The possibility of adverse neurologic events has fueled much of the concern about the safety of vaccines. This chapter presents a detailed discussion of the neurologic events considered by the committee. The chapter is organized into two main sections, demyelinating disease and nondemyelinating disease. Specific reports on the association of the vaccines under consideration and the neurologic disorders discussed in this chapter can be found in the subsequent chapters specific to each vaccine or vaccine component.
Acute demyelinating disease of the central and peripheral nervous systems can follow vital and some bacterial infections and can complicate the administration of inactivated antiviral vaccines. The acute monophasic central nervous system disease is variably known as postvaccinal encephalomyelitis, postinfectious encephalomyelitis, or acute disseminated encephalomyelitis (ADEM). The peripheral nervous system complication is known as postinfectious neuritis, acute inflammatory demyelinating polyneuritis, or the Guillain-Barré syndrome (GBS) and is characterized by the rapid onset of flaccid motor weakness with depression of tendon reflexes and inflammatory demyelination of peripheral nerves.
Both of these demyelinating complications were noted after the introduction of rabies vaccines grown in animal brain or spinal cord. Pasteur's
first rabies vaccine of the 1880s was produced from desiccated infected rabbit spinal cord, and occasional cases of acute encephalomyelitis were seen following multiple injections of the vaccine. These were initially thought to result from inadequate attenuation or inactivation of the virus or the activation of some endogenous agent in the human brain. Because early attenuated or inactivated rabies vaccines were prepared in animal nervous system tissue, the question that the causal factor might be some factor within animal tissues was also raised (Hemachudha et al., 1987a,b). On rare occasions, a clinically and histologically similar encephalomyelitis also complicated injection of the vaccinia virus used for the prevention of smallpox, although this vaccine contained no animal neural tissue. ADEM also has been seen after natural infections with measles, varicella, mumps, rubella, and other viruses (Johnson et al., 1985).
Thomas Rivers, the father of American virology, worked extensively with vaccinia virus and was intrigued by the similarity of the demyelinating complication of vaccination and the histopathologic changes seen after administration of rabies vaccines. With Schwenker, he carried out multiple inoculations of normal brain tissue into monkeys, and in 1935, they reported the induction of acute, experimental, allergic (autoimmune) encephalomyelitis (EAE) (Rivers and Schwenker, 1935). Subsequently, Kabat et al. (1947) found that EAE could consistently be induced by a single inoculation of brain tissue if it was mixed with adjuvant. Disease developed in 7 to 21 days in some species, and detailed studies of the pathogenesis of EAE were possible. Although multiple brain antigens have been implicated, myelin basic protein most readily induces the disease, and since EAE can be passively transferred with immune cells but not serum, cell-mediated immunity appears to be of primary pathogenetic importance. In drawing analogies to human diseases, it should be noted that different inbred strains of animals show different susceptibilities, and although myelin basic protein is similar between species, the encephalitogenic region of myelin basic protein differs between different species (Martin et al., 1992).
In Latin America, a rabies vaccine was prepared in unmyelinated neonatal mouse brains to avoid the use of central nervous system myelin. Multiple injections of these preparations into humans, however, were complicated in some cases by an acute polyneuritis similar to GBS (Held and Adaros, 1972). It was assumed that the induction of autoimmunity to a peripheral nerve antigen might be the mechanism. In 1955, Waksman and Adams reported that rabbits injected with peripheral nerve tissue in adjuvant developed an experimental allergic (autoimmune) neuritis (EAN) resembling GBS. The predominant protein related to EAN is a peripheral
neurospecific polypeptide protein of the peripheral nerve, and the disease appeared to depend largely on cell-mediated immunity.
Acute Disseminated Encephalomyelitis
ADEM is characterized by acute depression of consciousness and multifocal neurologic findings that usually occur a few days or weeks following vaccine administration or virus-like disease. It is characterized pathologically by diffuse foci of perivenular inflammation and demyelination that are most prominent in the white matter of the brain and spinal cord. A definitive diagnosis of ADEM can be made only pathologically. However, recent imaging studies with enhanced magnetic resonance imagers have defined a characteristic pattern of multiple enhancing white matter lesions in patients with ADEM, and in the future, magnetic resonance imaging findings may give better data on nonfatal, nonbiopsied cases of suspected postimmunization ADEM.
The establishment of a relation between acute central and peripheral nervous system demyelinating disease and infections and vaccines has opened the question of a possible relation to chronic demyelinating disease, specifically, multiple sclerosis. When mean levels of antibody to measles virus are assayed in the serum and spinal fluid of patients with multiple sclerosis, they are consistently higher than those in controls, and in some studies elevated levels of antibodies to a variety of different viruses have been found in serum and spinal fluid (Johnson et al., 1985). The persistence of these agents in patients with multiple sclerosis has not been established. In the diagnosis of multiple sclerosis, demyelinating lesions not only must occur in multiple locations within the nervous system but must also occur at different times. A prospective study of patients with multiple sclerosis showed that exacerbations appeared to be more frequent after nonspecific viral illnesses (Sibley et al., 1985). Therefore, it would be feasible that vaccines also might precipitate an exacerbation either in a patient who was predisposed to develop the disease or in a patient with already established disease. However, there is no clear-cut causal relation between any virus or vaccine and multiple sclerosis.
