3
Neurologic Disorders

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.

DEMYELINATING DISEASE

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



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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 3 Neurologic Disorders 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. DEMYELINATING DISEASE 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

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 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). Experimental Models 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

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 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. Multiple Sclerosis 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. Focal Lesions 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-

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 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. Guillain-Barré Syndrome Historical Background 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

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 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

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 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. Diagnostic Criteria 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). Antecedent Events 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.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 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. Features Required for Diagnosis Progressive motor weakness of more than one limb. The degree ranges from minimal weakness of the legs, with or without mild ataxia, to total paralysis of the muscles of all four extremities and of the trunk, bulbar and facial paralysis, and external ophthalmoplegia. Areflexia (loss of tendon jerks). Universal areflexia is the rule, although distal areflexia with definite hyporeflexia of the biceps and knee jerks suffices if other features are consistent. Features Strongly Supportive of the Diagnosis Clinical features (ranked in order of importance) Progression. Symptoms and signs of motor weakness develop rapidly but cease to progress by 4 weeks into the illness. Approximately 50 percent of patients will reach the nadir by 2 weeks, 80 percent by 3 weeks, and more than 90 percent by 4 weeks. Relative symmetry. Symmetry is seldom absolute, but usually, if one limb is affected, the opposite limb is affected as well. Mild sensory symptoms or signs. Cranial nerve involvement. Facial weakness occurs in approximately 50 percent of patients and is frequently bilateral. Other cranial nerves may be involved, particularly those innervating the tongue and muscles of deglutition and sometimes the extraocular motor nerves. On occasion (less than 5 percent), the neuropathy may begin in the nerves to the extraocular muscles or other cranial nerves. Recovery. Recovery usually begins 2 to 4 weeks after progression Source: Adapted from Asbury et al. (1978).

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality stops. Recovery may be delayed for months. Most patients recover functionally. Autonomic dysfunction. Tachycardia and other arrhythmias, postural hypotension, hypertension, and vasomotor symptoms, when present, support the diagnosis. These findings may fluctuate. Care must be exercised to exclude other bases for these symptoms, such as pulmonary embolism. Absence of fever at the onset of neuritic symptoms. Variant clinical features (not ranked in order of importance) Fever at the time of onset of neuritic symptoms. Severe sensory loss with pain. Progression beyond 4 weeks. Occasionally, a patient's disease will continue to progress for many weeks longer than 4 weeks or the patient will have a minor relapse. Cessation of progression without recovery or with major permanent residual deficit remaining. Sphincter function. Usually, the sphincter is not affected, but transient bladder paralysis may occur during the evolution of symptoms. Central nervous system involvement. Ordinarily, Guillain-Barré syndrome is thought of as a disease of the peripheral nervous system. Evidence of central nervous system involvement is controversial. In occasional patients, such findings as severe ataxia interpretable as cerebellar in origin, dysarthria, extensor plantar responses, and ill-defined sensory levels are demonstrable, and these need not exclude the diagnosis if other features are typical. Cerebrospinal fluid (CSF) features strongly supportive of the diagnosis CSF protein. After the first week of symptoms, CSF protein levels are elevated or have been shown to rise on serial lumbar punctures. CSF cells. Counts of 10 or fewer mononuclear leukocytes/mm3 of CSF. Variant CSF features supportive of diagnosis No increase in the level of CSF protein in the period from 1 to 10 weeks after the onset of symptoms (rare). Counts of 11 to 50 mononuclear leukocytes/mm3 of CSF. Electrodiagnostic features strongly supportive of the diagnosis. Approximately 80 percent of patients will have evidence of nerve conduction slowing or blockage at some point during the illness. Conduction velocity is usually less than 60 percent of normal, but the

