Guillain-Barr6 Syndrome Following Administration of Live Measles Vaccine
CHARLES GROSE, M.D. San Francisco, California ILYA SPIGLAND, M.D. Bronx, New York
In a 19 month old girl and a 10 month old girl the Gulllain-Barre syndrome developed within a week after they received, respectively, live measles-rubella vaccine and live mea@es vaccine. The older child was immune to rubella at the time of vaccination, but both girls demonstrated a primary measles antibody response. Serum obtained during the acute and convalescent stages from the younger child was tested for antibodies against the herpes viruses (herpes stmplex, Epsteln-Barr virus, cytomegalovirus and varicella-zoster) and found to be negative. Although the etiology of the Guillain-Barre syndrome is not understood, the onset of this syndrome is often associated with a recent viral infection. In a study of 24 children and young adults with the Guillain-Barre syndrome, seven were found to have definite serologic evidence of acute Epstein-Barr virus infection whereas an additional five had suggestive findings [ 11. Eleven of the 12 other children had low or stable antibody titers; the youngest of these was a 19 month old girl who had received live measles-rubella vaccine five days before the onset of her peripheral neuropathy. At the time, the association of her neurologic disease with the vaccination was considered fortuitous and not discussed. However, four years later, we have seen a second remarkably similar case following a live measles vaccination. In this report we present the two cases and their virologic studies. CASE REPORTS Case 1.
From the Division of Pediatric Immunology, M679, Department of Pediatrics, University of California, San Francisco, San Francisco, California 94143, and the Division of Virology and Departments of Pathology and Pediatrics, Montefiore Hospital and Medical Center, Albert Einstein College of Medicine, Bronx, New York 10467. Requests for reprints should be addressed to Dr. Charles Grose. Manuscript accepted July 31, 1975.
A 19 month old girl, who received combined live measles-rubeila vaccine on February 24, awoke on March 1 and was unable to stand and support her own weight. During the next four days, the weakness progressed and also included the upper extremities and facial muscles bilaterally. On examination, her extremities were flaccid and areflexic. A sample of cerebrospinal fluid obtained on March 7 contained 95 mg/lOO ml protein and 2 mononuclear cells/mm3; a repeat lumbar puncture one week later demonstrated an acettular spinal fluid with a protein content of 250 mg/lOO ml. Over the next eight weeks the motor function in her extremities gradually returned to normal.
March 1976
The American Journal of Medicine
Volume 60
441
GUILLAIN-BARRE SYNDROME-GROSE,
SPIGLAND
Case 2. A 10 month old girl was given live measles vactine as well as her second DPT (diptheria-pertussis-tetanus vaccine) and trivalent oral poliovaccine (OPV) on March 28. She had received her first DPT and OPV eight months earlier. One day after her three immunizations she became febrile and refused to drink. Because of continuing fever and worsening dehydration, she was hospitalized on March 31. When examined one day after admission, the child was first noted to have hypotonic extremities (lower more than upper) with depressed deep tendon reflexes. The cerebrospinal fluid on April 2 contained 228 mg/lOO ml protein and 1 mononuclear cell/mm3. Over the next three days nearly complete tetraplegia developed. An electroencephalogram showed a normal pattern for the patient’s age. Her neurologic status remained stable for a week, after which her muscular strength began to improve quite rapidly. The second specimen of spinal fluid, which was obtained on April 8, contained 320 mg/lOO ml protein and no cells.