Both optic neuritis and transverse myelitis often are components of diffuse demyelinating diseases, both ADEM and multiple sclerosis. When they occur in isolation, their mechanisms and pathologies are usually un-
known, although it is suspected that they represent unifocal, acute episodes of demyelination. Transverse myelitis is characterized by the acute onset of signs of spinal cord disease, usually involving the descending motor tracts and the ascending sensory fibers, suggesting a lesion at one level of the spinal cord. By enhanced magnetic resonance imaging, the apparent lesion in the spinal cord extends over many segments of the spinal cord. The annual incidence of transverse myelitis in Rochester, Minnesota, from 1970 to 1980 was 7.4 per 100,000 people (Beghi et al., 1982). The authors noted that this incidence is approximately sixfold higher than a rate calculated for Israel. They attributed this to differences in how successful the two studies were at identifying all cases of transverse myelitis.
Optic neuritis represents a lesion in the optic nerve behind the orbit but anterior to the optic chiasm. This cranial nerve is an extension of the central nervous system, and so when there is demyelinating disease, it represents central demyelination, not peripheral nerve demyelination. When the lesion is central to the orbit, the optic disk appears normal; this clinical form of optic neuritis is called retrobulbar neuritis. When the lesion or inflammation is very near the orbit, swelling of the optic disk can be seen on fundoscopic examination; this clinical form is called papillitis. This clinical distinction does not imply a different pathogenesis or pathology. Retrobulbar neuritis or papillitis in young adults is a very common early symptom of multiple sclerosis. Optic neuritis may occur as a solitary unexplained monophasic disease, and it may accompany the acute monophasic disease ADEM. No population-based incidence rates were identified.
Instances of acute ascending paralysis have been on record since the early nineteenth century, but it was the description by Guillain, Barré, and Strohl in 1916 of two cases (including cerebrospinal fluid findings) that was critical and discriminating enough to delineate a new syndrome. Those authors described acute areflexic weakness without fever, meningismus, or constitutional symptoms in two young infantrymen who both made a complete and rapid recovery. Using the newly introduced diagnostic technique of lumbar puncture, Guillain, Barré, and Strohl showed that the spinal fluid protein level was elevated but without an accompanying pleocytosis. These are the essential elements of GBS. Now, more than 75 years later, a great deal of descriptive and phenomenologic information has been added to the original observations, all of which indicate that this disorder is immune system mediated and targets peripheral nerves. Nevertheless, the critical
questions as to the nature and regulation of this abnormal immune response, the nosologic limits of the disorder, and the identities of the specific antigens that were responsible for the syndrome are still not known.
Clinical and Laboratory Features
Guillain-Barré syndrome has recently been fully reviewed in several publications (Arnason and Soliven, 1992; Asbury and Gibbs, 1990; Hughes, 1990; Ropper, 1992; Ropper et al., 1991). The symptoms of GBS usually appear over the course of a single day and may continue to progress for from as few as 3 or 4 days up to 3 or 4 weeks. The symptoms in over 90 percent of the patients plateau by 4 weeks. The major symptom is weakness. generally symmetrical, usually ascending, and usually affecting the legs more than the arms. In a smaller proportion of patients, the symptoms begin in the arms or cranial nerves and descend. About 30 percent of all patients require respiratory support at some stage of the illness, and weakness of the tongue, swallowing, and facial muscles is common in up to 50 percent of all patients with GBS. Paresthesias and even painfulness are experienced in a majority of the patients, but major sensory deficits are not frequent. Ataxia of stance and gait may be an early sign. Reflexes disappear early and return only late in the recovery phase. Fever and constitutional symptoms are generally not present, although in children a degree of meningismus may be noted in a quarter to a third of the patients. The mortality rate is 5 percent or less. For survivors, recovery is the rule, requiring anywhere from a few weeks to well over a year. Some 15 to 20 percent of survivors manifest some residual findings, and 5 percent or more have serious residual disabilities.
Factors affecting prognosis are age (older people do more poorly), the fulminance and severity of the neuropathy, the severity of the electrodiagnostic findings early in the disease, and early treatment, either plasmapheresis or high-dose intravenous immunoglobulin (Cornblath et al., 1988; McKhann et al., 1988; van der Meché et al., 1992).
