Immunotherapy Clears Optic Neuritis, Lesions Prior to Symptoms

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Giving immunosuppressive therapy to patients with antibodies against aquaporin-4 protein (AQP4) and optic neuritis but no symptoms may help resolve observed lesions and prevent a relapse of neuromyelitis optica spectrum disorder (NMOSD), a case report suggests.

The case study, “Radiologically isolated aquaporin-4 antibody neuromyelitis optica spectrum disorder,” was published in the Multiple Sclerosis Journal.

In NMOSD, the immune system wrongly produces antibodies that attack proteins in cells that support the nervous system, causing inflammation in the spinal cord and in the optic nerve (optic neuritis), which connects the eyes to the brain. Most patients have high levels of antibodies against the AQP4 protein.

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Based on latest criteria, NMOSD can be diagnosed by the presence of both anti-AQP4 antibodies and symptoms consistent with an inflammatory event in the central nervous system (CNS; the brain and spinal cord), especially that involving the optic nerve or spinal cord.

However, anti-AQP4 antibodies have been detected many years before the development of clinical symptoms, raising questions on whether treatment should be started in AQP4-positive patients who are asymptomatic, or not yet showing symptoms.

Optic neuritis also is often a first NMOSD symptom and can be asymptomatic.

A team of researchers in Israel and the U.K. reported a case of extensive optic neuritis in an asymptomatic 12-year-old girl who was positive for anti-AQP4 antibodies. She was placed on immunosuppressive treatment, which effectively resolved the CNS lesions.

The girl, who had no family history of autoimmune diseases and felt she was in good health, was found to have right-sided optic disc swelling during a routine eye examination. The optic disc is a small, circular region where the optic nerve enters the back of the eye.

Her visual acuity, color vision, and visual fields were normal, and she denied having any headaches, vomiting, blurred vision, pain on eye movements, or other neurological complaints.

This prompted an MRI scan of her brain and spinal cord, which revealed extensive optic neuritis and a small spinal cord lesion. Blood tests also showed the presence of antibodies against AQP4.

Extensive screening for infectious and metabolic causes came back negative.

These findings suggested that the girl had NMOSD, even though she did not show symptoms and therefore did not meet the disease’s latest diagnostic criteria.

In this case, “it was felt by the clinicians that the potential risk of a clinical event justified pre-emptively treating with immune therapy,” the researchers wrote, adding that the alternative approach “would have been that of ‘watchful waiting’; that is, initiating treatment at the first sign of a clinical change, if this did in fact occur.”

The girl was given an immunosuppressive regimen consisting of high-dose corticosteroids (30 mg/kg) for five days, followed by one course of rituximab (two doses of 750 mg per square meter), a therapy often used off-label in NMOSD.

Rituximab works by suppressing B-cells, a type of immune cell responsible for the production of antibodies, including those involved in abnormal attacks.

She remained asymptomatic, and her optic disc swelling lessened after three months. An MRI showed resolution of the previously detected lesions and no new lesions.

Most children with AQP4-positive NMOSD experience relapses during their disease course and “suffer from higher visual disability compared to their adult counterparts, with optic neuritis presentation being associated with poor visual outcome,” the researchers wrote.

A previous study also showed that a delay in initial immunosuppressive treatment “was detrimental to vision,” and early treatment important for eyesight recovery and preservation, they added.

As such, “the radiological resolution seen in our patient following the acute treatment may suggest that the early diagnosis and treatment prevented the incident clinical attack,” the team wrote.

In addition, “it remains challenging for clinicians to decide on the duration of immunosuppressive therapies for patients who have been in remission with no subsequent relapses,” with a previous study showing that discontinuation “may increase the risk of relapse … even after 5 years of remission,” the researchers wrote.

“With the associated severe [complications] reported in [AQP4-positive] NMOSD, prognostic biomarkers for disease severity are required to avoid both under- and over-treatment of these patients,” they added.

Dalia Rotstein, MD, a neurologist at St. Michael’s Hospital and an assistant professor of medicine at the University of Toronto, in Canada, wrote in a comment article accompanying the case report: “We cannot know if and when [the girl] would have developed symptoms in the absence of such therapy, but this case underscores the full spectrum of [anti-AQP4] antibody disease activity, including the possibility, albeit rare, of very mild or asymptomatic cases.”

While on one hand, the well-established damaging consequences of anti-AQP4 antibodies might call for early and sustained immunosuppressive therapy, on the other the need for potentially lifelong immunosuppression “carries its own burdens,” Rotstein wrote.

“If, in the future, other asymptomatic patients are identified and followed off therapy, we could learn more about predictive biomarkers, [underlying] mechanisms and clinical evolution from the earliest stages of [AQP4-positive] NMOSD, although patients would have to be very closely watched to allow for rapid intervention if symptoms manifest,” Rotstein added.