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality process is patchy and not all nerves are affected. Distal latencies may be increased to as much as three times normal. Use of F-wave responses often gives a good indication of slowing over proximal portions of the nerve trunks and roots. Up to 20 percent of patients will have normal conduction study results. Results of conduction studies may not become abnormal until several weeks into the illness. Features Casting Doubt on the Diagnosis Marked, persistent asymmetry of weakness. Persistent bladder or bowel dysfunction. Bladder or bowel dysfunction at onset. More than 50 mononuclear leukocytes/mm3 in CSF. Presence of polymorphonuclear leukocytes in CSF. Sharp sensory level. Features That Rule out the Diagnosis A current history of hexacarbon abuse (the volatile solvents n-hexane and methyl n-butyl ketone). This includes huffing of paint lacquer vapors or addictive glue sniffing. Abnormal porphyrin metabolism indicating a diagnosis of acute intermittent porphyria. This would manifest as increased excretion of porphobilinogen and d-aminolevulinic acid in the urine. A history or finding of recent diphtheritic infection, either faucial or wound, with or without myocarditis. Features clinically consistent with lead neuropathy (upper limb weakness with prominent wrist drop; may be asymmetrical) and evidence of lead intoxication. The occurrence of a purely sensory syndrome. A definite diagnosis of a condition such as poliomyelitis, botulism, hysterical paralysis, or toxic neuropathy (e.g., from nitrofurantoin, dapsone, or organophosphorus compounds), which occasionally may be confused with Guillain-Barré syndrome. 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;

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 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: Reduction in conduction velocity in two or more motor nerves. <80 percent of the lower limit of normal (LLN) if the amplitude is >80 percent of LLN. <70 percent of LLN if the amplitude is <80 percent of LLN. Conduction block or abnormal temporal dispersion in one or more motor nerves: either the peroneal nerve between the ankle and below the fibular head, median nerve between the wrist and elbow, or the ulnar nerve between the wrist and below the elbow. Criteria for partial conduction block: >15 percent change in duration between proximal and distal sites and >20 percent drop in the negative-peak area or peak-to-peak amplitude between the proximal and distal sites. Prolonged distal latencies in two or more nerves. >125 percent of the upper limit of normal (ULN) if the amplitude is >80 percent of LLN. >150 percent of ULN if the amplitude is <80 percent of LLN. Absent F-waves or prolonged minimum F-wave latencies (10-15 trials) in two or more motor nerves. >120 percent of ULN if the amplitude is >80 percent of LLN. >150 percent of ULN if the amplitude is <80 percent of LLN. 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

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality TABLE 3-1 Demyelinating Disorders Encountered with Rabies Vaccines Vaccine Components Incidence of Neuroparalytic Events Distribution Pattern of Neuroparalytic Events Type of Event Encephalomyelitis (%) GBS (%) Mature brain and spinal cord (Semple vaccine) 1:300-1:3,000 Uniform 85 15 Suckling mouse brain 1:7.500 Clustered 0 100 Human diploid cell vaccine 0   0 0 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.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 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). NON-DEMYELINATING DISEASE Encephalopathy 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-

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 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.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Changes Proposed by DHHS in the Definition of Encephalopathy in the Aids to Interpretation of the Vaccine Injury Table The term encephalopathy means any acute or chronic significant acquired abnormality of, or injury to, or impairment of function of, the brain. Acute encephalopathy shall be defined as follows: An acute encephalopathy should be sufficiently severe to require health care intervention and hospitalization. For children less than 24 months of age who present without an associated seizure event, an acute encephalopathy shall be defined as a significantly decreased level of consciousness, specifically stupor or coma, lasting for at least 24 hours. Those children less than 24 months of age who present following a seizure shall be viewed as having an acute encephalopathy if their stupor or coma persists beyond 24 hours and cannot be attributed to a postictal state or medication. For children 24 months of age or older, an acute encephalopathy is one that persists for at least 24 hours and that is characterized by at least two of the following: a significant change in mental status that is not medication related; specifically a confusional state or a delirium, or a psychosis; a significantly decreased level of consciousness, which is independent of a seizure and cannot be attributed to the effects of medication; or a seizure associated with loss of consciousness. Increased intracranial pressure may be a clinical features of acute encephalopathy in any age group. The following clinical features alone, or in combination, do not qualify as evidence of an acute encephalopathy or a significant change in either mental status or level of consciousness as de scribed above: Sleepiness, irritability (fussiness), high-pitched and unusual screaming, persistent inconsolable crying, and bulging fontanelle. Seizures in themselves are not sufficient to constitute a diagnosis of encephalopathy. In the absence of other evidence of an acute encephalopathy, seizures shall not be viewed as the first symptom or manifestation of the onset of an encephalopathy. Chronic encephalopathy is defined as persistence of the acute findings over an extended period, usually several months to years beyond the acute episode. Individuals who return to a normal neurologic state after the acute encephalopathy shall not be presumed to have suffered residual neurologic damage from the vaccine; any subsequent chronic encephalopathy shall not be presumed to be a sequela of the acute encephalopathy. Children with evidence of a chronic encephalopathy secondary to genetic, prenatal, or perinatal factors shall not be considered to have a condition set forth in the Vaccine Injury Table. Source: Adapted from U.S. Department of Health and Human Services (1992).