Cerebrospinal fluid is normal in the first few days of illness, but the protein content rises toward the end of the first week and remains elevated for several months in over 90 percent of patients. Spinal fluid cell counts are below 10 cells, mostly lymphocytes, per mm3, but in human immunodeficiency virus (HIV)-positive individuals, spinal fluid cell counts may be as high as 100 to 200/mm3.
The characteristic electrodiagnostic features are those of demyelination with variable degrees of admixed, presumably secondary, axonal degeneration. These abnormalities include prolongation of distal latencies and F-wave latencies, particularly as early features; slowing of nerve conduction velocity, frequently in a multifocal pattern; conduction block; and
chronodispersion of evoked compound action potentials. In some cases axonal degeneration predominates, as determined by electrodiagnostic criteria and, when studied, by pathologic observation (Feasby et al., 1986, 1993). Whether axonal degeneration may be a primary event in GBS is controversial. At worst, nerve trunks may be completely inexcitable. Widespread axonal degeneration is associated with prolonged and incomplete recovery.
In 1978, diagnostic criteria for GBS were promulgated in response to a request from the National Institutes of Health (Asbury et al., 1978). These criteria continue to be in general use and are reproduced in the box entitled Definition of Guillain-Barré Syndrome and Criteria for Diagnosis; recently proposed electrodiagnostic criteria are given in the box entitled Proposed Electrodiagnostic Criteria for Demyelination of Peripheral Nerve (Asbury and Cornblath, 1990). The features required for diagnosis include progressive motor weakness and areflexia. The features that are strongly supportive of the diagnosis include progression for less than 4 weeks, relative symmetry, mild sensory symptoms or signs, frequent cranial nerve involvement, a high proportion of functional recovery, some autonomic dysfunction, and the absence of fever at the onset of neuropathy. Electrodiagnostic and spinal fluid findings are also included in the criteria. In addition, a number of features that either cast doubt on the diagnosis or rule it out are elaborated. Efforts to refine and detail these criteria, including electrodiagnostic criteria (Asbury and Cornblath, 1990), have continued (Arnason and Soliven, 1992; Asbury, 1981).
Over half of all patients with GBS have a history of a preceding acute infectious illness, either respiratory or gastrointestinal, in the 1 to 4 weeks prior to the onset of neuropathic symptoms. Although the basis for the preceding illness remains unidentified in many patients, several infectious agents are strongly associated with GBS. Nonviral infectious agents include Campylobacter jejuni, which is perhaps the most common, and Mycoplasma pneumoniae. Certain viral infections are also strongly associated with GBS, including cytomegalovirus and Epstein-Barr virus, vaccinia virus used for smallpox vaccination, and HIV. A host of other viral infections, including measles, mumps, and hepatitis B, have been reported as antecedent events, but it is unclear whether their occurrence preceding GBS exceeds that from chance alone. Less commonly, vaccines, surgical procedures, and malignant disorders, particularly Hodgkin's disease and other lymphomas, are either antecedent events or underlying conditions.
Definition of Guillain-Barré Syndrome and Criteria for Diagnosis
Guillain-Barré syndrome is a recognizable entity for which the basis for diagnosis is descriptive on the basis of the present state of knowledge. The features that allow a diagnosis include clinical, laboratory, and electrodiagnostic criteria. The problem is not with the recognition of a typical case but with knowing the boundaries by which the core disorder is delimited. The following criteria are established, in light of current knowledge and opinion, to define those limits.
The presence of preceding events is frequent, but they are not essential to the diagnosis. Most commonly, preceding events are viral infections, but the association of Guillain-Barré syndrome with preceding surgery, inoculations, and Mycoplasma infections is also known. In addition, Guillain-Barré syndrome occurs more frequently than by chance in the setting of preexisting illnesses such as Hodgkin's disease, lymphoma, or lupus erythematosus. Many patients with Guillain-Barré syndrome have no history of any of these events, and the diagnosis should be made independently of them.
Source: Adapted from Asbury et al. (1978).
Vaccinations are an infrequent antecedent event in patients with GBS, probably occurring in less than 1 to 5 percent of all cases. In most large series of GBS, recent vaccination either is not mentioned or is described in an occasional person. Hankey (1987) noted that 5 of 109 subjects had recently been vaccinated (two with diphtheria and tetanus toxoids and pertussis vaccine [DPT] and one each with rubella vaccine, tetanus toxoid, and cholera and typhoid vaccines). Winer and colleagues (1988) noted six recent vaccinees in a series of 100 consecutive cases of GBS, but they also found five recent vaccinees in the 100 case controls.
Vaccinations have also had major public policy implications in relation to GBS. In the swine flu incident of 1976-1977 (Langmuir et al., 1984;
Proposed Electrodiagnostic Criteria for Demyelination of Peripheral Nerve
These criteria concern nerve conduction studies (including proximal nerve segments) in which the predominant process is demyelination. Must have three of the following features:
Source: Adapted from Asbury and Cornblath (1990).
