How Safe Is Universal Hepatitis B Vaccination?
Burton A. Waisbren, Sr., M.D., F.A.C.P.'s writings on the topic
Note: these two articles were obtained from here, with the primary article being followed by a few case reports of encephalomyelitis following vaccination
How Safe Is Universal Hepatitis B Vaccination?
INTRODUCTION
Universal hepatitis B vaccination of infants in the United States, regardless of risk factors, was first proposed by Margolis and his coworkers of the hepatitis branch of the Center for Disease Control and Prevention in Atlanta, Georgia.(1,2) The concept was endorsed and augmented by West and his coworkers at the Merck Sharpe and Dohme research laboratories in West Point, Pennsylvania.(3) The rationale presented for universal vaccination of infants in the U.S. stemmed from the failure of the current strategies for controlling this disease and not from trials that demonstrated the effectiveness or safety of a universal hepatitis B vaccination program.(4,5) In spite of this, universal hepatitis B vaccination is achieving wide spread acceptance among medical organizations and is being vigorously pursued in many sections of the country.(5,6)
To be presented here are four patterns that raise some concerns about vaccinating all babies in the U.S. with the hepatitis B vaccine. The patterns are as follows: The historical pattern of events that followed the introduction of an antirabies vaccine in the late 1800's and of warnings regarding probable occurrence of vaccine complications given by medical scientists during the past 50 years; the pattern revealed by animal experimentation that showed that viruses and viral particles may cause demyelination and autoimmunity in a variety of species; the pattern of autoimmunity and demyelination that has been caused by the hepatitis B infection, itself; the pattern of clinical reports that reveal that demyelination and autoimmunity have appeared in patients vaccinated with hepatitis B vaccines.
Reasonable steps that might be taken to address the concerns evoked by the above patterns will be discussed.
Postvaccinal Encephalomyelitis and Warnings by Medical Scientists
Postvaccinal encephalomyelitis has been recognized and accepted as a clinical entity since it first occurred after Pasteur's antirabies vaccine was used.(7) At first the encephalomyelitis was thought to be caused by the nervous tissue in which the virus used for the vaccine was grown.(7) However, postvaccinal encephalomyelitis has appeared in patients who received vaccine grown in duck eggs, so it is now thought that the syndrome is caused by something present in the dead virus.(8) Postvaccinal encephalomyelitis has since been observed after a wide variety of vaccinations.
Within the past 30 years representatives of the medical establishment have discussed and warned about neurologic complications of various vaccines.(9-12) Wilson, in his 1967 monograph regarding vaccine complications, pointed out that there are no insurance policies without premiums and that strict attention must be paid to the premiums exacted by each vaccine.(9) Miller, in 1954, discussed the neurologic sequelae of vaccination and the difficulty of these complications being recognized and accepted.(10) Zuckerman, in an article in 1974 in Nature entitled "Hepatitis Vaccine: A note of caution" pointed out that autoimmunity might well follow the hepatitis B vaccinations because the disease, itself, involved autoimmunity.(11) He suggested, "careful assessment of all vaccine effects on the immune system."(11) As late as 1988, Hilleman, who some call the "father" of hepatitis B vaccine, warned "the message from the hypothetical hepatitis B example is that the administration of antigens or monoclonal antibodies that directly or indirectly raise antibodies that attach to host cell receptors may carry large liabilities even though they might provide a convenient means for preventing viral access to host cells... antibodies attached to cell receptors may invite the same kinds of adverse response that are believed to be responsible for a variety of autoimmune disorders." (12)
Experiments In Animals That Lead To Concerns about the Hepatitis B Vaccine
Experiments done on animals in the past 60 years have yielded data that add to the concerns about present day viral vaccines. These experiments have shown that polypeptide chains of the types found in viruses that are homologous or nearly homologous with myelin can cause demyelination and have shown that viruses, themselves, can cause demyelination.(13)
The experiments started in 1956 when Rivers showed that myelin injected into monkeys caused demyelination.(14) Wakesman expanded these studies and developed an experimental model in which myelin and adjuvant consistently caused demyelinating disease in mice and rabbits.(15) This has been widely accepted as a model for demyelinating diseases in humans and is called experimental allergic encephalomyelitis (EAE).(16) Stohlman found that a DNA virus called JHM could cause demyelination in mice.(17) Oldstone then presented experimental evidence that autoimmunity in humans was caused by polypeptides in viruses that were homologous to those in human tissue.(18) Fujinami and Oldstone produced EAE in rabbits with proteins from hepatitis B virus that had polypeptides in it that were homologous with myelin.(19) Ziegler produced EAE in rabbits with the Swine Flu Vaccine and adjuvants.(20)
Westall and Root-Bernstein presented data that suggested a syndrome they called Multiple-Antigen-Mediated-Autoimmunity (MAMA) could occur in animals and humans.(21) They postulated that the MAMA Syndrome was operative in postvaccinal encephalomyelitis as well as in EAE.(21) Root-Bernstein hypothesized that this syndrome could occur in humans if four conditions were met. The first was demonstrated homology between an antigen and host tissue. The second was the presence simultaneously, of more than one antigen. The third was complementarity between the antigens shown to be present. The fourth was the additional presence of a bacterial adjuvant. As will be discussed later, all of these requirements can be tested for as a possible explanation for post hepatitis B vaccine reactions.
