Progressive disability in MS explained?

The differences in the course of lesions may help neurologists distinguish between multiple sclerosis (MS) and other demyelinating disorders in new findings that may help explain the differences in the course of the disease, particularly progressive disability in MS.

Results from a retrospective study show that complete resolution of brain damage on MRI was more common in patients with myelin-oligodendrocytes-glycoprotein-IgG (MOGAD) associated disorders. Complete resolution occurred in 72% of the group with MOGAD, compared to 17% of people with multiple sclerosis (MS) and 14% of those with aquaporin-4 neuromyelitis optic spectrum disorder positive (AQP4 + NMOSD).

Dr Eoin Flanagan

“What we found, with MOGAD in particular, many of the lesions have completely disappeared,” said co-investigator Eoin Flanagan, MBBCh, neurologist, Mayo Clinic, Rochester, Minnesota. Medscape Medical News. “This fits with the fact that MOGAD has a fairly good prognosis and that patients do not develop much long-term disability with this disease,” he said.

The researchers also investigated whether scarring could explain the lack of slowly progressing disability in patients with AQP4 + NMOSD and MOGAD compared to patients with MS.

“The differences in wound healing that we have found will help doctors distinguish between these three diseases more easily for easier diagnosis. More importantly, our findings improve our understanding of the mechanisms of nerve damage in these three diseases and may suggest an important role for these scars in the development of long-term disability in MS, ”Flanagan said in a statement.

The results were published online July 14 in Neurology.

Evolution of lesions

MOGAD, AQP4 + NMOSD and MS are inflammatory demyelinating disorders that share certain manifestations. However, these disorders differ in important ways, including the severity of the attacks and their clinical course.

Although patients with MOGAD and AQP4 + NMOSD usually have severe seizures that result in major disability, the clinical course of these disorders is better than the initial seizures suggest. In contrast, patients with MS have relatively mild seizures that are associated with a high risk of progressive disability.

Previous studies of these demyelinating disorders have looked at the shape and location of the lesions but have not changed over time. Observing the development and resolution of these lesions could provide information on the course of the disease and influence the treatment and monitoring of disease activity, the current researchers note.

They retrospectively identified consecutive patients with MOGAD, AQP4 + NMOSD, or MS who presented to the Mayo Clinic between January 2000 and August 2019. Data from a cohort of MS patients in Olmsted County , Minnesota, were also included.

Eligible participants had had a first stroke or myelitis, had undergone an MRI of the brain or spinal cord within 6 weeks of the nadir of the attack, and had undergone a follow-up MRI more than 6 months after the attack.

Patients who experienced a relapse during follow-up in the same region as the initial attack were excluded. Concomitant brain attacks and myelitis were analyzed separately.

An index lesion was identified for each patient. The index lesion was defined as an acute lesion which provided an anatomical explanation for clinical symptoms. If several lesions were present, the largest of them was chosen as the index lesion. MRI scans were reviewed by neuroradiologists who were unfamiliar with patient diagnoses and serology results.

Of the 156 participants, 67 had MS (76% female), 51 had AQP4 + NMOSD (80% female) and 38 had MOGAD (45% female). The median age at first attack for the groups was 37, 53, and 25, respectively.

In addition, 63 patients had relapsing-remitting MS, two had a single attack of progressive MS, and two had clinically isolated syndrome. No patient with NMOSD or MOGAD developed progressive disease at final follow-up.

The participants suffered a total of 81 strokes and 91 myelitis attacks. Sixteen patients had had both a stroke and an attack of myelitis.

Symptoms corresponding to baseline brain lesions were brainstem or cerebellar syndrome (56), encephalopathy or focal symptoms (12), or combinations of these (13). Among the patients with an attack of index myelitis, 31 had cervical involvement, 21 had thoracic involvement and 39 had involvement of both regions.