Safranek et al., 1991; Schonberger et al., 1979), the risk of developing GBS in the 6 weeks following vaccination was some six- to eightfold greater than that for those who were not vaccinated, even though the overall incidence was only about 1 per 100,000 vaccinees. What it was about the swine flu vaccine that led to GBS on rare occasions has never been discovered; nevertheless, the capacity of that particular vaccine to trigger excess cases of GBS is thoroughly documented. In addition, the clinical features of GBS following swine flu vaccination resembled in all respects those
Demyelinating Disorders Encountered with Rabies Vaccines
Incidence of Neuroparalytic Events
Distribution Pattern of Neuroparalytic Events
Type of Event
Mature brain and spinal cord (Semple vaccine)
Suckling mouse brain
Human diploid cell vaccine
following other antecedent events or no antecedent events. Monitoring for GBS following the administration of other influenza vaccines in the years subsequent to the 1976-1977 swine flu vaccine incident did not disclose any excess cases of GBS (Hurwitz et al., 1981; Kaplan et al., 1983; Roscelli et al., 1991).
It has been known for decades that GBS occurs following the administration of another vaccine, namely, rabies vaccine produced from the nervous tissue of an infected animal (Table 3-1). Because they are inexpensive, these vaccines are still made and used in certain parts of the world, including Asia and South America. Vaccine made from mature sheep or goat brain and then inactivated with phenol (Semple vaccine) causes encephalomyelitis as its main neurologic adverse event, and the reported incidence of such events is from I per 300 to I per 3,000 vaccinees (Hemachudha et al., 1987b, 1988). A small proportion, perhaps 15 percent, of Semple vaccinees who develop a neuroparalytic adverse event have characteristic GBS. Of interest, these patients develop high levels of antibody to myelin basic protein, a central myelin constituent in serum and cerebrospinal fluid (Hemachudha et al., 1987a, 1988). In contrast, rabies vaccine produced from infected suckling mouse brain induces, on occasion (approximately 1 in 7,500 vaccinees), a GBS-like syndrome (Lopez Adaros and Held, 1971). The clinical features tend to be unusually severe (Cabrera et al., 1987). These individuals rarely develop antibody titers to myelin basic protein (Hemachudha et al., 1988), which is consistent with the fact that the suckling mouse brain is unmyelinated. It is not clear what the basis for GBS might be following the administration of either Semple rabies vaccine or suckling mouse brain rabies vaccine, but most authorities believe that the neuroparalytic events that occur following receipt of these two rabies vaccines are related to an immune response to admixed neural constituents in the inoculum.
As discussed elsewhere in this chapter, the expected latency between an antecedent event (when infection or administration of antigen occurs) and the first symptoms of GBS is mainly between 7 and 21 days. Occasional cases appear to have latencies of between 22 and 42 days. All evidence indicates that GBS is immune mediated via a delayed-type hypersensitivity mechanism. Taken together, these two observations allow a range of latencies to be stated for GBS, that is, 5 days to 6 weeks. Similarly, ADEM is widely believed to be the human counterpart of experimental allergic encephalomyelitis, and EAE has an observed latency of about 10 to 20 days. ADEM has a similar clinical latency, and its pathologic features also have all of the hallmarks of a delayed-type hypersensitivity response. On the basis of these observations and inferences, a conservative estimate of the limits of the latencies for both GBS and ADEM is considered to be from 5 days to 6 weeks throughout this report.
Pathology and Pathogenesis
A characteristic pathologic feature of GBS is the presence of mono-nuclear cell infiltrates in peripheral nerves and roots in both a diffuse and a perivenular distribution (Arnason and Soliven, 1992; Asbury et al., 1969). Lesions are patchy and variable, and some patients may show almost no cellular inflammation (Honavar et al., 1991). Lesions are most prominent in the proximal plexuses and roots, particularly the ventral root, but may be found scattered throughout the peripheral nervous system, including the autonomic trunks and intramuscular twigs. Demyelination often corresponds to the distribution of cellular infiltration, but demyelination is quite extensive even in those patients in whom cellular infiltration is minimal. Axonal degeneration occurs, presumably as a secondary event at sites where lesions are intense, but the extent and distribution of axonal degeneration vary widely from patient to patient. The extent of axonal degeneration has a strong effect on the rate and completeness of recovery.