Finally, the HLA patterns of experimental animals has been shown to influence their susceptibility to experimental demyelinating diseases.(22)
Hepatitis B Infection Causes Autoimmunity and Demyelination
Another group of patterns regarding the consideration of universal hepatitis vaccination, without factoring in risk factors that have been largely ignored, are those revealed by the findings that the infection, itself, causes autoimmunity and demyelination. In 1977, London first reported that autoimmune disease was caused by circulating immune complexes caused by viral antibody association.(23) In 1987, Tsukada reported demyelinizing neuropathy associated with the hepatitis B infection.(24) Discussions and case reports regarding autoimmunity occurring with the hepatitis B infection have been presented by Vento et al and McFarlane et al.(25,26) As early as 1976, Zuckerman cautioned that since autoimmunity is involved in the pathogenesis of hepatitis B infections that it might be augmented by a hepatitis B vaccination.(11)
Reports Of Demyelination and Autoimmunity After Hepatitis B Vaccination
Clinical experiences since the general release of hepatitis B vaccines suggest that clinical counterparts of the animal studies and autoimmunity that occurs after the hepatitis B infection occur after hepatitis B vaccination. The first report of demyelination after the hepatitis B vaccination was that of Ribera and Dutka in 1983. The complication was transient.(27) The authors stated inflammatory polyradiculoneuropathies after both viral diseases and vaccinations have been widely reported.(27) They emphasized the necessity of continued surveillance of the use of hepatitis B vaccine.(27) I have noted seven cases of a neurologic picture resembling multiple sclerosis (MS) after hepatitis B vaccination.(28) In 1987, Fried et al reported uveitis that occurred in a 20-year-old nurse after a booster dose of hepatitis B vaccine.(29) They pointed out that there is a higher than normal level of hepatitis B antibodies in some uveitis patients. They postulated that these antibodies combined with surface antigens in the vaccine could form a disease producing immune complex.(29)
Shaw et al reported a post marketing surveillance study regarding neurologic events after the hepatitis B vaccine in 1988.(30) An estimated 850,000 individuals had received the vaccine by the time of their study. They found ten cases of Bell's palsy, nine cases of Guillain-Barre Syndrome, five cases of lumbar radiculopathy, three cases of brachial plexus neuropathy, five cases of optic neuritis, and four cases of transverse myelitis. They concluded, on the basis of the controversial epidemiologic methods used to study the Swine Flu epidemic of 1976, that the risk of the vaccine was outweighed by the prophylactic benefits in "high risk groups."(30,31) However, even using these methods, they concluded that the demyelinating disease, Guillain-Barre Syndrome, occurred more often in individuals who had been vaccinated than in the general population.(30) In 1988, Biron et al reported a case of myasthenia gravis that occurred after anesthesia and a hepatitis B vaccination.(32) They postulated that the autoimmune disease was due to the "challenge" to the immune system by the vaccine.(32) In 1989, Goolsby reported a case of erythema nodosum that occurred after recombinant hepatitis B vaccine.(33) In 1991, Herroelen et al reported on two patients who developed symptoms of increasing demyelination after a vaccination of recombinant hepatitis B vaccine.(34) He mentioned that their HLA patterns might be a contributing factor. Seven hundred reports of adverse reactions to the hepatitis B vaccine were sent in to the Vaccine Adverse Events Reporting Systems (VAERS) between October 1990 and September 1991.(35) This system was set up via the National Childhood Vaccine Injury Act of 1986. Sixteen percent of these reports were of damage presumed to be to the myelin of the nervous system. There were 21 cases of facial paralysis and six cases of MS. Eighty-two of the complications occurred in patients who received plasma derived vaccine and 18 occurred in those who received recombinant vaccine.(35) This difference can be explained by the fact that at the time the VAERS were examined, the recombinant vaccine had just come into general use. In 1990, in the World Health Organization Drug Information Bulletin two cases of optic neuritis and one case of Guillain-Barre Syndrome were reported to be among the 200 reports of adverse reactions that were reported by the Australian National Regulatory Body.(36) One patient had vertigo and diplopia attributed to demyelination eight months after the vaccination.(36)
In 1993, Trevisani et al reported a case of transverse myelitis that followed a recombinant vaccination in an 11 year-old girl.(37) Their arguments for a causal link between the vaccination and the transverse myelitis were the temporal association (21 days), the previous report of Shaw's in which the same complication occurred, and no clinical evidence of any other cause of the disease.(37) They pointed out that transverse myelitis was occasionally found in patients with hepatitis B.(37) This suggested to them that there might be antigenic determinants held in common with the capsular antigen of the hepatitis B vaccine and myelin.(37)
In 1993, Nadler et al reported a case of "classic MS," the prodromal of which appeared 10 days after a recombinant vaccination.(38) They stated that the benefits of the hepatitis B vaccination, among the population for "which it is usually recommended," far out weigh any potential risks.(38) In 1990, there was a report in the British Medical Journal of vasculitis related to the hepatitis B vaccination.(39) It was felt to be due to immune complex disease. In 1993, Brezin et al reported visual loss and eosinophilia after a recombinant hepatitis B vaccine.(40)
In 1995, Kaplanski et al reported a case of central nervous system demyelination that occurred in a 37-year-old man two weeks after receiving the third hepatitis B injection.(41) This patient had the same haplotype as the patient reported by Herroelen.(34) They suggested that the hepatitis B vaccination could potentially induce CNS demyelination in patients with HLA, B7, DR2 haplotype, whether or not these patients have a history of MS.(41)
Vautier and Carty in 1994 reported a case of classic rheumatoid arthritis that followed a hepatitis B vaccination.(42) They brought up the fact that the patient was HLA, DR4 positive which would be consistent with both animal and previous clinical reports regarding complications of the hepatitis B vaccine.(22,33,42) Hassan and Oldham reported two cases of reactive arthritis and Reiter's Syndrome that occurred after a recombinant hepatitis B vaccine.(43) They cite a personal communication from the manufacturer that stated that in 11 cases reported to them of reactive arthritis following recombinant hepatitis B vaccine that six had a recurrence of symptoms after a second vaccination.(43)
In 1995, Tartaglina et al reported a case of postvaccinal myelitis that occurred one month after a hepatitis B vaccination..(44) They suggested that complications of this sort may be under reported because there can be a delay in symptom occurrences.(44) In the case they reported, symptoms did not occur until one month after a single injection of the vaccine. No other cause of the myelitis was shown by a MRI.(44)
DISCUSSION
How might the concerns evoked by the material that has been presented be addressed?
