Case Reports: Postvaccinal Encephalomyelitis
Following Hepatitis 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!
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.
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
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.
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.
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.
Back to Hepatitis B section menu
Table I: Seventeen articles that have appeared in the medical
literature between 1983 through 1998 that suggest adverse reactions after vaccination
against hepatitis B.
||Suggested Adverse Reaction
NEJM 1983; 309:614-15
Lancet 1987; 2:631-32
AMJ Epid. 1988; 127:337-52
Arch Int. Med 1988; 148:2685
NEJM 1989; 321:1198-99
||Inf. Dis. News 1992; 5:2
Lancet 1991; 338:1174-75
World Health Organization Adverse Drug Reaction Bulletin August 1990
J. Hepatol 1993; 19:317-8
||Clin. Infect. Dis. 1993; 17:928-29
BMJ 1990; 301:1281
Lancet 1993; 342:563-4
Neurol Neurosurg Psychiatry 1995 ; 58:758-59
Br. J. Rheumatol 1994; 33:991
BMJ 1994; 309:94
Reiter Syndrome and Arthritis
Lancet 1988; 351:637-41
Autism & Colitis
JAMA 1997; 278:1176-78
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
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
9. Herroelen L, de Keyser J, Ebinger G. Central nervous system
demyelination after immunization with recombinant hepatitis B vaccine. Lancet 1991;
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
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
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;
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
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.
Back to Hepatitis B section menu