Lymphocytes in the infiltrate are primarily T cells, with CD4-positive cells predominating in early lesions and CD8-positive cells being the most plentiful in mature lesions. Bone marrow-derived macrophages swarm into the lesions and constitute by far the most numerous pathologic cell types in nerves. Myelin destruction appears to be macrophage mediated, either by myelin lamellar stripping by macrophage processes or by vesicular disruption of myelin. The role of lymphocytes in myelin destruction is unclear. The pathologic appearance of GBS is characteristic of a delayed-type hypersensitivity response and closely resembles the lesions of experimental allergic neuritis (Waksman and Adams, 1955). In addition, there is abundant evidence of immune system activation in patients with GBS, including greatly increased levels of circulating soluble interleukin-2 receptor and
cytokines such as tumor necrosis factor and evidence of complement activation both in peripheral blood and in cerebrospinal fluid. The specific epitopes and their origins, whether derived from the host or the infectious agent, or both, remain uncertain. Numerous anti-nerve antibodies that bind to various protein, glycoprotein, and glycolipid moieties have been described in patients with GBS, but none occur in more than a fraction of cases. Whereas the P2 myelin protein, which is specific for peripheral nerve, and selected peptide fragments of it are capable of inducing experimental allergic neuritis under appropriate conditions, the P2 myelin protein does not appear to play a role in GBS.
A large number of studies have examined the incidence of GBS in many parts of the world. These show a relatively uniform occurrence of about 1 to 2 cases per 100,000 population per year in all populations examined, mainly occurring throughout the year and in all age groups. Epidemic outbreaks have been rare and imperfectly documented. The swine flu incident of 1976-1977 is, perhaps, the most completely described outbreak (Langmuir et al., 1984; Safranek et al., 1991; Schonberger et al., 1979). The unusual circumstances of the swine flu incident should be noted. Over 40 million people were vaccinated in a period of a few weeks, an unprecedented mass vaccination program. It is likely that the excess cases of GBS might not have been detected if the numbers of people vaccinated had not been so large. A seasonal incidence of clinical GBS occurs annually in children and young adults in the northern part of the People's Republic of China (McKhann et al., 1991, in press), although the electrodiagnostic and pathologic features in these cases indicate a severe axonal lesion and not the usual demyelinating process with inflammation of the delayed hypersensitivity type.
A persistent problem has been the uncertainty about the expected incidence of GBS unrelated to vaccination in the cohort under 5 years of age. There is reasonably good information to suggest that the overall incidence of GBS for all ages is about 1 case per 1,000,000 population per month. Many authorities have suggested that the incidence of GBS in the pediatric age group (0-16 years of age) is lower than that in adults. For a number of years, the literature has provided data indicating that the incidence of GBS in the cohort under the age of 5 years is higher than that in children older than that (Beghi et al., 1985b; Coe, 1989; Soffer et al., 1978) and one study found a high incidence in preschool children of 5.4 cases per 100,000 per year (Kibel et al., 1983). Other observers have found a lower incidence of GBS in children, with the incidence distributed evenly from infancy to the teenage years (Hurwitz et al., 1981; Rantala et al., 1991; Uhari et al., 1989).
Recently, several population-based studies of the incidence of GBS applied strict criteria for the diagnosis of GBS, and relatively full case ascertainment appears to have been achieved (Hankey, 1987; Roman et al., unpublished observations, 1993; Winner and Evans, 1990). All of these studies indicate an incidence of GBS in the preschool age group of between 1.0 and 1.5 cases per 100,000 children per year, which is similar to the expected incidence in adults. The annual incidence of GBS in children in these studies is on the order of 0.1 cases per 100,000 children between the ages of 5 and 14 years (Winner and Evans, 1990) and 0.62 per 100,000 children and teenagers between the ages of 10 and 19 years (Hankey, 1987).
To obtain an idea of whether excess cases of GBS in relation to childhood vaccination occur each year, the following paradigm might be considered. Approximately 3,000 cases of GBS occur in the United States each year. If the preschool-age cohort makes up about 9 percent of the population, that would account for 270 cases per year if the incidence rate was uniform. As indicated above, the incidence of GBS in preschool children may well approximate the overall expected incidence in adults. Using some other assumptions, one can arrive at an estimate that about 6 percent of preschool-age children are within 5 days to 6 weeks of their most recent vaccination. If this is true, then one would expect about 16 cases of GBS per year in recently vaccinated preschool-age children. It is uncertain how many of these cases of GBS would be by chance alone and would be unrelated to vaccination. Nevertheless, excess cases of GBS occurring 5 days to 6 weeks after vaccination of preschool-age children have not been noted in the population-based studies mentioned above. This issue was also considered above in the section Antecedent Events. The data from the Monitoring System for Adverse Events Following Immunization show fewer cases of GBS per year, but such an analysis does not allow for the systematic underreporting that probably occurred.
Summary of Demyelinating Diseases
In evaluating the vaccines considered in this report for a causal relation with demyelinating disease, several facts need to be considered:
Natural infections with measles and mumps viruses have been associated with ADEM.
ADEM and GBS in humans, similar to EAE or EAN in experimental animals, generally occur after an interval of 5 days to 6 weeks following infection (not clinical disease) or injection of antigen.
ADEM and GBS can occur after the administration of either live attenuated or killed vaccines (in the case of vaccinia virus and the swine influenza vaccines, respectively).