Parents of babies and adolescents who have little chance of being exposed to hepatitis B should be made aware of the potential dangers of the vaccine. A perspective, inclusive, long term follow up study of a large number of individuals who have received the vaccine should be done and the results should be made available to the parents of children who are to be vaccinated. While these admittedly tedious studies are being conducted, databases available through societies such as the Multiple Sclerosis Society might be used to determine if an inordinate number of patients with multiple sclerosis had received a hepatitis B vaccination prior to being diagnosed.
The literally hundreds of individuals who have been reported to VAERS and pharmaceutical companies, who claim to have suffered demyelination and autoimmunity from a hepatitis B vaccine, should be followed up to determine their HLA patterns to ascertain if host factors are partially causative of the complication.(22,33)
A large group of individuals who are to be vaccinated should have before and after determinations by the methods of Zhang, Wucherpfennig and Strominger of the percentage of their T-cells that exhibit antimyelin activity to determine if vaccination does evoke such cells in some individuals with certain HLA patterns.(47,48)
The ability of vaccines when injected with adjuvant into animals to cause EAE should be tested using the methods of Fujinami and Ziegler.(19,20)
The hypothesis and studies of Westall and Root-Bernstein that indicate a multifactorial pathogenesis of postvaccinal encephalomyelitis suggest a series of studies that could be done on vaccines and on patients who developed complications after the hepatitis B vaccination.(21) Hepatitis B vaccine and all other vaccines should be tested for the extent of their polypeptide homology with human tissue.(13,21) If significant homology were to be demonstrated, the offending polypeptides could be removed from the vaccine or synthetic vaccines could be produced without them.(49,50) If such a homology were to be demonstrated, it would fulfill the first requirement for the provocative hypothetical MAMA Syndrome of Westall and Root-Bernstein.(21) The second requirement for the MAMA Syndrome is that multiple antigens are present.(21) These could be tested for by serologic studies for the Epstein-Barr Virus and other viruses that already have been indicted in this syndrome.(21) The third requirement that complementarity between antigens must be demonstrated could be tested for by complementarity studies between the hepatitis B vaccine and other antigens uncovered by the aforementioned serologic tests.(51) The fourth requirement that an adjuvant be present could be tested for by serologically determining whether muramyl peptides are present.(52) These peptides are well established adjuvants and are ubiquitous as part of the cell walls of all bacteria.(52)
The above-mentioned studies might well yield information that would not only make all vaccines safer, but could lead to means to prevent postvaccinal autoimmunity by the methods shown to work in animals by Westall and Root-Bernstein and Norga et al.(53,54)
Finally, it should be emphasized that the concerns voiced above in no way denigrate worldwide programs that are attempting to reduce hepatitis B in populations of extremely high risk, both internationally and in the U.S.(55) Certainly, there should be no abrupt stopping of present vaccination programs in the U.S., but it does seem reasonable to develop an informed consent that discloses to parents the potential dangers of the vaccine. Parents then would be able to intelligently decide whether the risk involved justifies their child receiving the vaccination. This might be particularly reasonable in areas of the U.S. in which the incidence of hepatitis B is very low.
REFERENCES
1. Kane, MA, Alter MJ, Hadler SC, Margolis HS. Hepatitis B infection in the United States. Recent trends and future strategies for control. Am J Med 1989; 87:11S-13S.
2. Shaprio CN, Margolis HS. Hepatitis B epidemiology and prevention. Epidemiol Rev 1990; 12:221-7.
3. West DJ, Margolis HS. Prevention of hepatitis B virus infection in the U.S.: A pediatric perspective. Pediatr Infect Dis J 1992; 11:866-74.
4. Margolis HS, Alter MJ, Hadler SC, Margolis HS. Hepatitis B: Evolving epidemiology and implications for control. Semin Liver Dis 1991; 11:84-92.
5. American Academy of Pediatrics Committee on Infectious Diseases. Universal hepatitis B immunization. Pediatrics 1992; 89:795-800.
6. Hepatitis B virus: A comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991; 40:RR-13, 1-25.
7. Swamy HS, Anisya V, Nandi SS, Kaliaperumal VG. Neurological complications due to semple-type antirabies vaccine. Clinical and therapeutic aspects. J Assoc Physicians India 1991; 39(9):667-69.