Full resolution

The results showed that 72% of patients with MOGAD experienced complete resolution of the lesion of the cerebral index, compared to 17% of patients with MS and 14% of patients with NMOSD (P <.001>

Similarly, 79% of the MOGAD group experienced complete resolution of the myelitis index lesion, compared to no member of the MS or NMOSD groups (P

Complete resolution of all T2 abnormalities during MRI follow-up was more frequent in the MOGAD group than in the other two groups.

For stroke, complete resolution occurred in 39% of patients with MOGAD, 10% of patients with NMOSD, and 5% of patients with MS. For spinal cord attacks, complete resolution occurred in 79% of patients with MOGAD, compared to none of patients with NMOSD or MS.

The median reduction in the T2 lesion area on the follow-up axial brain MRI was greater in patients with MOGAD (213 mm2) than in those with NMOSD (104 mm2; P = .02) or MS (36 mm2; P <.001>

Reductions in lesion size on MRI sagittal spine follow-up were similar between MOGAD (262 mm2) and NMOSD (309 mm2) groups; both experienced greater reductions than the MS group (23 mm2; P <.001>

Prevention of injuries

Flanagan noted that the diagnosis of MOGAD is based on an MOG antibody test, but sometimes false positive results occur.

“A single follow-up MRI may be helpful, showing that if all of the lesions went away, you would be more confident it would be MOGAD,” he said.

Study participants with MS experienced less wound healing than patients with MOGAD or NMOSD.

“We now have drugs that are very effective in MS to prevent new lesions from appearing,” Flanagan said. The study emphasizes the importance of injury prevention, “because when you have an injury it tends to stick around and not fully recover,” he added.

He noted that lesion resolution in the study population may reflect remyelination. Future research examining whether remyelination is more effective in MOGAD than in other disorders could potentially lead to new approaches for the treatment of MS, Flanagan said.

“Maybe some of the MOGAD lesions are from edema. When we use steroids it tends to resolve itself and not leave a scar. So that’s another possibility. We would like to understand that better,” did he declare.

Differences in pathology

Commenting on the findings of Medscape Medical News, Bruce Cree, MD, PhD, professor of neurology, Weill Institute for Neurosciences, University of California, San Francisco, noted that the study is one of the first to systematically examine and compare the course of MRI lesions in three disease states. .

Dr Bruce Cree

“What they’ve pinpointed is the differences in the underlying pathology of these three different diseases,” said Cree, who was not involved in the research.

The cross-sectional comparison of the study was its main strength, he noted.

“The main weakness, from my perspective, is that in all three of these disorders, optic nerve damage is very common,” Cree said. “In this article, no analysis of optic nerve damage by MRI was performed.”

The researchers recognize this limitation and explain that they did not have a consistent and dedicated orbital imagery for such an analysis.

Cree noted that the results also serve as a reminder that the pathogenesis of MOGAD is not yet clear.

“We know that these anti-MOG antibodies are associated with this demyelinating disorder, but it remains to be clearly demonstrated whether these antibodies have a pathogenic role,” Cree said. “What actually happens in these lesions is also not fully understood.”

The finding that MOGAD lesions can resolve completely suggests that repair mechanisms are at work in the brain and spinal cord, he noted.

Being able to understand and understand what these mechanisms are at work and why they occur in MOGAD but not in NMOSD or MS “would be of enormous clinical benefit,” he said.

The current study also highlights the importance of incorporating imaging into clinical trials that study these rare disorders, particularly serial imaging for MOGAD, Cree added.

This imaging is vital not only to develop new treatments but also to understand the clinical impact of a given drug. “We really need rigorous imaging to be applied to these rare diseases, as has been done with MS,” Cree concluded.

The study was funded by the National Institute of Neurological Disorders and Stroke. Flanagan received research support from MedImmune / Viela Bio. Cree is working with two of the researchers on the steering committee of the N-MOmentum trial of inebilizumab in patients with NMOSD. He did not report any relevant financial relationship.

Neurology. Published online July 14, 2021. Summary

Follow Erik Greb on Twitter: @MedscapeErik.

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