Thus, it is biologically plausible that injection of an inactivated virus, bacterium, or live attenuated virus might induce in the susceptible host an autoimmune response by deregulation of the immune response, by nonspecific activation of the T cells directed against myelin proteins, or by autoimmunity triggered by sequence similarities of proteins in the vaccine to host proteins such as those of myelin. The latter mechanism might evoke a response to a self-antigen, so-called molecular mimicry (Fujinami and Oldstone, 1989).
Historically, encephalopathy has been a vague term that is difficult to define. Encephalopathy has been used in the literature to characterize a constellation of signs and symptoms reflecting a generalized disturbance in brain function (Institute of Medicine, 1991). Encephalopathy has been defined as ''a diffuse interference with brain function resulting from a generalized or multifocal insult that causes a widespread disorder in the function of neurons'' (Dodson, 1978, p. 416). Fenichel (1982) noted that the terms encephalopathy and encephalitis are used interchangeably to denote a variety of symptoms including alterations in behavior or state of consciousness, convulsions, headache, and focal neurologic deficit. In general, when pleocytosis in cerebrospinal fluid is present, the term encephalitis is used, implying an inflammatory response within the brain. The term encephalopathy is used when an illness clinically appears like an encephalitis but no inflammatory response is evident (Cherry et al., 1988). Encephalitis is a type of encephalopathy. That is, every case of encephalitis is also a case of encephalopathy, but not every case of encephalopathy is due to an inflammatory response, and thus is not a case of encephalitis.
There are both clinical and pathologic definitions of encephalopathy. For a patient to be considered to have a case of encephalopathy, the patient must have clinical signs and there must be reason to assume there is an underlying pathologic, structural, or persistent biochemical abnormality. For example, seizures can result from extremes of temperature or metabolic changes with no underlying pathologic, structural, or persistent biochemical change. Recurrent seizures without any known precipitating event, on the other hand, could imply a pathologic change sufficient to use the term encephalopathy. Alternatively, there may be pathologic changes in the brain without clinically detectable signs. For example, an increase in size or number of astrocytes may be detectable pathologically, but be sufficiently mild to have only a subclinical association.
Recently, in proposed changes to the Aids to Interpretation of the Vac-
cine Injury Table, encephalopathy has been strictly defined (U.S. Department of Health and Human Services, 1992). The Vaccine Injury Table defines the vaccines and adverse events that are covered under the National Vaccine Injury Compensation Program. Health care providers must report the occurrence of an adverse event listed in the table if it falls within the specified latencies from vaccination. The box in Chapter 10 includes the current Vaccine Injury Table and Aids to Interpretation. Some proposed changes are reproduced in this chapter in the box entitled Changes Proposed by DHHS in the Definition of Encephalopathy in the Aids to Interpretation of the Vaccine Injury Table.
This definition of acute and chronic encephalopathy is useful because of its precision, and the committee considered this proposed definition as it reviewed the evidence. As is made clear throughout the report, the evidence reviewed by the committee varied greatly in both the quality and quantity of clinical details provided. Very few studies provided enough detail to ascertain whether the cases of encephalopathy reported meet the criteria proposed in the Vaccine Injury Table. The committee read and considered all reports of encephalopathy, regardless of the extent of documentation of the adverse event. Although a 24-hour period for the duration of stupor or coma associated with encephalopathy is a widely accepted and reasonable standard based on a unit of time (a day), the committee felt that it is not an absolute. However, this distinction regarding the time period did not affect the final conclusions regarding encephalopathy.
The occurrence of encephalopathy in a child does not imply a particular severity or duration of illness, nor does it indicate that a child will have irreversible brain injury. Many children do recover from serious neurologic illnesses and therefore may not have permanent neurologic sequelae (Institute of Medicine, 1991). The annual incidence of encephalitis in Olmsted County. Minnesota, from 1950 to 1981 was 7.4 per 100,000 people (Beghi et al., 1984). The incidence in children less than age 1 year was 22.5, in children between age 1 and 4 years it was 15.2, and in children between ages 5 and 9 years it was 30.2 per 100,000. There was a case fatality rate of 3.8 percent.
Aseptic meningitis refers to inflammation of the meninges, not of the brain. It can result from a variety of infectious, toxic, chemical, or physical agents. No bacterial organism can be identified in or isolated from the cerebrospinal fluid, but serologic studies often implicate a viral etiology. Mumps virus and polioviruses can cause aseptic meningitis. The annual incidence of aseptic meningitis in Olmsted County, Minnesota, from 1950 to 1981 was 10.9 per 100,000 population (Nicolosi et al., 1986). The incidence was markedly higher in children under age 1 year (82.4 per 100,000) and slightly higher in children between 1 and 4 years old (16.2 per 100,000). No deaths occurred in any of the 183 individuals with aseptic meningitis.