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 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.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 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. Descriptive Epidemiology 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-

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 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 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. Neuropathy The term neuropathy as used here designates those disorders of peripheral nerve other than GBS that have, on occasion, been described in relation

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 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 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 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

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 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). REFERENCES Arnason BG, Soliven B. Acute inflammatory demyelinating polyradiculoneuropathy. In: Dyck PJ, et al., eds. Peripheral Neuropathy, 3rd edition. Philadelphia: W.B. Saunders; 1992. Asbury AK. Diagnostic considerations in Guillain-Barré syndrome. Annals of Neurology 1981;9(Suppl.):1-5. Asbury AK, Cornblath DR. Assessment of current diagnostic criteria for Guillain-Barré syndrome. Annals of Neurology 1990;27(Suppl.):S21-S24. Asbury AK, Gibbs CJ Jr, eds. Autoimmune neuropathies: Guillain-Barré syndrome. Annals of Neurology 1990;27(Suppl.):S1-S79. Asbury AK, Arnason BG, Adams RD. The inflammatory lesion in idiopathic polyneuritis. Medicine 1969;48:173-215. Asbury AK, Arnason BG, Karp HR, McFarlin DE. Criteria for diagnosis of Guillain-Barré syndrome. Annals of Neurology 1978;3:565-566. Barbanti-Brodano G, Oyanagi S, Katz M. Koprowski H. Presence of two different viral agents in brain cells of patients with subacute sclerosing panencephalitis (SSPE). Proceedings of the Society for Experimental Biology and Medicine 1970;134:230-236. Baublis JV, Payne RE. Measles antigen and syncytium formation in brain cell cultures from subacute sclerosing panencephalitis (SSPE). Proceedings of the Society for Experimental Biology and Medicine 1968;19:543-597. Beghi E, Kurland LT, Mulder DW. Incidence of acute transverse myelitis in Rochester, Minnesota, 1970-1980, and implications with respect to influenza vaccine. Neuroepidemiology 1982;1:176-188. Beghi E, Nicolosi A, Kurland LT, Mulder DW, Hauser WA, Shuster L. Encephalitis and aseptic meningitis, Olmsted County, Minnesota, 1950-1981. I. Epidemiology. Annals of Neurology 1984; 16:283-294. Beghi E, Kurland LT, Mulder DW, Nicolosi A. Brachial plexus neuropathy in the population of Rochester, Minnesota, 1970-1981. Annals of Neurology 1985a;18:320-323. Beghi E, Kurland LT, Mulder DW, Wiederholt WC. Guillain-Barré syndrome: clinicoepidemiologic features and effect of influenza vaccine. Archives of Neurology 1985b;42:1053-1057. Bouteille M, Fontaine C, Vedredd CL, Delarue J. Sur un cas d'encephalite subaigue a inclusions: etude anatomo-clinique et ultrastructurate. Revue Neurologique 1965:113:454-458. Bussens P, Pilette J. Complications meconnues de la vaccination antipoliomyelitique par voie orale. [Unrecognized complications of oral antipoliomyelitis vaccination.] Revue Medicale de Liege 1976;31:608-611. Cabrera J, Griffin DE, Johnson RT. Unusual features of the Guillain-Barré syndrome after rabies vaccine prepared in suckling mouse brain. Journal of Neurological Science 1987;81:239-245. Cherry JD. Brunell PA, Golden GS, Karzon DT. Report of the task force on pertussis and pertussis immunization—1988. Pediatrics 1988;81 (6, Pt 2):939-984.