The New England Journal of Medicine -- February 1, 2001 -- Vol. 344, No. 5
To the Editor:
We are troubled by the suggestion in the review article on multiple sclerosis by Noseworthy and colleagues (Sept. 28 issue) (1) that hepatitis B vaccine should be administered only to persons at substantial risk for exposure to the virus. The concern that hepatitis B vaccine may cause multiple sclerosis stems from case reports of demyelination beginning within months after vaccination. The World Health Organization and the Viral Hepatitis Prevention Board have reviewed preliminary results from ongoing controlled studies and other evidence. They have concluded that a causal association between hepatitis B immunization and demyelinating diseases of the central nervous system has not been demonstrated and that there is no need to change policies regarding immunization against hepatitis B. (2,3)
Decisions about immunization for patients with multiple sclerosis are best made by the patient and his or her physician. Immune stimulation from vaccination could theoretically exacerbate multiple sclerosis, but this possibility has not been specifically addressed for hepatitis B vaccine. The best available evidence on the safety of vaccination in patients with multiple sclerosis comes from a randomized, controlled trial of influenza vaccination, which found no differences in attack rates or disease progression between patients receiving vaccine and those receiving placebo. (4)
Hepatitis B causes
an estimated 4 million acute infections worldwide each year and is responsible
for tens of thousands of deaths from liver cirrhosis or primary liver cancer.
Hepatitis B vaccines are safe and highly effective. Unsubstantiated concern
that hepatitis B vaccine may cause or exacerbate multiple sclerosis must
be weighed against the very strong record of vaccines in protecting against
disease and death.
Thomas Verstraeten, M.D.
Centers for Disease Control and Prevention
Atlanta, GA 30333
1. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med 2000;343:938-52.
2. Lack of evidence that hepatitis B vaccine causes multiple sclerosis. Wkly Epidemiol Rec 1997;72:149-52.
3. Hall A, Kane M, Roure C, Meheus A. Multiple sclerosis and hepatitis B vaccine? Vaccine 1999;17:2473-5.
4. Miller AE, Morgante LA, Buchwald LY, et al. A multicenter, randomized, double-blind, placebo-controlled trial of influenza immunization in multiple sclerosis. Neurology 1997;48:312-4.
Noseworthy et al. note that cognitive impairment may become troublesome in patients with multiple sclerosis but do not develop the point further, except to state that prominent cortical signs rarely dominate the clinical picture. In fact, great strides have been made in the past five years in understanding the patterns and severity of cognitive impairment in the various forms of this disorder. Classically, patients with multiple sclerosis have been found to have bradyphrenia, impaired attention and concentration, reduced manual speed and dexterity, and defects in memory retrieval. (1,2) However, recent research has also demonstrated different degrees of cortical language deficits, including impairments in naming, aural comprehension, and letter and category fluency, in patients with the relapsing-remitting and chronic progressive forms of multiple sclerosis. (3)
Another recent study demonstrated that cognitive and other neurologic deficits referable to cortical sites may be caused by lesions at the gray matter-white matter junction and that cognitive dysfunction in patients with multiple sclerosis may progress rapidly, even in the absence of motor deficits or other evidence of clinical deterioration. (4) Finally, a recent study of rates of global and regional cortical cerebral glucose metabolism demonstrated significantly reduced rates in patients with multiple sclerosis as compared with normal controls. (5) These reductions in the rate of cerebral glucose metabolism correlated well with the total area of the lesion, as well as with the degree of cognitive dysfunction, indicating that the lesion burden in white matter is associated with a deterioration of neural function in the cerebral cortex. (5)
For these reasons,
initial and serial neuropsychological assessments of patterns of deficit
can have an important supporting role in the diagnosis of multiple sclerosis,
as well as in the ongoing assessment of disease progression, and neurocognitive
rehabilitation can help patients circumvent their deficits.
J.P. Newman, Ph.D.
Hadassah University Hospital
91120 Jerusalem, Israel
1. Lezak MD. Neuropsychological assessment. 3rd ed. New York: Oxford University Press, 1995.
2. Foong J, Rozewicz L, Chong WK, Thomson AJ, Miller DH, Ron MA. A comparison of neuropsychological deficits in primary and secondary progressive multiple sclerosis. J Neurol 2000;247:97-101.