Changes Proposed by DHHS in the Definition of Encephalopathy in the Aids to Interpretation of the Vaccine Injury Table
Source: Adapted from U.S. Department of Health and Human Services (1992).
Subacute Sclerosing Panencephalitis
Clinical and Laboratory Features
Subacute sclerosing panencephalitis (SSPE) is a rare form of panencephalitis primarily affecting children and adolescents. It is characterized by the insidious onset of a progressive cerebral dysfunction developing over the course of weeks or months. Initially, there usually is an alteration in personality and a deterioration in school performance. Myoclonic jerks follow some 2 months later. These jerks are involuntary, but the affected patient remains conscious and is frequently thought to be stumbling or simply clumsy. The jerks tend to disappear during sleep. As the disease progresses, so does the myoclonus, often reaching a frequency of 1 every 10 seconds. Ultimately, extrapyramidal dyskinesias such as athetosis, chorea, ballismus, and dystonic posturing develop. The patient becomes extremely spastic and has difficulty swallowing. There is a progressive loss of vision resulting from focal chorioretinitis, cortical blindness, or optic atrophy. In the terminal stages of SSPE, the patient becomes unresponsive and vegetates in a decorticate state, compounded by hypothalamic dysfunction with vasomotor instability, hypothermia, and alterations in blood pressure and pulse rate. An encephalographic pattern of paroxysmal bursts of two- to three-cycle-per-second high-voltage slow waves with associated spike discharges and then a short period of flattened activity—the so-called burst-suppression pattern—is characteristic. The myoclonic jerks tend to coincide with the paroxysmal electroencephalographic bursts. The entire course of SSPE is quite variable, lasting from weeks to years with periods of remission. The average patient dies within 2 years of the onset of this disease, but in rare cases, patients have remained in the vegetative state for 10 or more years.
The diagnosis is suggested by the clinical presentation and is strengthened by the detection of high titers of serum antibodies against measles virus and the presence of oligoclonal measles virus antibodies in the cerebrospinal fluid. The ultimate confirmation is based on the classical appearance of Cowdry type A inclusion bodies as well as the detection of measles antigen in the brain tissue obtained by biopsy or at autopsy.
Pathology and Pathogenesis
The neuropathology of SSPE—involving both the grey and the white matter—is that of a subacute encephalitis accompanied by demyelination. There are lesions in the cerebral cortex, hippocampus, cerebellar cortex, basal ganglia, brainstem, and spinal cord. Eosinophilic intranuclear and intracytoplasmic inclusion bodies are seen in the neurons and glia. Immunocytochemical studies show the presence of measles virus antigen.
SSPE is a result of an aberrant measles virus infection. The nature of the aberration is not well understood, but viruses isolated from the brains and lymphoid tissues of these patients are not typical measles viruses. They show various degrees of defectiveness, which in some cases require complex techniques of "rescue" before they would replicate in tissue culture. The central question that remains is whether the original measles virus infection involved a defective measles virus or whether the virus became altered during the prolonged period of latency in the host. If the former is the case, this would suggest a wholly exogenous etiology of SSPE. If the latter is the case, then one would have to consider the possibility of an a priori abnormality in the host.
Although SSPE has had several original descriptions, Dawson is usually credited with the identification of this disease when he described the inclusion bodies in the neurons in 1933 (Dawson, 1933, 1934). Van Bogaert identified the lesions in the white matter in 1945 (Van Bogaert, 1945). Bouteille and coworkers (1965) identified the ultrastructural pattern resembling the nucleocapsids of a paramyxovirus, which led Connolly and co-workers to the immunological identification of measles virus within the lesions (Connolly et al., 1967). Tissue cultures derived from the brains of patients with SSPE were shown to contain similar inclusions bearing measles virus antigen (Baublis and Payne, 1968). They also contained structures resembling paramyxovirus nucleocapsids (Katz et al., 1969). Measles virus was finally cultured from a patient's brain tissue by cocultivation of the brain cells with indicator cells (Horta-Barbosa et al., 1969; Payne et al., 1969) and by a deliberate fusion with indicator cells (Barbanti-Brodano et al., 1970). Later, Horta-Barbosa et al. (1971) also isolated the virus from lymph node biopsy specimens from patients in the early stages of the disease.
SSPE usually affects children younger than 12 years of age, but cases of SSPE in young adults in their 20s have been reported. Boys are more frequently affected than girls. The incidence of SSPE has decreased dramatically since the beginning of immunization with the live attenuated measles virus vaccine (Modlin et al., 1977). Estimates of the incidence of SSPE after natural measles infection range from 5 to 20 cases per 1 million children with clinical measles infection per year (Halsey et al., 1978).
