Central Nervous System Infections With Immunomodulatory Therapies

Serious central nervous system infections may occur in the setting of immunomodulatory drug use. It is important for neurologists to be aware of the incidence, diagnosis, management, and treatment of these infections.

Infectious disease has long been recognized as a complication of broad immunosuppression. However, the frequency with which infectious disease is observed appears to be lower and the spectrum of infectious complications narrower with immunomodulatory drugs, a class of agents having a more restricted effect on the immune system. An increasingly broad spectrum of immunomodulating agents has been used in the treatment of neurologic disorders, particularly in the management of multiple sclerosis. The recognition of progressive multifocal leukoencephalopathy (PML) in association with the use of natalizumab, an α4β1 integrin inhibitor used in the treatment of multiple sclerosis, heralded concerns about infections associated with the use of immunomodulatory therapy. While the observation of PML with natalizumab remains the most striking example to date, other immunomodulatory treatments may also be associated with an increased risk of PML. Furthermore, other infectious diseases, including herpes simplex virus, varicella-zoster virus, and tuberculosis, are also associated with the use of immunomodulatory agents. The use of screening tests, careful monitoring, and immunization and the initiation of prophylactic treatment to address potential infectious complications associated with use of immunomodulatory therapies is evolving; at the same time, the armamentarium of neuroimmunodulatory therapies continues to expand.

A comprehensive understanding of natalizumab-associated PML is illustrative of the potential pathogenic effects of immunomodulatory agents that lead to infectious complications, as well as the recognition and potential treatment strategies of these complications. The current knowledge of immunotherapy-associated PML incidence, clinical and radiographic features, and management are discussed in detail in this article. Increased risk of herpetic and other infectious complications has also been encountered with immunomodulation. Strategies in relation to minimizing risk and decreasing chances of encountering infectious complications associated with the use of such therapies, including those related to PML, tuberculosis, herpes simplex virus, and varicella-zoster virus, are highlighted.