8. Label LS, Batts DH. Transverse myelitis caused by duck embryo rabies vacc. Arch Neurol 1982; 39:426-30.
9. Wilson GS. The hazards of immunization. The Athlone Press. 1967.
10. Miller H, Stanton J. Neurologic sequence of prophylactic inoculation. Q J Med 1954; 23:1-27.
11. Zuckerman AJ. Hepatitis Vaccine: A note of caution. Nature 1975; 255:104-5.
12. Hilleman MR. Perspectives in the quest for a vaccine against AIDS in 1988 in human retroviruses, in cancer, and AIDs. Approaches to prevention and therapy. P 306. Alan R. Liss Inc., New York.
13. Jahnke U, Fischer EH, Alvord EC Jr. Sequence homology between certain viral proteins and proteins related to encephalomyelitis and neuritis. Science 1985; 229:282-84.
Rivers TM, Schwentker FF. Encephalomyelitis accompanied by myelitis destruction experimentally produced in monkeys. J Exp Med 1935; 61:689.
15. Wakesman BH, Adams RD. Allergic neuritis: An experimental disease of rabbits induced by the injection of peripheral nervous system tissue and adjuvants. J Exp Med 1955; 102:213-34.
16. Alvord EC, Kies MW, Suckling AJ (eds). Experimental allergic encephalomyelitis: A useful model for multiple sclerosis. New York: Liss, 1984.
17. Stohlman SA, Weiner LP. Chronic central nervous system demyelination in mice after JHM virus infection. Neurology 1981; 31:38-44.
18. Oldstone MB. Virus induced autoimmunity: Molecular mimicry as a route to autoimmune disease. J Autoimmun 1989; 2 suppl:187-94.
19. Fujinami RS, Oldstone MB. Amino acid homology between the encephalitogenic site of myelin based protein and virus: Mechanism for autoimmunity. Science. 1985; 230:1043-45.
20. Ziegler DW, Gardner JJ, Warfield DT, Walls HH. Experimental allergic neuritis-like disease in rabbits after injection with influenza vaccines mixed with gangliosides and adjuvants. Infect Immun 1983; 42:824-30.
21. Root-Bernstein RS. Multiple-Antigen-Mediated-Autoimmunity (MAMA) in AIDS: A possible model for post infectious autoimmune complications. Res Immunol 1990; 141:321-39.
22. Rose JW. Virus-induced demyelination: From animal models to human disease. Mayo Clin Proc 1992; 67:903-6.
23. London WT. Hepatitis B virus and antigen antibody complex diseases. N Engl J Med 1977; 296:1528-29.
24. Tsukada N, Koh CS, Inoue A, Yanagisawa N. Demyelinating neuropathy associated with hepatitis B virus infection, detection on immune complexes composed of hepatitis B virus surface antigen. J Neurol Sci 1987; 77:203-16.
25. Vento S, Eddleston A. Autoimmunity and liver diseases. Prog Liver Dis 1990; 9:335-43.
26. McFarlane BM, Bridger CB, Smith HM, Antonov KA, Naoumov N, Williams R, McFarlane IG. Autoimmune mechanisms in chronic hepatitis B and delta virus infections. Eur J Gastroenterol and Hepatol 1995; 7:615-21.
Ribera EF, Dutka AJ. Polyneuropathy associated with administration of hepatitis B vaccine (letter). N Engl J Med 1983; 309:614-15.
28. Waisbren BA. Other side of the coin (letter). Inf Dis News 1992; 5:2.
29. Fried M, Conen D, Conzelmann M., Steinemann E. Uveitis after hepatitis B vaccination (letter). Lancet 1987; 2:631-32.
30. Shaw FE Jr, Graham DJ, Guess HA, et al. Post-marketing surveillance for neurologic adverse events reported after hepatitis B vaccination. Experience of the first three years. AM J Epidimiol 1988; 127:337-52.
31. Poser CM. Swine influenza vaccination. Truth and consequences. Arch Neurol 1985; 42:1090-92.
32. Biron P, Monopetit P, Infante-Rivard C, Lery L. Myasthenia gravis after general anesthesia and hepatitis B vaccine. Arch Intern Med 1988; 148:2685.
33. Goolsby PL. Erythema nodosum after Recombivax HB hepatitis B vaccine. N Engl J Med 1989; 321:1198-99.
34. Herroelen L, de Keyser J, Ebinger G. Central nervous system demyelination after immunization with recombinant hepatitis B vaccine. Lancet 1991; 338:1174-75.
35. Data obtained from VAERS through the Freedom of Information Act.
36. Anonymous. Hepatitis B vaccines: Reported reactions. World Health Organization Adverse Drug Reaction Bulletin. Aug 1990.
37. Trevisani F, Gattinara GC, Caraceni P, et al. Transverse myelitis following hepatitis B vaccination. J Hepatol 1993; 19:317-18.
38. Nadler JP. Multiple sclerosis and hepatitis B vaccination (letter). Clin Infect Dis 1993; 17:928-29.
39. Cockwell P, Allen MB, Page R. Vasculitis related to hepatitis B vaccine. BMJ 1990; 301:1281.
Brezin A, Lautier-Frau M, Hamedani M, Rogeaux O, Hoang PL. Visual loss and eosinophilia after recombinant hepatitis B vaccine. Lancet 1993; 342:563-4.