VIRAL STUDIES Viral antibody tests were performed in microtiter by the methods of hemagglutination-inhibition (HAI) for measles, mumps and rubella and complement-fixation (CF) for herpes simplex, cytomegalovirus and varicella-zoster. The Epstein-Barr virus antibody tests were carried out in the laboratory of Drs. Werner and Gertrude Henle at the Children’s Hospital of Philadelphia by the same fluorescent methods as previously described [I]. Serums were collected in Case 1 on the 6th and 16th days after the administration of live measles-rubella vaccination (M-R-VAX, Merck Sharp and Dohme). The measles antlbody titer was less than 1:8 In the serum obtained during the acute stage and I:64 in the serum obtained during convalescence: the rubella titer was I:256 in both serums. Serums in Case 2 were obtained 6, 21 and 55 days after the administration of live measles vaccine (Attenuvax, Merck Sharp and Dohme). The measles antibody titer was less than I:8 in the first serum and I:64 in the second and third serums. The three serums were also tested for antibodies to the following viruses: rubella, mumps, herpes simplex, EpsteinBarr virus, cytomegalovirus and varicella-zoster; all serums were negative. Both patients had throat swabs and urine samples collected within 48 hours of admission and inoculated into various cell cultures. The specimens in Case 1 were negative for virus-isolation. The throat swab in Case 2 contained poliovirus type 1 (presumably vaccine strain) as identified by neutralization with reference enteroviral antiserums: a second throat swab taken 11 days later did not demonstrate either poliovirus or other viruses.’ The urine sample did not yield any virus.
442
March 1978
The American Journal of Medicine
COMMENTS
In their survey live measles not include drome. This with natural
of the neurologic
vaccination [2] any cases of syndrome has (wild) measles
disorders
following
Landrigan and Witte did the Guillain-Barre synoccurred in association infection [3,4] and, like
other neurologic sequelae of measles, could be expected to follow attenuated (vaccine) measles infection also. Although one of the patients in this report
had combined measles-rubella vaccine, a rubella HAI antibody titer of I:256 is not compatible with a primary vaccine-rubella infection of six days’ duration but instead indicates that this child was already immune to rubella when immunized [5]. Both patients had a primary measles (vaccine-strain) infection as demonstrated by the seroconversion following immunization. The poliovirus type 1 which was isolated from the second child was not considered to be etiologically related to the patient’s disease which in no way resembled the neurologic manifestations of poliovirus. The isolation of only type 1 poliovirus seven days after her second trivalent OPV probably indicated that an immunity to poliovirus types 2 and 3 had developed after her first OPV at age two months. The absence of poliovirus from her second throat swab demonstrated an appropriate primary immune response to and eradication of poliovirus type 1 from her oropharynx. The time interval between vaccination and onset of the peripheral neuropathy was less than 1 week in both cases. We have also described a child in whom a peripheral facial palsy developed during the late incubation period of a wild measles infection, before the appearance of measles HAI antibodies [6]. Taken together, these three cases suggest an occasional role for measles virus (both vaccine and wild strains) in the pathologic process which leads to demyelinization. By testing for various viral antibodies in serum obtained during the acute and convalescent stage in the younger patient, we determined that the Guillain-Barre syndrome could occur in a patient who had no serologic evidence of past or recent infection with any of the four human herpes viruses: herpes simplex, varicella-zoster, Epstein-Barr virus and cytomegalovirus. The Guillain-Barre syndrome, therefore, does not appear to be simply the manifestation of a reactivation of a known latent herpes virus infection. These two cases again emphasize the need to carefully document the neurologic diseases which follow infections with live viral vaccines. Of utmost importance are serums obtained during the acute and convalescent periods for appropriate viral antibody titers.
Volume 60
GUILLAIN-BARRE
SYNDROME-GROSE,
SPIGLAND
REFERENCES 1.
2. 3.
Grose C, Henle W, Henle G, Feorino PM: Primary EpsteinBarr virus infections in acute neurolooic diseases. N Enol J Med 292: 392, 1975. Landrigan PJ, Witte JJ: Neurologic disorders following live measles virus vaccination. JAMA 223: 1459. 1973. Miller HG, Stanton JB, Gibbon JL: Para-infectious encephalomyelitis and related syndromes. Cl J Med 25: 427, 1956.
4.
5.
6.
March 1076
Lidin-Janson G, Strannegard 0: Two cases of Guillain-Barre syndrome and encephalitis after measles. Br Med J 2: 572, 1972. Cooper LZ, Giles JP, Krugman B: Clinical trial with live attenuated rubella virus vaccine, HPV-77 strain. Am J Dis Child 115: 655, 1968. Pollack MA, Grose C, Friend H: Measles associated with Bell’s palsy. Am J Dis Child 129: 747, 1975.
