Mar 15, 2019 Differential diagnosis may help spot NINJAs

A newly described autoimmune disease shares features with multiple sclerosis but isn't detected by conventional tests

The newly described autoimmune condition is proposed to be named 'normal-appearing Imaging-associated, neuroimmunologically justified, autoimmune encephalomyelitis' and abbreviated as NINJA

©  metamorworks / Getty

An autoimmune disease, known as normal-appearing Imaging-associated, neuroimmunologically justified, autoimmune encephalomyelitis, or NINJA, has emerged as a new condition that is similar, yet different, to multiple sclerosis (MS). It isn’t detected by the commonly used method of magnetic resonance imaging (MRI).

MS is a chronic autoimmune disease in which the protective coating of nerve cells is damaged by the body’s own immune system causing a wide range of symptoms depending on which part of the nervous system is affected. This makes MS particularly difficult to diagnose; there is no one test that confirms that a patient has the disease.

Diffusion tensor imaging analysis in patients with NINJA.

© 2019 National Center of Neurology and Psychiatry

“To diagnose MS, neurologists need to rule out a range of other explanations for the patient’s symptoms” says Takashi Yamamura, director of the Multiple Sclerosis Center, National Center of Neurology and Psychiatry (NCNP), Tokyo. “Before MRI was developed, this was a time-consuming and frustrating process as a diagnosis relied on evaluating clinical parameters to demonstrate the spread of disease” he adds.

MRI is a powerful tool for detecting the lesion-forming scar tissue that develops in response to nerve damage. When an MRI reveals brain lesions that are consistent with MS, the diagnosis is quite easy. However, some patients who, despite showing clinical features of MS, have normal-appearing brain and spinal cord MRIs. This raises the question of whether such MRI-negative patients actually have MS or another neuroimmunological disorder.

Takashi Yamamura, Youwei Lin, Daiki Takewaki and colleagues identified 11 patients out of 550 individuals who attended the Multiple Sclerosis Center of the NCNP in 2016. These patients fulfilled the widely-used McDonald criteria for diagnosing MS but showed no abnormalities on conventional MRIs. Yet these patients were severely disabled and often presented muscle weakness, visual impairments, sensory disturbances and cognitive symptoms.

Interestingly, when the researchers examined nerve fibre connectivity using Diffusion Tensor Imaging (DTI), which uses existing MRI technology to detect the movement of water molecules within tissues, they found extensive abnormalities in white matter compared to healthy controls. These patients also had high levels of circulating plasmablasts, cells with the potential to produce antibodies against their own proteins (auto-antibodies). The patients showed clinical improvement following the removal of these antibodies or steroid pulse therapy to dampen the immune response.

“Our findings suggest that these patients could have an autoimmune-mediated neurological disorder, involving as yet unknown auto-antibodies, that is different from MS” Yamamura explains.

Following exclusion of a wide range of other autoimmune, infectious, degenerative, and neoplastic disorders, the researchers concluded that the identified patients have a new and distinct autoimmune disease that they propose calling “normal-appearing Imaging-associated, neuroimmunologically justified, autoimmune encephalomyelitis, abbreviated as NINJA.”

“Our next goal is to define the immunological biomarkers and the disease mechanisms underlying NINJA. We have not yet excluded the possibility that NINJA is not a single disease but composed of heterogeneous conditions” says Yamamura.

The program-affiliated researchers contributing to this research are from the National Center of Neurology and Psychiatry, Tokyo.


  1. Takewaki, D., Lin, Y., Sato, W., Ono, H., Nakamura, M., et al. Normal brain imaging accompanies neuroimmunologically justified, autoimmune encephalomyelitis. Neurology Neuroimmunology & Neuroinflammation 5, e456 (2018). | Article

If you want to receive updates, sign up for the NAN-BYO Research newsletter.