41. Kaplanski G, Retornaz F, Durand J, Soubeyrand J. Central nervous system demyelination after vaccination against hepatitis B and HLA haplotype. J Neurol Neurosurg Psychiatry 1995; 58:758-59.
Vautier G, Carty JE. Acute seropositive rheumatoid arthritis occurring after hepatitis vaccination. Br J Rheumatol 1994; 33:991.
43. Hassan W, Oldham R. Reiter's syndrome and reactive arthritis in health care workers after vaccination. BMJ 1994; 309:94.
44. Tartaglino LM, Heiman-Patherson T, Friedman DP, Flanders AE. MR imaging in a case of postvaccination myelitis. AJNR Am J Neuroradiol 1995; 16:581-2.
45. Colditz GA. The nurse's health study: A cohort of US women followed since 1976. J Am Women's Assoc 1995; 50:40-4.
46. Glynn RJ, Buring JE, Manson JE, LaMotte F, Hennekens CH. Adherence to aspirin in the prevention of myocardial infarction. The Physicians' Health Study. Arch Intern Med 1994; 154:2649.
47. Zhang J, Markovic-Plese S, Lacet B, Raus J, Weiner HL, Hafler DA. Increased frequency of Interleukin-2 responsive T-cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. J Exp Med 1994; 179:973-84.
48. Wucherpfennig KW, Strominger JL. Molecular mimicry in T-cell mediated autoimmunity: Viral peptides activate human T-cell clones specific for myelin basic protein. Cell 1995; 80:695-705.
49. Janke U, Fischer EH, Alvord EC Jr. Sequence homology between certain viral proteins and proteins related to encephalomyelitis and neuritis. Science 1985; 229:282-4.
50. Sela M, Arnon R. Synthetic approaches to vaccines for infectious and autoimmune disease. Vaccine 1992; 10:971-6.
51. Westall FC, Robinson AB, Caccam J, et al. Essential chemical requirements for induction of allergic encephalomyelitis. Nature 1971; 229:22-24.
52. Hazenberg M.P., de Visser H. Assay for N-acetyluramyl-L-alanine amidase in serum by determination of muramic acid released from the peptidoglycan of Brevibacterium diverticulum. Eur J Clin Chem Biochem 1992; 30:141-44.
Westall FC, Root-Bernstein RS. Cause and prevention of postinfectious and postvaccinal neuropathies in light of a new theory of autoimmunity. Lancet 1986; 2:251-2.
54. Norga K, Paemen L, Masure S, et al. Prevention of acute autoimmune encephalomyelitis and abrogation of relapses in murine models of multiple sclerosis by the protease inhibitor D-penicillamine. Inflamm Res 1995; 44:529-34.
55. Zuckerman AJ. Editor. Prevention of hepatitis B in the newborn, children, and adolescents. Royal College of Physicians London, UK 1996; 113.
Case Reports: Postvaccinal Encephalomyelitis
Following Hepatitis B Vaccination.
Burton A. Waisbren, Sr., M.D., F.A.C.P.
Only that shall happen
which has happened.
Only that occurs
which has occurred.
There is nothing new beneath the sun!
Ecclesiastes 1.4
INTRODUCTION
The general acceptance of the concept of universal vaccination against hepatitis B, regardless of risk factors, makes it incumbent on physicians to be aware of the complications that have been reported to occur following the hepatitis B vaccination.(1-19) These complications have included a wide variety of reactions, most of which fit into an autoimmune category (3-19, Table 1). It is in this frame of reference that the two cases of postvaccinal encephalomyelitis seen by the author are being reported. A theoretic framework that might explain the pathogenesis of this complication and the studies suggested by this framework are discussed.
CASE REPORTS
Case 1
The patient is a 43-year-old female nurse who was in good health until August 1988. She had received two injections of hepatitis B vaccine in June 1988. Four weeks after the first vaccination, her husband noted that she began to have difficulty in concentrating and to have frequent severe headaches. She was taking a postgraduate course in nursing and contrary to her scholastic efforts in the past, she had difficulty in understanding and placing in context the relatively simple concepts that were being presented. In spite of headaches and cognition difficulties, she continued to work as a nurse. In October 1988 she developed a rash in her axilla which was nondescript in nature and which subsided in a month. She remained chronically ill with headaches, arthralgia and cognition defects, but she continued to try to work.
By mid-January 1989, her headaches had become too severe and she had to stop work. On January 19, 1989 her headaches increased even more in intensity and she became semiconscious. She was hospitalized and was in a deep coma for two weeks. No apparent cause of the coma was recognized and with supportive care, she gradually improved. Extensive studies in the hospital failed to definitely diagnose the etiology of her disease. They are summarized as follows: Cerebrospinal fluid studies showed 40 mononuclear cells, 79% were lymphocytes and 15% were monocytes. The sugar and protein content was normal. Serology studies of the cerebrospinal fluid that included studies for herpes simplex 1 and 2, measles, mumps, adenovirus, coxsackie virus, cytomegalovirus, herpes zoster and equine encephalitis were normal. Serum antinuclear antibodies were done three times. One showed a 1:40 titer of a speckled pattern, one showed a 1:80 titer of a homogeneous pattern, and the other was negative. The IgG titer against the Epstein-Barr virus was 1:160. Electrophoresis study of the cerebrospinal fluid was normal. A hepatitis B surface antibody test was positive. A Lyme test was positive with a fluorescent antibody titer of 1:512. Subsequent tests for Lyme antibodies were negative. A sedimentation rate was 4 mm/hr. A MRI of the brain and spinal cord was normal. A wide range of what might be called routine laboratory tests done on comatose patients was all normal. She was in the hospital for one month and diagnoses that were entertained, but not proven by the coterie of specialists who saw her were: Herpes meningitis, Lyme disease, and lupus erythematosus. She was discharged somewhat improved, but two weeks later she had to be readmitted to the hospital because of hypotension, weakness, anemia, low grade fever, joint pains and myalgia.