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Clark C, Hashim G, Rosenberg R. Transverse myelitis following rubeola vaccination. Neurology 1977;27:360. Coe CJ. Guillain-Barré syndrome in Korean children. Yonsei Medical Journal 1989;30:81-87. Combes MA, Clark WK. Sciatic nerve injury following intragluteal injection: pathogenesis and prevention. American Journal of Diseases in Children 1960;100:579. Connolly JH, Allen IV, Hurwitz LJ, Miller JH. Measles-virus antibody and antigen in subacute sclerosing panencephalitis. Lancet 1967;1:542-544. Connolly JH, Allen IV, Hurwitz LJ, Millar JH. Subacute sclerosing panencephalitis: clinical. pathological, epidemiological, and virological findings in three patients. Quebec Journal of Medicine 1968;37:625-644. Cornblath DR, Mellits ED, Griffin JW, and the GBS Study Group. Motor conduction studies in the Guillain-Barré syndrome: description and prognostic value. Annals of Neurology 1988;23:354-359. Dawson JR. Cellular inclusions in cerebral lesions of lethargic encephalitis. American Journal of Pathology 1933;9:7-15. Dawson JR. Cellular inclusions in cerebral lesions of epidemic encephalitis (second report). Archives of Neurology and Psychiatry 1934;31:685-700. Dodson WE. Metabolic encephalopathies in neurological pathophysiology. In: Eliasson SG, Prensky AL, Hardin WB Jr, eds. Neurological Pathophysiology. New York: Oxford; 1978. Feasby TE, Gilbert JJ, Brown WF, Bolton CF, Hahn AF, Koopman WF, et al. An acute axonal form of Guillain-Barré polyneuropathy. Brain 1986;109:1115-1126. Feasby TE, Hahan AF, Brown WF, Bolton CF, Gilbert JJ, Koopman WJ. Severe axonal degeneration in acute Guillain-Barré syndrome: evidence of two different mechanisms? Journal of the Neurological Sciences 1993;116:185-192. Fenichel GM. Neurological complications of immunization. Annals of Neurology 1982;12:119-128. Fujinatal RS, Oldstone MB. Molecular mimicry as a mechanism for virus-induced autoimmunity. Immunological Research 1989;8:3-15. Guillain G, Barré JA, Strohl A. Sur un syndrome de radiculonevrite avec hyperalbuminose due liquide cephalo-rachidien sans reaction cellulaire: remarques sure les caracteres cliniques et graphiques des reflexes tendineux. Bulletins et Memoires Societé Medicale des Hopitaux de Paris 1916;40:1462-1470. Halsey NA, Modlin JF, Jabbour JT. Subacute sclerosing panencephalitis (SSPE): an epidemiologic review. In: Stevens JG, et al., eds. Persistent Viruses. New York: Academic Press: 1978:101-114. Hankey GJ. Guillain-Barré syndrome in Western Australia. 1980-1985. Medical Journal of Australia 1987;146:130-133. Held JR, Adaros HL. Neurological disease in man following administration of suckling mouse brain antirabies vaccine. Bulletin of the World Health Organization 1972;46:321-327. Hemachudha T, Griffin DE, Giffels JJ, Johnson RT, Moser AB, Phanuphak P. Myelin basic protein as an encephalitogen in encephalomyelitis and polyneuritis following rabies vaccination. New England Journal of Medicine 1987a;316:369-374. Hemachudha T, Phanuphak P, Johnson RT, Griffin DE, Ratanavongsiri J, Siriprasomsup W. Neurologic complications of Semple-type rabies vaccine: clinical and immunologic studies. Neurology 1987b;37:550-556. Hemachudha T, Griffin DE, Chen WW, Johnson RT. Immunologic studies of rabies vaccination-induced Guillain-Barré syndrome. Neurology 1988;38:375-378. Honavar M, Tharakan JK, Hughes RA, Leibowitz S, Winer JB. A clinicopathological study of the Guillain-Barré syndrome: nine cases and literature review. Brain 1991;114:1245-1269.