Case Report: Focus on CNS Pathology May Benefit Rescue From Rebound MS

Share this content:
Case Report: Focus on CNS Pathology May Benefit Rescue From Rebound MS
Case Report: Focus on CNS Pathology May Benefit Rescue From Rebound MS

Aggressive immunosuppressive therapy that targets both T and B lymphocytes may be the strategy needed to control the intense central nervous system (CNS) inflammation that occurs when multiple sclerosis (MS) activity rebounds in patients who discontinue natalizumab, according to a recent case study published in Multiple Sclerosis Journal.1

The pathogenesis and treatment of rebound MS — a life-threatening complication affecting 20% to 40% of patients with MS who discontinue natalizumab  — have been unclear, but a team of researchers affiliated with the University of Montreal in Quebec, Canada, has made headway. They used a fatal case of severe CNS inflammatory demyelination after natalizumab discontinuation to immunologically and pathologically characterize rebound MS and propose a rescue strategy.

The case was that of a 32-year-old woman who had been diagnosed with relapsing-remitting MS about 10 years prior.  The patient was clinically and radiologically stabilized (expanded disability status scale [EDSS] score of 2.0) with natalizumab therapy, and she remained stabilized on natalizumab for 2 years. Seropositivity for JC Virus (JCV), however, emerged, and the patient agreed to be switched from NTZ to glatiramer acetate.

Four months later, the patient was hospitalized for motor and cognitive impairment. A panel of laboratory measures, including cerebrospinal fluide (CSF) analysis, was negative, but magnetic resonance imaging (MRI) showed CNS deterioration. Methylprednisolone was administered without improvement, and the patient deteriorated further, with the EDSS score increasing to 9.5 (incapable of significant interactions). This prompted a second CSF analysis and MRI scan. The results of the CSF analysis were similar to the previous one and several new lesions were visible on MRI. The patient continued to decline despite care, and she died 4 days after active care was stopped.

Antemortem blood and CSF were analyzed and compared with postmortem data. Immune cells isolated from the case's CNS parenchyma also were characterized via flow cytometry.

Postmortem pathological analysis of the brain revealed a multitude of active inflammatory demyelinating lesions typical of an immunopathological MS pattern II. Monocytes and macrophages and B cells were enriched in the CNS parenchyma, and CD8 T lymphocytes predominated in CNS tissue whereas CD4 T lymphocytes were predominant in the CSF. Further, CNS-infiltrating lymphocytes expressed high levels of adhesion molecules, granzyme B, interferon-gamma, and interleukin -17. The research team pointed out that the CNS profile markedly differed from the CSF profile, especially regarding T lymphocyte subsets, confirming other research in which it was proposed that CSF analysis may give an incomplete or inaccurate picture of CNS inflammation.2

“Our data support a primary role of T and B lymphocytes in driving CNS damage,” the authors wrote. “This also suggests that CD8+ T lymphocytes, which are dispensable in most traditional animal models of MS, play a crucial role in human neuroinflammatory conditions.”

The findings led the researchers to suggest that, although ethical and technical challenges limit the use of gradient-based isolation of CNS infiltrating cells, gradient-based isolation of immune cells from the CNS parenchyma could aid in understanding the pathophysiology of fatal CNS inflammatory diseases. They also concluded that their findings provide a rationale for aggressive anti-inflammatory therapy that targets T and B lymphocytes in CNS tissue in cases of rebound MS following natalizumab withdrawal.  

References

Larochelle C, Metz I, Lécuyer MA, et al. Immunological and pathological characterization of fatal rebound MS activity following natalizumab withdrawal. Mult Scler. 2016 Apr 1. [Epub ahead of print]

Planas R, Metz I, Ortiz Y, et al. Central role of Th2/Tc2 lymphocytes in pattern II multiple sclerosis lesions. Ann Clin Transl Neurol. 2015;2(9):875-893.

You must be a registered member of Neurology Advisor to post a comment.

Sign Up for Free e-newsletters



CME Focus