Residual Seizure Disorder
Seizures are paroxysmal neurologic events that can occur with or without a loss of consciousness and can include a variety of sensory experiences (e.g., auditory seizures), motor manifestations (e.g., focal motor or tonic-
clonic seizures), or both. The terms fits and convulsions are frequently used synonyms for motor seizures. In addition, seizures can occur with or without fever. Febrile seizures are well-defined, relatively common events that are precipitated by fever in children under 5 years of age who do not harbor an underlying seizure disorder. If more than one seizure occurs within 24 hours or if the seizures last longer than 10 minutes or are accompanied by transient focal neurologic features, they are termed complex febrile seizures. Acute symptomatic seizures are those that occur in association with an acute process that affects the brain, such as head trauma or a bacterial infection. Afebrile seizures are those that occur in the absence of fever or other acute provocation. Recurrent afebrile seizures are referred to as epilepsy. Infantile spasms are a type of epileptic disorder in young children and are characterized by flexor, extensor, and mixed flexor-extensor seizures that tend to occur in clusters (Kellaway et al., 1979). The earliest manifestations of infantile spasms are subtle and are easily missed, making it difficult to identify the precise age at onset.
Recently, the National Vaccine Injury Compensation Program proposed clarification of its definition of residual seizure disorder as a seizure occurring within 72 hours of vaccination followed by two or more afebrile seizures over the next 12 months, with the seizures separated by at least 24 hours (U.S. Department of Health and Human Services, 1992). Continuing seizures in subsequent years would be anticipated. The clarifications define an afebrile seizure as one that occurs with a temperature of <101°F (rectally) or <100°F (orally). This definition is considered in the remainder of this report. When a definition for a seizure in a specific study being evaluated varies from those stated above, the definition used in the study is given.
Sensorineural deafness is a form of hearing loss resulting from pathologic changes in the end organ structures within the cochlea or in the neural connections between the cochlea and the cochlear nuclei in the brainstem. This usually arises from toxic, metabolic, or ischemic events. Viral infection of the cochlea can lead to sensorineural deafness as well. It is plausible that the live attenuated viruses used in vaccines can infect the cochlea, but there is no evidence that this occurs. No population-based incidence rates were identified.
The term neuropathy as used here designates those disorders of peripheral nerve other than GBS that have, on occasion, been described in relation
to vaccine administration. Most reports fall into two clinical categories, mononeuropathy and brachial neuritis. Diagnosis in both instances rests upon the clinical and electrodiagnostic features.
Mononeuropathy means a dysfunction limited to the distribution of a single peripheral nerve that is large enough to be named. The deficit may be motor, sensory, or both and may be either partial or complete. When mononeuropathy occurs in association with vaccination, the onset is usually acute or subacute. In some instances, mononeuropathy is clearly related to intraneural injection of vaccine, as with radial nerve palsy with wrist drop following a misdirected deltoid injection (Ling and Loong, 1976). Inadvertent intraneural administration of any injectable is likely to produce a mononeuropathy and is usually painful in nature (Combes and Clark, 1960; Scheinberg and Allensworth, 1957; Sunderland, 1968).
In other cases, the affected nerve trunk lies at a distance from the injection site. The basis for this type of mononeuropathy is unclear. Patients with mononeuropathies tend to recover, but usually after many weeks or months. Latencies of greater than 4 weeks between vaccination and the onset of mononeuropathy render an association between mononeuropathy and vaccine administration highly unlikely.
Brachial neuritis, also known as brachial plexus neuropathy or, in the United Kingdom, as neuralgic amyotrophy, has been linked to vaccination or administration of antiserum since brachial neuritis was first described a half century ago. Clinically, most cases of brachial neuritis are heralded by a deep, steady, often severe aching pain in the shoulder and upper arm. Patients usually wish to lie still with the arm in the position of least pain. As the pain subsides in days or weeks, weakness and marked atrophy of selected arm and shoulder muscles are noted, usually unilaterally. Particularly commonly affected muscles (and nerves) are the serratus anterior with scapular winging (long thoracic nerve), the deltoid muscle (axillary nerve), and the infraspinatus muscle (suprascapular nerve). A patch or patches of sensory involvement are present in half or more of the patients. In as many as one-third of the patients, the distribution of muscle weakness and atrophy is bilateral (Tsairis et al., 1972). By clinical and electrodiagnostic criteria, lesions are focal or multifocal and localize in the brachial plexus and sometimes in the more distal nerve trunks. The character of the lesion is axonal without conduction block. Recovery, which occurs mainly as a result of regeneration and collateral reinnervation, is slow and often requires from 12
to 30 months. About 15 percent of all cases of brachial neuritis occur following vaccination or antiserum administration (Tsairis et al., 1972). Brachial neuritis may be present on the same side as or the opposite side of the injection. The latency ranges from a few days to 3 or at most 4 weeks. Little is known of the basis or mechanism of brachial neuritis. The annual incidence of brachial neuritis in Rochester, Minnesota, from 1970 to 1981 was estimated to be 1.64 per 100,000 individuals (Beghi et al., 1985a).
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