3. Friend KB, Rabin BM, Groninger L, Deluty RH, Bever C, Grattan L. Language functions in patients with multiple sclerosis. Clin Neuropsychol 1999;13:78-94.
4. Jeffery DR, Absher J, Pfeiffer FE, Jackson H. Cortical deficits in multiple sclerosis on the basis of subcortical lesions. Mult Scler 2000;6:50-5.
5. Blinkenberg M, Rune K, Jensen CV, et al. Cortical cerebral metabolism correlates with MRI lesion load and cognitive dysfunction in MS. Neurology 2000;54:558-64.
The letter by Drs. DeStefano and Verstraeten makes several important points. Although there has been controversy with regard to a possible association between the administration of hepatitis B vaccine and multiple sclerosis, studies conducted to look for a relation have found no evidence of an association, (1,2,3) and this result is further supported by two articles in this issue of the Journal. (4,5) The Viral Hepatitis Prevention Board concluded that the data available did not demonstrate a causal association between hepatitis B vaccine and demyelinating diseases of the central nervous system, and that all countries should maintain established hepatitis B immunization programs and develop universal-immunization programs for infants and adolescents. (6) Careful scientific study can almost never completely discount reports of strong temporal associations between a small number of cases of a relatively common illness and widespread exposure to a vaccine. However, we accept that such associations cannot be the basis for alterations in important public health initiatives. Others have concluded that coincidence is the most plausible explanation for any temporal association between vaccination and multiple sclerosis. (7)
We view this as an important clarification, since national health policy in the United States and other countries recommends universal hepatitis B immunization for infants and adolescents. This policy has benefited public health by substantially reducing the considerable morbidity and mortality associated with acute and chronic hepatitis B infection. Readers should, therefore, be aware that the best scientific data available do not demonstrate an association between hepatitis B immunization and multiple sclerosis.
We agree with the statement by DeStefano and Verstraeten that the decision about whether or not to administer hepatitis B vaccine to patients with multiple sclerosis is "best made by the patient and his or her physician." This was the spirit underlying the statement in our article, and we regret that it appeared to question the wisdom of global hepatitis B immunization. The concern expressed in our article should not diminish the importance of hepatitis B immunization for children worldwide. The absence of definitive evidence of an association and the apparent safety of immunization against influenza suggest that hepatitis B vaccine is usually safe for patients with multiple sclerosis. The two reports in this issue of the Journal provide reassurance that hepatitis B vaccination is safe in patients with multiple sclerosis. (4,5) If there is continued concern about the apparent development of multiple sclerosis or the worsening of existing inflammatory demyelinating disease, the question might best be studied prospectively with magnetic resonance imaging, as we stated in our review.
Dr. Newman correctly
highlights several of the advances that have been made in our understanding
of the neurobehavioral consequences of multiple sclerosis.
John H. Noseworthy,
Gregory A. Poland, M.D.
Rochester, MN 55905
Editor's note: Dr. Poland receives funding from Merck Research Laboratories.
1. Sadovnick AD, Scheifele DW. School-based hepatitis B vaccination programme and adolescent multiple sclerosis. Lancet 2000;355:549-50.
2. Shaw FE Jr, Graham DJ, Guess HA, et al. Postmarketing surveillance for neurologic adverse events reported after hepatitis B vaccination: experience of the first three years. Am J Epidemiol 1988;127:337-52.
3. Lack of evidence that hepatitis B vaccine causes multiple sclerosis. Wkly Epidemiol Rec 1997;72:149-52.
4. Confavreux C, Suissa S, Saddier P, Bourdes V, Vukusic S. Vaccinations and the risk of relapse in multiple sclerosis. N Engl J Med 2001;344:319-26.
5. Ascherio A, Zhang SM, Hernan MA, et al. Hepatitis B vaccination and the risk of multiple sclerosis. N Engl J Med 2001;344:327-32.
6. Hall A, Kane M, Roure C, Meheus A. Multiple sclerosis and hepatitis B vaccine? Vaccine 1999;17:2473-5.
7. Monteyne P, Andre
FE. Is there a causal link between hepatitis B vaccination and multiple
2001 by the Massachusetts Medical Society.