from Infections in Medicine ^®

Douglas R. Jeffery, MD, PhD

Abstract

The administration of vaccines to patients suffering from multiple sclerosis (MS) has long been controversial because of the immune-mediated nature of myelin destruction in MS. Numerous case reports have suggested that both onset and worsening of MS may occur following vaccination against a variety of illnesses. Postulated mechanisms include molecular mimicry and a nonspecific adjuvant-like effect of vaccines on cellular immunity. Double-blind prospective studies, however, have shown that influenza vaccination is safe in MS patients. Hepatitis B vaccine has also become controversial but there are no well-controlled prospective studies demonstrating its safety or lack thereof.

Introduction

Multiple sclerosis (MS) is a neurologic disorder in which CNS myelin is destroyed by immune-mediated mechanisms. There are approximately 350,000 patients with MS in the United States. Among young adults, this disease now constitutes a leading cause of disability.^[1] There are 2 main theories of pathogenesis. One holds that MS is truly autoimmune and normal myelin antigens are the target of a T-cell-mediated attack possibly initiated by molecular mimicry and perpetuated by an aberrant immune response. The other holds that MS represents a chronic viral infection of the CNS in which the immune system targets abnormal myelin antigens.

Whatever the cause, inflammation and demyelination in MS are immune-mediated events in which T cells are thought to play a primary role. It is hypothesized that antigen-presenting cells in the periphery interact with T cells, resulting in the activation of T cells and the subsequent initiation of a T_H1 cytokine response. This results in the trafficking of T cells and macrophages across the blood-brain barrier, leading to the destruction of myelin and axons by activated macrophages, T cells, B cells, and toxic effects of cytokines on oligodendrocytes.

The pathologic hallmark of MS is perivascular lymphocytic infiltration in which both macrophages and T cells are found within active lesions.^[2,3] In addition to demyelination, axonal transection may occur during the course of the inflammatory response, suggesting that irreversible damage may be an early event in the course of the disease.^[4]

Disease activity in patients with MS varies over time and is widely variable between individuals. One event capable of activating the inflammatory response in MS is a viral upper respiratory tract infection (URTI).^[5,6] Exacerbations or attacks in MS are defined as the appearance of new neurologic symptoms or the significant worsening of existing neurologic symptoms accompanied by objective deficits and occurring in the absence of systemic illness. The physiologic underpinning of the appearance of new neurologic symptoms in MS is inflammation within regions of the nervous system that mediate important motor or sensory functions. In patients with relapsing-remitting MS, exacerbations vary in frequency, occurring at an average of about 1 or 2 per year. The most frequent event preceding a relapse is a viral infection.^[6,7] In one study, 27% of viral infections were followed by MS relapses and fully 8% of all relapses were associated with viral infection. The most common forms of infection were viral URTI and gastroenteritis.

The mechanism responsible for immune activation following infection might involve a nonspecific effect of increased cell-mediated immunity, molecular mimicry, or the release of proinflammatory cytokines. Interferon-gamma (IFN-gamma) and tumor necrosis factor a are released following viral infections, and their levels are elevated before attacks and in clinical disease progression.^[8] In addition, the administration of IFN-gamma increases relapse rates in patients with MS.^[9] Since vaccines act by simulating viral or bacterial infection, they could stimulate a cytokine cascade, resulting in increased immune-mediated inflammatory demyelination. Alternatively, some vaccines could contain antigens sufficiently similar to myelin antigens to induce an immune response directed against myelin.

Despite numerous case reports of neurologic deterioration following vaccination in patients with MS, the majority of controlled trials have not shown an increase in disease activity following vaccination against a wide variety of infectious illnesses.^[9-14] Nevertheless, it is clear that vaccination may appear to be temporally related to relapse onset and probably trigger relapse in rare instances. As a result, the most important consideration in deciding whether to administer vaccines to patients with MS is to weigh the consequences of the disease being vaccinated against versus the risk that vaccination may result in increased MS disease activity.