In April 1989, because her titer against the Borrelia antigen had been elevated, it was decided to treat her empirically for Lyme disease and she was given 2 grams of ceftriaxone IV for two weeks with no clinical response. She remained a semi-invalid with generalized weakness and mental confusion.
In August 1989, she developed slurred speech and a drooping right eye, so a course of IV penicillin was given, again, empirically for presumed chronic Lyme disease. There was no clinical response.
In November 1989, she noted difficulty with her sight and an ophthalmologist found optic neuritis. She continued to have fatigue, unsteadiness on her feet, visual problems, headaches, lack of concentration, generalized joint pains and weakness of her right arm and leg.
In January 1990, she was seen by myself. Based on the history of the two hepatitis B vaccine injections, the physical findings which included hyperactive knee and ankle reflexes, weakness of the right arm, absent abdominal reflexes, and the extensive negative studies that had been done, a diagnosis of postvaccinal encephalomyelitis and acquired autoimmune disease was made.
During the ensuing eight years the patient has noted gradual improvement in regard to fatigue and steadiness on her feet. She continues to have less mental activity than before and still has hyperreflexia, loss of visual acuity, absent abdominal reflexes and some weakness of her right arm and hand. In November 1997, a MRI of her brain failed to show any finding suggestive of multiple sclerosis. There has been no progression of symptoms.
Case 2
This 44-year-old female nurse received the hepatitis B vaccine in July 1988. Prior to this she had been extremely active and had no significant symptoms. Two weeks after the injection, she developed lethargy, joint pains and myalgia. The symptoms continued, but she continued to work until mid-September when she consulted a rheumatologist who found that she had an ANA titer of 1:500. He placed her on ten aspirins a day with no clinical response. In late December 1988, she had an episode at home in which she had a hazy sensorium and was semiconscious. An examination at an emergency room was nonrevealing except that a mitral prolapse was found and it was felt that it might have had a casual relationship to the event.
She continued to be chronically ill. In January 1989, a diagnosis of lupus erythematosus was made and she was started on chloroquine. Her ANA titer was markedly elevated at that time. There was no response clinically to the chloroquine sulfate. She continued to have headaches, lack of concentration, and unsteadiness on her feet and was unable to function in her profession.
On July 7, 1993, she lapsed into a deep coma, which lasted for one month. During a month in the hospital, she was only semiconscious and was incontinent. She was seen by numerous physicians and given an extensive medical work up. The presumptive diagnosis was lupus encephalomyelitis. A summary of significant laboratory results done in the hospital and subsequently is as follows: A brain biopsy was done which revealed thickened vascular walls surrounded by inflammatory cells. No evidence of a virus infection was seen. A culture of the brain tissue was negative for virus, bacterial, and fungal growth. The spinal fluid was sterile and acellular with normal protein and sugar concentrations. A MRI showed scattered areas of increased signal in the brain stem and in both hemisphere and the thalamus. Serology studies showed high titers against herpes simplex, varicella zoster, rubeola and mumps. Serial studies for mycoplasma and Legionnaires disease were negative. There were antibodies against the hepatitis B surface antigen. Her IgG (2740 mg/dl), and IgA (490 mg/dl), were elevated, Compliment C4 was low at 9 mg/dl, ANA was 1:512, anti-DNA antibody was 1:512.
After a month in which there was no apparent result to therapy with prednisone it was decided to try a course of plasmapheresis (August 1993). She was plasmapheresed on three occasions. There was a definite response to this and she gradually regained full consciousness. As she came out of her coma, optic neuritis developed and she became blind in her right eye.
I first saw her and examined her records in March of 1994. At that time, she was being maintained on prednisone 20 mg per day, Prozac 20 mg and multiple vitamins. She had multiple joint pains, cognition difficulties, and chronic fatigue and had not regained the sight in her right eye. She had hyperactive knee and ankle reflexes, absent abdominal reflexes, balance problems, and still had cognitive difficulties.
When contacted in May of 1998, she stated that there was little change in her condition. Several neurologists have assured her after their examinations that she does not have multiple sclerosis. There has been no further evidence that she may have had lupus erythematosus.
DISCUSSION
The most likely diagnosis in both of these patients by exclusion and consideration of their course is postvaccinal encephalomyelitis.(20-23) There does not seem to be any other probable initiating factors that could be involved other then that the patients received hepatitis B vaccine.
