A history of viral infections of the central nervous system

foundations, milestones, and patterns

John Booss1,*; Alex C. Tselis2    1 Departments of Neurology and Laboratory Medicine, Yale University School of Medicine, New Haven, CT and Department of Veterans Affairs Medical Center, VA Connecticut, West Haven, CT, USA
2 Department of Neurology, School of Medicine, Wayne State University, Detroit, MI, USA
* Correspondence to: John Booss, Professor Emeritus, Yale University School of Medicine, Neurology Service, VA Connecticut, West Haven, CT 06516, USA. email address: john.booss@yale.edu

Introduction

There is an innate fascination, and horror, on considering infection of the brain by a virus. The brain is the most complex biologic organization known, yet it can be devastated by a small spool of nucleic acid wrapped by a protein, with perhaps an additional coat of lipid. From both perspectives, submicroscopic size and markedly limited genomic coding capacity, viruses are the David in the confrontation with Goliath. Yet viruses can wreak havoc on the brain, the spinal cord, and the peripheral nervous system (PNS), often leaving death or disability in their wake. In this historic review we will discuss the evolution of germ theory and the definition of viruses as a class of infectious agents as a foundation. The early discoveries, early milestones, in viral infections of the nervous system will set the scene for the chapters on the modern understanding of topics and specific viral agents that follow. Our goal is to provide perspective for the reader, to demonstrate the emergence of patterns (Gaddis, 2002).

“Neurovirology” is a term of relatively recent vintage, no more than decades old. Yet evidence of viral infections of the nervous system is ancient – millennia old. Richard Johnson has recounted a charming anecdote of how the term neurovirology was devised by Elizabeth Hartmann, an administrator at the National Institutes of Health. She inserted it as shorthand on his 1961 Special Fellowship application. When Johnson protested that no such word existed, Hartmann, not illogically, pointed out that since several terms such as neurophysiology and neurochemistry existed, “why not neurovirology?” (Johnson, 1995). In contrast to the relatively recent minting of the term, evidence of the effects of viral infection of the nervous system, specifically polio, is found on an Egyptian funerary stela from at least three millennia ago. It depicts a typically withered leg of an Egyptian, Roma. He lived during the 18th or 19th dynasties, i.e., some time from the 16th to the 12th centuries BCE (Nunn, 1996). But perhaps the oldest known viral disease of the nervous system is rabies. Laws concerning rabid dogs are included in the Mesopotamian “Laws of Eschnunna,” before 1800 BCE. Rabies is likely the oldest disease identified as communicable (Kaplan and Meslin, 1996).

How should one begin? Given the three to four millennia between the first recognition of neurologic diseases shown ultimately to be of viral origin to the naming of neurovirology as a field of explicit study, how does one tell the story of viral infections of the nervous system? Complicating the telling, there is considerable chronologic overlap of the discoveries of the agents of virologic illnesses of the nervous system (D. Harter, personal communication, 2011). For example lymphocytic choriomeningitis virus (LCM), so named for its tropism for the meninges and causing viral meningitis, was first isolated during the investigation of St. Louis encephalitis (Armstrong and Lillie, 1934). In another example, herpes simplex virus (HSV), the most important cause of treatable sporadic encephalitis, was at one time offered as a cause of epidemic encephalitis lethargica (Zinsser, 1928; Levaditi, 1929). It was over a decade later that HSV was isolated and shown pathologically to be the cause of sporadic encephalitis in an infant (Smith et al., 1941). Thus one confronts the dilemma of how to relate a history, part of which can be given chronologically, and much of which is best understood when discussed by topic. Perhaps a hybrid approach is necessary.

Science builds on “the cumulative discoveries of the past” (Sinsheimer, 1988). Hence it is crucial to give the conceptual and experimental foundations on which the science of the virology of the nervous system rests. It begins with the rational understanding of medicine embodied in the Hippocratic tradition. The crucial development of germ theory rests on that base of rational medicine, and in turn provides the basis from which the demonstration of the nature of viruses can depart. Tobacco mosaic virus, foot and mouth disease (FMD), and yellow fever were the first diseases of plants, animals, and humans respectively to be shown to be of viral origin.

Two viral diseases of the nervous system, rabies and polio, were among the first human diseases to be shown to be viral in nature and serve to open up the history of the virology of the central nervous system (CNS). Because of the chronologic overlap of discovery among categories of viral diseases of the nervous system, it seemed best to tell that part of the story by topic. We will discuss the viral studies in various topics, such as epidemic and sporadic encephalitis, aseptic meningitis, myelitis and the slow viral diseases of the CNS, as separate entities, each with its own chronology and pattern of understanding. Within each category we will attempt to identify those investigations which have served to define the field, the milestones. We begin our discussion of the foundations with the antecedents of germ theory, starting with the tradition of Hippocrates, and the irrational beliefs that the Hippocratic school replaced.

Foundations

Hippocratic medicine and Galen

The first foundation is the establishment of medicine on rational thought and observation, replacing beliefs in supernatural forces. When adverse to human well-being, C-E. A. Winslow (1944) termed the several causes the demonic theory of disease. These included witches, spirits of the disembodied dead, and supernatural beings (Fig. 1.1). Another manifestation of supernatural beliefs was that disease reflected the response of a wrathful god. Finally, according to Winslow, disease could be the result of occult forces, a metaphysical belief in forces which lay “beyond the framework of the known physical universe.” These were beliefs which were overcome by the Hippocratic school of medicine based at the Greek isle of Cos.