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Horta-Barbosa L, Fuccillo DA, Sever JL. Subacute sclerosing panencephalitis: isolation of measles virus from a brain biopsy. Nature 1969;221:974. Horta-Barbosa L. Hamilton R, Wittig B, Fuccillo DA, Sever JL. Subacute sclerosing panencephalitis: isolation of suppressed measles virus from lymph node biopsies. Science 1971;173:840-841. Hughes RA. Guillain-Barré Syndrome. London: Springer-Verlag; 1990. Hurwitz ES, Schonberger LB, Nelson DB, Holman RC. Guillain-Barré syndrome and the 1978-1979 influenza vaccine. New England Journal of Medicine 1981;304:1557-1561. Institute of Medicine. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: National Academy Press; 1991. Johnson. RT. Viral aspects of multiple sclerosis. Handbook of Clinical Neurology 1985;3:319-336. Johnson RT, Griffin DE, Gendelman HE. Postinfectious encephalomyelitis. Seminars in Neurology 1985;5:180-190. Kabat EA, Wolf A, Bezer AE. The rapid production of acute disseminated encephalomyelitis in rhesus monkey by injection of heterologous and homologous brain tissue with adjuvants. Journal of Experimental Medicine 1947;85:117-130. Kaplan JE, Schonberger LB, Hurwitz ES, Katona P. Guillain-Barré syndrome in the United States. 1978-1981: additional observations from the national surveillance system. Neurology 1983;33:633-637. Katz M, Oyanagi S, Koprowski H. Structures resembling myxovirus nucleocapsids in cells cultures from brains. Nature 1969;222:888-890. Kellaway P, Krachoby RA, Frost JD, Zion T. Precise characterization and quantification of infantile spasms. Annals of Neurology 1979;6:214-218. Kibel MA. Guillain-Barré syndrome in childhood. South African Medical Journal 1983;63:715. Langmuir AD, Bregman DJ, Kurland LT, Nathanson N, Victor M. An epidemiologic and clinical evaluation of Guillain-Barré syndrome reported in association with the administration of swine influenza vaccines. American Journal of Epidemiology 1984;119:841-879. Ling CM, Loong SC. Injection injury of the radial nerve. Injury 1976;8:60-62. Lopez Adaros H, Held JR. Guillain-Barré syndrome associated with immunization against rabies: epidemiological aspects. Research Publications of the Association for Research in Nervous and Mental Disease 1971;49:178-186. Martin R, McFarland H, McFarlin D. Immunological aspects of demyelinating diseases. Annual Review of Immunology 1992;10:153-183. McKhann GM, Griffin JW, Cornblath DR, Mellits ED, Fisher RS, Quaskey SA. Plasmapheresis and Guillain-Barré syndrome: analysis of prognostic factors and the effect of plasmapheresis. Annals of Neurology 1988;23:347-353. McKhann GM, Cornblath DR, Ho TW, Li CY, Bai AY, Wu HS, Yei QF, et al. Clinical and electrophysiological aspects of acute paralytic disease of children and young adults in northern China. Lancet 1991;38:593-597. McKhann GM, Cornblath DR, Griffin JW, Ho TW, Li CY, Jiang Z, et al. Acute motor axonal neuropathy: a frequent cause of acute flaccid paralysis in China. Annals of Neurology, In press. Modlin JF, Jabbour JT, Witte JJ, Halsey NA. Epidemiologic studies of measles, measles vaccine, and subacute sclerosing panencephalitis. Pediatrics 1977;59:505-512. Nicolosi A, Hauser WA, Beghi E, Kurland LT. Epidemiology of central nervous system infections in Olmsted County, Minnesota, 1950-1981. Journal of Infectious Diseases 1986;154:399-408. Payne FE, Baublis JV, Itabashi HH. Isolation of measles virus from cell cultures of brain from