The American Journal ol Medkine
Volume 60
443
CHARLES GROSE, M.D. San Francisco, California ILYA SPIGLAND, M.D. Bronx, New York
In a 19 month old girl and a 10 month old girl the Gulllain-Barre syndrome developed within a week after they received, respectively, live measles-rubella vaccine and live mea@es vaccine. The older child was immune to rubella at the time of vaccination, but both girls demonstrated a primary measles antibody response. Serum obtained during the acute and convalescent stages from the younger child was tested for antibodies against the herpes viruses (herpes stmplex, Epsteln-Barr virus, cytomegalovirus and varicella-zoster) and found to be negative. Although the etiology of the Guillain-Barre syndrome is not understood, the onset of this syndrome is often associated with a recent viral infection. In a study of 24 children and young adults with the Guillain-Barre syndrome, seven were found to have definite serologic evidence of acute Epstein-Barr virus infection whereas an additional five had suggestive findings [ 11. Eleven of the 12 other children had low or stable antibody titers; the youngest of these was a 19 month old girl who had received live measles-rubella vaccine five days before the onset of her peripheral neuropathy. At the time, the association of her neurologic disease with the vaccination was considered fortuitous and not discussed. However, four years later, we have seen a second remarkably similar case following a live measles vaccination. In this report we present the two cases and their virologic studies. CASE REPORTS Case 1.
From the Division of Pediatric Immunology, M679, Department of Pediatrics, University of California, San Francisco, San Francisco, California 94143, and the Division of Virology and Departments of Pathology and Pediatrics, Montefiore Hospital and Medical Center, Albert Einstein College of Medicine, Bronx, New York 10467. Requests for reprints should be addressed to Dr. Charles Grose. Manuscript accepted July 31, 1975.
A 19 month old girl, who received combined live measles-rubeila vaccine on February 24, awoke on March 1 and was unable to stand and support her own weight. During the next four days, the weakness progressed and also included the upper extremities and facial muscles bilaterally. On examination, her extremities were flaccid and areflexic. A sample of cerebrospinal fluid obtained on March 7 contained 95 mg/lOO ml protein and 2 mononuclear cells/mm3; a repeat lumbar puncture one week later demonstrated an acettular spinal fluid with a protein content of 250 mg/lOO ml. Over the next eight weeks the motor function in her extremities gradually returned to normal.
March 1976
The American Journal of Medicine
Volume 60
441
GUILLAIN-BARRE SYNDROME-GROSE,
SPIGLAND
Case 2. A 10 month old girl was given live measles vactine as well as her second DPT (diptheria-pertussis-tetanus vaccine) and trivalent oral poliovaccine (OPV) on March 28. She had received her first DPT and OPV eight months earlier. One day after her three immunizations she became febrile and refused to drink. Because of continuing fever and worsening dehydration, she was hospitalized on March 31. When examined one day after admission, the child was first noted to have hypotonic extremities (lower more than upper) with depressed deep tendon reflexes. The cerebrospinal fluid on April 2 contained 228 mg/lOO ml protein and 1 mononuclear cell/mm3. Over the next three days nearly complete tetraplegia developed. An electroencephalogram showed a normal pattern for the patient’s age. Her neurologic status remained stable for a week, after which her muscular strength began to improve quite rapidly. The second specimen of spinal fluid, which was obtained on April 8, contained 320 mg/lOO ml protein and no cells.
