Massive Multiple Sclerosis Reactivation in A 72-Year-Old Man After Natalizumab Discontinuation: A Case Report

Abstract

Natalizumab is a monoclonal antibody with excellent efficacy in controlling multiple sclerosis activity. However, its discontinuation can lead to a massive inflammatory reactivation. So far, the decision to discontinue or continue disease-modifying therapy in older patients remains a matter of debate and the final choice is based on several clinical features including age, time since last relapse, number of previous therapies, and disease duration.

In this report, we describe a massive multiple sclerosis reactivation in a 72-year-old patient with diabetes and hypertension who had to stop natalizumab due to a high JCV index after 12 years of treatment, during which clinical and radiological stability were maintained. This severe relapse resulted in a widespread high activity on brain MRI and an EDSS worsening.

This case confirms that the management of natalizumab discontinuation is challenging, even in older patients. Factors such as age and comorbidities can further complicate the choice of alternative treatments.

Introduction

Multiple Sclerosis (MS) is the leading cause of non-traumatic disability among young adults [1]. So far, more than nineteen Disease-Modifying Treatments (DMTs) have been approved for the treatment of MS, each characterized by distinct mechanisms, safety profiles, and tolerability [2]. Natalizumab (NTZ) is a monoclonal antibody that selectively blocks the alfa-4 subunit of integrins, thereby inhibiting the passage of leukocytes across the blood-brain barrier. Despite its great efficacy in controlling MS activity, NTZ discontinuation represents a real challenge for physicians, as it could lead to a massive inflammatory reactivation known as rebound [3]. The most common cause of NTZ discontinuation is the John Cunningham virus (JCV) positivity, which can lead to severe and often fatal encephalitis known as Progressive Multifocal Leukoencephalitis (PML) [4]. JCV is a ubiquitous virus whose seroconversion increases with age, being detected in 60-80% of the population at the age of seventy. The higher prevalence of JCV among older individuals, coupled with the natural reduction of MS activity with age reduces NTZ usage in older patients. Whether age plays a protective role in mitigating rebound after NTZ discontinuation has still to be elucidated.

Case

A 72-year-old patient diagnosed with insulin-dependent diabetes and hypertension at the age of 50, presented with his first neurological symptom in 2001, characterized by a left-eye optic neuritis, which was successfully treated with intravenous steroid. An MRI showed multiple periventricular lesions without enhancement, while no lesions were detected in the spinal cord. A strict neurological follow up ensued until February 2005, when the patient received the diagnosis of MS following the onset of hypoesthesia in the left hemiface. A new periventricular lesion and a lesion in the medulla oblongata were observed on MRI, prompting the initiation of treatment with Interferon beta 1b (Betaferon) three times a week. In September 2008, he developed hypoesthesia and weakness in both arms and his left leg, accompanied by severe hyperglycemia (384 mg/dl). Increasing insulin doses led to an improvement of the neurological symptoms. Nevertheless, he also received a three-day course of intravenous steroids (500mg). In June 2011, the annual MRI showed the presence of 6 new encephalic lesions and a new spinal cord lesion. Consequently, Betaferon was discontinued and a new therapy with NTZ was started. Under NTZ treatment the patient enjoyed 12 years of clinical and radiological stability, maintaining a stable EDSS score of 3.5.

In April 2015, after 36 infusions, a Stratify test routinely conducted for NTZ surveillance regimen, yielded a positive result with an index of 1.97. Due to the PML risk, the patient began a strict radiological follow-up with new MRI scans every 3-6 months. The infusion schedule gradually transitioned from a 4-week regimen to a 6-week one. The patient continued NTZ treatment for an additional 7 years, until October 2022, when, due to advanced age and the high PML risk, with persistent JCV titer between 1.90 and 2.10, along with a total number of 95 infusions, the decision was made to discontinue NTZ. After 5 months, in March 2023, the patient developed gait ataxia. He underwent a new brain and spinal cord MRI which revealed ten new lesions with contrast enhancement (Figure 1). For this reason, a five-day steroid treatment was initiated, resulting in a partial recovery. A further brain and spinal cord MRI performed one month later (April 2023) showed a complete radiological stability.

    

    

    Figure 1: In the left column T1 images with new Gad enhancing lesions (blue arrows) and the corresponding FLAIR images in the center (red arrows); in the right column two more enhancing lesions (yellow arrows).