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality a patient with subacute sclerosing panencephalitis. New England Journal of Medicine 1969;281:585-589. Pollard JD, Selby G. Relapsing neuropathy due to tetanus toxoid: report of a case. Journal of Neurological Science 1978;37:113-125. Rantala H, Uhari M, Niemela M. Occurrence, clinical manifestations, and prognosis of Guillain-Barré syndrome. Archives of Disease in Childhood 1991;66:706-709. Rivers TM, Schwenker FF. Encephalomyelitis accompanied by myelin destruction experimentally produced in monkeys. Journal of Experimental Medicine 1935;61:689-702. Ropper AH. The Guillain-Barré syndrome. New England Journal of Medicine 1992;326:1130-1136. Ropper AH, Wijdicks EF, Truax BT. Guillain-Barré syndrome. Philadelphia: F.A. Davis; 1991. Roscelli JD, Bass JW, Pang L. Guillain-Barré syndrome and influenza vaccination in the US Army. 1980-1988. American Journal of Epidemiology 1991;133:952-955. Safranek TJ, Lawrence DN, Kurland LT, Culver DH, Wiederholt WC, Hayner NS, et al. Reassessment of the association between Guillain-Barré syndrome and receipt of swine influenza vaccine in 1976-1977: results of a two-state study. Expert Neurology Group. American Journal of Epidemiology 1991;133:940-951. Scheinberg L, Allensworth M. Sciatic neuropathy in infants related to antibiotic injections. Pediatrics 1957;19:261-265. Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, Keenlyside RA, Ziegler DW, Retailliau HF, et al. Guillain-Barré syndrome following vaccination in the National Influenza Immunization Program, United States, 1976-1977. American Journal of Epidemiology 1979;110:105-123. Sibley WA, Bamford CR, Clark K. Clinical viral infections and multiple sclerosis. Lancet 1985;1:1313-1315. Soffer D, Feldman S, Alter M. Epidemiology of Guillain-Barré syndrome. Neurology 1978;28:686-690. Sunderland S. Nerves and Nerve Injuries. Baltimore: The Williams & Wilkins Company; 1968. Tsairis P, Dyck PJ, Mulder DW. Natural history of brachial plexus neuropathy: report on 99 patients. Archives of Neurology 1972;27:109-117. Uhari M, Rantala H, Niemela M. Cluster of childhood Guillain-Barré cases after an oral poliovaccine campaign (letter). Lancet 1989;2:440-441. U.S. Department of Health and Human Services. U.S. Public Health Service, National Vaccine Injury Compensation Program; Revision of the Vaccine Injury Table; Proposed Rule. Federal Register, 42 CFR Part 100, August 14, 1992;57(158):36877-36885. Van Bogaert L. Une leucoencephalite sclerosante subaigue. Journal de Neurologie de la Psychiatrie 1945;8:101-120. van der Meché FG, Schmitz PI, Dutch Guillain-Barré Study Group. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barré syndrome. New England Journal of Medicine 1992;326:1123-1129. Waksman BH, Adams RD. Allergic neuritis: an experimental disease of rabbits induced by the injection of peripheral nervous tissue and adjuvants. Journal of Experimental Medicine 1955;102:213-235. Winer JB, Hughes RA, Anderson MJ, Jones DM, Kangro J, Watkins RP. A prospective study of acute idiopathic neuropathy, II. Antecedent events. Journal of Neurology, Neurosurgery and Psychiatry 1988;51:613-618. Winner SJ, Evans G. Age-specific incidence of Guillain-Barré syndrome in Oxfordshire. Quarterly Journal of Medicine 1990;77(New Series): 1297-1304.