VIRAL STUDIES Viral antibody tests were performed in microtiter by the methods of hemagglutination-inhibition (HAI) for measles, mumps and rubella and complement-fixation (CF) for herpes simplex, cytomegalovirus and varicella-zoster. The Epstein-Barr virus antibody tests were carried out in the laboratory of Drs. Werner and Gertrude Henle at the Children’s Hospital of Philadelphia by the same fluorescent methods as previously described [I]. Serums were collected in Case 1 on the 6th and 16th days after the administration of live measles-rubella vaccination (M-R-VAX, Merck Sharp and Dohme). The measles antlbody titer was less than 1:8 In the serum obtained during the acute stage and I:64 in the serum obtained during convalescence: the rubella titer was I:256 in both serums. Serums in Case 2 were obtained 6, 21 and 55 days after the administration of live measles vaccine (Attenuvax, Merck Sharp and Dohme). The measles antibody titer was less than I:8 in the first serum and I:64 in the second and third serums. The three serums were also tested for antibodies to the following viruses: rubella, mumps, herpes simplex, EpsteinBarr virus, cytomegalovirus and varicella-zoster; all serums were negative. Both patients had throat swabs and urine samples collected within 48 hours of admission and inoculated into various cell cultures. The specimens in Case 1 were negative for virus-isolation. The throat swab in Case 2 contained poliovirus type 1 (presumably vaccine strain) as identified by neutralization with reference enteroviral antiserums: a second throat swab taken 11 days later did not demonstrate either poliovirus or other viruses.’ The urine sample did not yield any virus.
442
March 1978
The American Journal of Medicine
COMMENTS
In their survey live measles not include drome. This with natural
of the neurologic
vaccination [2] any cases of syndrome has (wild) measles
disorders
following
Landrigan and Witte did the Guillain-Barre synoccurred in association infection [3,4] and, like
other neurologic sequelae of measles, could be expected to follow attenuated (vaccine) measles infection also. Although one of the patients in this report
had combined measles-rubella vaccine, a rubella HAI antibody titer of I:256 is not compatible with a primary vaccine-rubella infection of six days’ duration but instead indicates that this child was already immune to rubella when immunized [5]. Both patients had a primary measles (vaccine-strain) infection as demonstrated by the seroconversion following immunization. The poliovirus type 1 which was isolated from the second child was not considered to be etiologically related to the patient’s disease which in no way resembled the neurologic manifestations of poliovirus. The isolation of only type 1 poliovirus seven days after her second trivalent OPV probably indicated that an immunity to poliovirus types 2 and 3 had developed after her first OPV at age two months. The absence of poliovirus from her second throat swab demonstrated an appropriate primary immune response to and eradication of poliovirus type 1 from her oropharynx. The time interval between vaccination and onset of the peripheral neuropathy was less than 1 week in both cases. We have also described a child in whom a peripheral facial palsy developed during the late incubation period of a wild measles infection, before the appearance of measles HAI antibodies [6]. Taken together, these three cases suggest an occasional role for measles virus (both vaccine and wild strains) in the pathologic process which leads to demyelinization. By testing for various viral antibodies in serum obtained during the acute and convalescent stage in the younger patient, we determined that the Guillain-Barre syndrome could occur in a patient who had no serologic evidence of past or recent infection with any of the four human herpes viruses: herpes simplex, varicella-zoster, Epstein-Barr virus and cytomegalovirus. The Guillain-Barre syndrome, therefore, does not appear to be simply the manifestation of a reactivation of a known latent herpes virus infection. These two cases again emphasize the need to carefully document the neurologic diseases which follow infections with live viral vaccines. Of utmost importance are serums obtained during the acute and convalescent periods for appropriate viral antibody titers.
Volume 60
GUILLAIN-BARRE
SYNDROME-GROSE,
SPIGLAND
REFERENCES 1.
2. 3.
Grose C, Henle W, Henle G, Feorino PM: Primary EpsteinBarr virus infections in acute neurolooic diseases. N Enol J Med 292: 392, 1975. Landrigan PJ, Witte JJ: Neurologic disorders following live measles virus vaccination. JAMA 223: 1459. 1973. Miller HG, Stanton JB, Gibbon JL: Para-infectious encephalomyelitis and related syndromes. Cl J Med 25: 427, 1956.
4.
5.
6.
March 1076
Lidin-Janson G, Strannegard 0: Two cases of Guillain-Barre syndrome and encephalitis after measles. Br Med J 2: 572, 1972. Cooper LZ, Giles JP, Krugman B: Clinical trial with live attenuated rubella virus vaccine, HPV-77 strain. Am J Dis Child 115: 655, 1968. Pollack MA, Grose C, Friend H: Measles associated with Bell’s palsy. Am J Dis Child 129: 747, 1975.
The American Journal ol Medkine
Volume 60
443