The diagnosis of lupus erythematosus, which was considered in both of these cases, is untenable, in view of the fact that neither patient had enough major or minor criteria for the disease to make it an acceptable diagnosis.(24) The diagnosis of Lyme disease is equally untenable because of the lack of exposure and a characteristic skin rash in both cases and because Lyme titers have been shown to be present in other central nervous system diseases.(22,25,26) The fact that Lyme disease was suspected enough by consulting physicians to result in empirical treatment, suggests that other patients that have been diagnosed as having Lyme disease should be investigated to determine if they are actually suffering from acquired autoimmunity due to hepatitis B vaccine.
Other causes of chronic encephalomyelitis appear to have been ruled out by the numerous tests ordered by the many specialists who examined each patient. Thus, the prolonged course and residual findings in these cases best fit the clinical picture of postvaccinal encephalomyelitis, which has been described both after the sample rabies vaccine and the duck embryo vaccine.(20, 21,22) The description that seems to best describe this condition is that of Dodson who defined it as "a diffuse interference with brain function resulting from a generalized or multifocal insult that causes a widespread disorder in the functions of neurons."(28)
If one accepts the diagnosis of postvaccinal encephalomyelitis as the etiology of these two cases, there is a wealth of animal experimentation regarding this condition to consider. This is because there is a generally accepted and extensively studied animal model of this condition.(29,30,31) It is called experimental allergic encephalomyelitis (EAE).(29,30,31) It has been postulated that the requirements specific of this experimental model are: Exposure of the animal to a group of polypeptide chains that are homologous or nearly homologous to its myelin, (molecular mimicry); simultaneous exposure of the animal to an antigen that exhibits complementarity to the antigen that exhibited molecular mimicry; simultaneous exposure to a immunologic adjuvant (usually derived from tubercle bacilli); possession of the animal of a characteristic lymphocyte antigen pattern.(31,32)
The EAE model suggests experiments that might explain the pathogenesis of postvaccinal encephalomyelitis as it occurs in humans. These experiments might also shed light on the broader field of acquired autoimmunity of the type reported to occur after hepatitis B vaccination. Viral antigens have already been shown to exhibit molecular mimicry with human myelin. (33) That suggests that viral vaccines can be studied for this characteristic. Patients who develop postvaccinal encephalomyelitis or any other form of autoimmunity after having received a vaccination can be studied to see whether they have been exposed to any bacterial or viral antigens that exhibit complementarity to the vaccine antigens.(31) They can also be studied to see if they have been exposed to bacterial cell walls, which might contribute to their immunologic spectrum. The most likely substances that would cause this are muramyl peptides, which are universal immunologic adjuvants.(34) Bacterial infections such as those caused by streptococci or mycoplasma come to mind in this respect. Finally, patients who develop untoward vaccine reactions should have their HLA patterns determined to see if characteristic patterns surface. (15)
As interesting as the above theoretic considerations should be to basic scientists and developers of vaccines, the root reason for the presentation of these cases is to alert physicians that postvaccinal encephalomyelitis has occurred. Bayes in his seminal paper on statistics in 1761 pointed out that the probability that if something happens once, it will happen again.(35) The question remains as to how often this complication actually does occur. Certainly, it does not appear to occur often enough to discourage vaccination of individuals at high risk for acquiring hepatitis.(1) Whether it occurs often enough to discourage vaccination of low risk patients will only be known if clinicians are made aware of this possibility and if they report its occurrences. In the meantime, physicians will have to decide whether the possibility of acquired autoimmunity must be mentioned in the informed consent given to patients of low risk.
Table I: Seventeen articles that have appeared in the medical literature between 1983 through 1998 that suggest adverse reactions after vaccination against hepatitis B.
Reference Journal Suggested Adverse Reaction
3. NEJM 1983; 309:614-15 Polyneuropathy
4. Lancet 1987; 2:631-32 Uveitis
5. AMJ Epid. 1988; 127:337-52 Guillain-Barre Syndrome
6. Arch Int. Med 1988; 148:2685 Myesthemia Gravis
7. NEJM 1989; 321:1198-99 Erythema Nodosum
8. Inf. Dis. News 1992; 5:2 CNS Demyelination
9. Lancet 1991; 338:1174-75 CNS Demyelination
10. World Health Organization Adverse Drug Optic Neuritis
Reaction Bulletin August 1990
11. J. Hepatol 1993; 19:317-8 Transverse Myelitis
12. Clin. Infect. Dis. 1993; 17:928-29 CNS Demyelination
13. BMJ 1990; 301:1281 Vasculitis
14. Lancet 1993; 342:563-4 Visual Loss
15. J. Neurol Neurosurg Psychiatry 1995 ; CNS Demyelination
58:758-59
16. Br. J. Rheumatol 1994; 33:991 Rheumatoid Arthritis
17. BMJ 1994; 309:94 Reiter Syndrome and Arthritis
18. Lancet 1988; 351:637-41 Autism & Colitis
19. JAMA 1997; 278:1176-78 Hair Loss
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1. Kane, MA, Alter MJ, Hadler SC, Margolis HS. Hepatitis B infection in the United States. Recent trends and future strategies for control. Am J Med 1989; 87:11S-13S.
2. Hepatitis B virus: A comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991; 40:RR-13, 1-25.
3. Ribera EF, Dutka AJ. Polyneuropathy associated with administration of hepatitis B vaccine (letter). N Engl J Med 1983; 309:614-15.
