in part because AQP4-Ab serum levels differ greatly between NMOSD patients.
However, we do know that CNS lesion distribution tends to correlate with regions that have high AQP4-Ab expression and blood-brain barrier (BBB) permeability. BBB permeability is significant because evidence suggests that AQP4-Ab are synthesized peripherally and enter the CNS via a disrupted BBB.
Medical Imaging Aids in Diagnosis
There are a number of classical red flags in conventional neuroimaging that point to an NMOSD diagnosis. Wingerchuk and colleagues wrote, “MRI lesion patterns are a major arbiter of CNS demyelinating disease differential diagnosis. Several brain, optic nerve, and spinal cord patterns are characteristic or highly suggestive of NMOSD.”
In spinal cord MRI, acute NMOSD typically presents as a longitudinally extensive transverse myelitis (LETM) lesion associated with acute transverse myelitis. Other features that may be detected via spinal cord MRI are the rostral extension of the lesion into the brainstem and spinal cord swelling.
Chronic NMOSD usually manifests in spinal cord MRI as longitudinally extensive spinal cord atrophy, with or without the presence of focal or diffuse T2 signal change involving the atrophic section.
Holroyd and colleagues wrote, “Characteristic clinical and imaging features of optic neuritis are also seen in NMOSD. NMOSD patients are more likely to have bilateral optic neuritis or posterior involvement of the optic chiasm and optic tracts, as compared to patients with [multiple sclerosis].”
Read more about NMOSD diagnosis
Cerebral MRI scans may also demonstrate brain lesion patterns typical in NMOSD. Examples are the presence of lesions involving the dorsal medulla (which may be contiguous with an upper cervical spinal cord lesion), the presence of subcortical or deep white matter lesions, and the presence of extensive periependymal brain lesions.
As there are MRI lesions strongly associated with NMOSD, there are likewise a number of MRI lesions that might lead a physician to consider an alternative diagnosis. These include brain and spinal cord lesions that are highly suggestive of multiple sclerosis. In addition, physicians should be aware of comorbidities that may present with neurological symptoms that mimic NMOSD, such as sarcoidosis, cancer, and chronic infection.
The purpose of refining our diagnostic capabilities of NMOSD is that it leads to better (and faster) care. The diagnosis of CNS lesions is a highly specialized field that requires vast amounts of expertise and experience. No doubt we will continue to see NMOSD research conducted in a multidisciplinary setting, with radiologists playing a key role.
Carnero Contentti E, Correale J. Neuromyelitis optica spectrum disorders: from pathophysiology to therapeutic strategies. J Neuroinflammation. Published online September 16, 2021. doi:10.1186/s12974-021-02249-1
Holroyd KB, Manzano GS, Levy M. Update on neuromyelitis optica spectrum disorder. Curr Opin Ophthalmol. 2020;31(6):462-468. doi:10.1097/ICU.0000000000000703
Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177-189. doi:10.1212/WNL.0000000000001729