4. Fried M, Conen D, Conzelmann M., Steinemann E. Uveitis after hepatitis B vaccination (letter). Lancet 1987; 2:631-32.
5. Shaw FE Jr, Graham DJ, Guess HA, et al. Post-marketing surveillance for neurologic adverse events reported after hepatitis B vaccination. Experience of the first three years. AM J Epidimiol 1988; 127:337-52.
6. Biron P, Montpetit P, Infante-Rivard C, Lery L. Myasthenia gravis after general anesthesia and hepatitis B vaccine. Arch Intern Med 1988; 148:2685.
7. Goolsby PL. Erythema nodosum after Recombivax HB hepatitis B vaccine. N Engl J Med 1989; 321:1198-99.
8. Waisbren BA. Other side of the coin (letter). Inf Dis News 1992; 5:2.
9. Herroelen L, de Keyser J, Ebinger G. Central nervous system demyelination after immunization with recombinant hepatitis B vaccine. Lancet 1991; 338:1174-75.
10. Anonymous. Hepatitis B vaccines: reported reactions. World Health Organization Adverse Drug Reaction Bulletin. August 1990.
11. Trevisani F, Gattinara GC, Caraceni P, et al. Transverse myelitis following hepatitis B vaccination. J Hepatol 1993; 19:317-18.
12. Nadler JP. Multiple sclerosis and hepatitis B vaccination. Clin Infect Dis 1993; 17:928-29.
13. Cockwell P, Allen MB, Page R. Vasculitis related to hepatitis B vaccine. BMJ 1990; 301:1281.
Brezin A, Lautier-Frau M, Hamedani M, et al. Visual loss and eosinophilia after recombinant hepatitis B vaccine. Lancet 1993; 342:563-4.
15. Kaplanski G, Retornaz F, Durand J, Soubeyrand J. Central nervous system demyelination after vaccination against hepatitis B and HLA haplotype. J Neurol Neurosurg Psychiatry 1995; 58:758-59.
16. Vautier G, Carty JE. Acute sero-positive rheumatoid arthritis occurring after hepatitis vaccination. Br J Rheumatol 1994; 33:991.
17. Hassan W, Oldham R. Reiter's syndrome and reactive arthritis in health care workers after vaccination. BMJ 1994; 309:94.
18. Wakefield AJ, Murch SH, Anthony A, et al. Ileal - lymphoid hyperplasia, nonspecific colitis, and pervasive developmental disorder in children. Lancet 1998; 351:637-41.
19. Wise RP, Kiminyok P, Salive ME et al Hair loss after routine immunizations. JAMA 1997; 278:1176-78.
20. Label LS, Batts DH. Transverse myelitis caused by duck embryo vaccine arch. Neurol. 1982; 34:426-36.
21. Swamy H.s., Anisya V, Nandi SS, Kaliaperumd VG. Neurological complications due to Semple - type antirabies vaccine - clinical and therapeutic aspects. J Assoc Physicians India 1991; 39:667-669.
22. Stuart G, Krikorian KS. The neuroparalytic accidents of antirabies treatment. Ann Trop. Med. 1928; 23:327-377. (This article refers to the early literature in foreign languages).
23. Poser CM. Postvaccinal encephalitis (Letter). Ann Neurology 1983; 13:341-2.
24. Tan EM, Cohen AS, Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982; 25:1271-7.
25. Waisbren B.A., Cashman N, Schell RF, Johnson R. Borrelia Burgdorferi antibodies and amyotrophic lateral sclerosis. Lancet 1987; 2:332-3.
26. Garcia-Monco JC, Coleman JL, and Benach JL. Antibodies to myelitis basic protein in Lyme disease. Ji. of Inf. Dis. 1988; 158:667-668.
Schmutzhard E, Pohl P, & Stanek G. Borrelia Burgdorferi antibodies in patients with relapsing/remitting form and chronic progressive form of multiple sclerosis. J Neurol Neurosurg Psychiatry. 1988; 5:1215-1218.
Dodson WE, Metabolic encephalopathies in neurologic pathophysiology in: Eliason SG, Prensky AL, Hardin WB Jr. Ed. 1978. Neurological pathophysiology. New York, Oxford 1978.
29. Rivers JM & Schwentker. Encephalomyelitis accompanied by myelitis distraction experimentally produced in monkeys. J Exp. Med 1935; 61:689-702.
30. Shaw CM, Alvord FC. Adjuvant - antigen relationship in the production of experimental allergic encephalomyelitis in the guinea pig. J Exp. Med. 1962; 115:169-179.
31. Westall FC, Root-Bernstein RS. An explanation of prevention and suppression of experimental allergic encephalomyelitis. Mol. Immunol 1983; 2:169-177.
32. Root-Bernstein RS, Multiple-antigen-mediated autoimmunity (MAMA) in AIDS: a possible model for post-infectious autoimmune complications. Res Immunol 1990; 141:321-339.
33. Fujinami RS, Oldstone MB. Amino acid homology between the encephalitogenic site of myelin basic protein and virus. Mechanism for autoimmunity. Science 1985; 230:1043-45.
34. Hazenberg MP, de Visser H. Assay for n-acetyluramyl-L-alanine amidase in serum by determination of muramic acid released from the peptidoglycan of Brevibacterium divericatum. Eu J Clin Chem Biochem 1992; 30:141-44.
35. Bayes T. An essay towards solving a problem in the Doctrine of Chance 56. Reprinted in Biometrika 1985; 45:296-315.