Herpes
Zoster and Multiple Sclerosis
R.T.
Ross, Mary Cheang, Gail Landry, Loressa Klassen and Kathy
Doerksen
Abstract:
Background: Clinical experience suggests that young
multiple sclerosis patients may have herpes zoster (HZ) earlier
and more often than the general population. As there is evidence
of a relationship between varicella zoster virus (VZV) and
MS, a study of HZ and MS was undertaken. Methods:
Eight hundred and twenty-nine patient-members of the Manitoba
Chapter of the Canadian Multiple Sclerosis Society were surveyed
by mail. Six hundred and thirty-three (76%) responded. Questions
included: age at diagnosis of MS, history of HZ (yes, no,
probably), number of episodes of HZ and age at each occurrence,
date of birth, and sex of respondent. The controls were consecutive
patients with other neurological diseases (OND) attending
local neurological or neurosurgical clinics, plus practice-based
and population-based surveys of herpes zoster without reference
to any other disease. The OND controls were assessed at the
time of their outpatient visits. Results: In
the MS group with a positive/probable history of HZ, the HZ/MS
rate was 106/633 (16.8%); in the practice-based survey the
rate was 192/3534 (5.4%); and among the patients with OND
it was 42/616 (6.8%). The HZ occurred at an earlier age in
the MS group. The majority of male patients had HZ prior to
the diagnosis of MS. The date of diagnosis is more likely
to be a precise memory as opposed to the onset of symptoms.
More than one attack of HZ was also more common in the MS
group. Conclusions: This survey adds to the
evidence that patients with MS have a unique relationship
with the herpes zoster virus.
Résumé:
Herpes Zoster et sclérose en plaques. Introduction:
L'expérience clinique suggère que les
jeunes patients atteints de sclérose en plaques (SEP)
sont susceptibles de souffrir du zona plus tôt et plus
souvent que la population en général. Comme
il semble exister une relation entre l'herpesvirus varicellae
(HVV) et la SEP, nous avons effectué une étude
sur le zona et la SEP. Méthodes: Notre
enquête postale a porté sur huit cent vingt-neuf
patients, membres du chapitre manitobain de la Société
canadienne de la sclérose en plaques. Six cent trente-trois
patients (76%) ont répondu. Les questions suivantes
figuraient au questionnaire: l'âge au moment du diagnostic
de SEP, l'histoire de zona (oui, non, probablement), le nombre
d'épisodes de zona et l'âge au moment de chaque
épisode, la date de naissance et le sexe des répondants.
Des patients atteints d'autres maladies neurologiques (AMN),
qui se sont présentés de façon consécutive
à une clinique neurologique ou neurochirurgicale locale,
des études en milieu extra-hospitalier et des études
de population sur le zona sans référence à
toute autre maladie, ont servi de contrôles. Les contrôles
AMN ont été évalués au moment
de leur visite à la clinique externe. Résultats:
Dans le groupe SEP ayant une histoire positive/probable
de zona, le taux de zona/SEP était de 106/633 (16.8%);
dans l'étude extra-hospitalière le taux était
de 192/3534 (5.4%); et parmi les patients AMN il était
de 42/616 (6.8%). Le zona se retrouve à un âge
plus précoce dans le groupe SEP. La majorité
des hommes avaient eu leur zona avant le diagnostic de SEP.
La date du diagnostic était plus susceptible d'être
un souvenir précis contrairement au début des
symptômes. Il était plus fréquent d'observer
plus d'un épisode de zona dans le groupe SEP. Conclusions:
Cette étude appuie l'observations que les patients
qui ont une SEP ont une relation particulière avec
le virus de l'Herpes Zoster.
Can.
J. Neurol. Sci. 1999; 26:29-32
In
a treatment trial of 50 patients with multiple sclerosis (MS),
10 reported a history of herpes zoster (HZ).1 Eight
had HZ before the onset of MS and one had two attacks. There
are suggestions in the literature of a MS-varicella zoster
virus (VZV) relationship.2-4 There is a significant
geographic correlation between the prevalence of MS and varicella
in North America. Both have diminishing occurrence from north
to south.5 A distinctive population group in Western
Canada has significantly less varicella, MS and HZ than their
neighbours.6 In the tropics, varicella is often
a disease of late onset (average age 26), low contagion, and
is relatively uncommon. In these countries MS is extremely
rare.7
Methods
A
confidential, four-line questionnaire was mailed to the 829
patient-members of the Manitoba Chapter of the Multiple Sclerosis
Society of Canada. The questions were: age and sex of the
respondent; age at diagnosis of MS; a history of shingles
(answers: yes, probably, no); if yes, at what ages did the
shingles occur and how many times? There was no other identifying
information requested. Any responses with the same date of
birth, sex, and dates of MS and HZ were presumed to be duplicates
and only one was kept. There were 633 responses (76%), 463
female. The controls were unselected patients with other neurological
diseases (OND) attending local neurological and neurosurgical
outpatient clinics. When they had completed their outpatient
appointments they were asked if they would take part in a
four-question survey. The only information offered was: complete
confidentiality, the survey was not related to their present
illness, and was entirely voluntary. Ninety-eight percent
agreed to participate and were then handed a questionnaire
asking &endash; age and sex; have you had shingles (answers:
yes, probably, no); if yes, at what age and how many times?
No assistance was offered by the surveyor. Six hundred and
sixteen OND patients were surveyed (Table
1). Three hundred and twenty-two were female (52%), a
lower percentage than MS patients (63%). These patients were
also found to be generally older.
The
MS patients were also compared to a reported practice-based
study and a population-based study with respect to age at
diagnosis and number of episodes of HZ.8,9 The
mail and OND surveys were approved by the Ethics Committee
of the University of Manitoba, Faculty of Medicine, and the
Board of Directors of the Manitoba Chapter of the Multiple
Sclerosis Society of Canada gave permission for the mail survey.
No participating patient was identified. Consent was obtained
from all patients and controls according to the Declaration
of Helsinki.
Statistical
Methods
HZ
rates between groups were compared by calculating odds ratios
and 95% confidence intervals, along with a chi-square test.
Mantel-Haenszel stratified analysis by age and sex was performed
along with homogeneity of odds ratios assessed by the Breslow-Day
test.10 Logistic regression analysis also provided age and
sex adjusted ratios. Age specific rates from published population8,9
were used to generate expected rates of HZ in the MS samples
and OND controls. These expected numbers in the MS sample
were then compared to the actual positive HZ cases by chi-square
test. Significance levels were set at alpha = 0.05. Analyses
were computed using SAS 6.12 (SAS Institute, Cary N.C.) and
Statxact (Cytel Software Corporation).
Results
The
two surveyed groups were not precisely comparable. Of the
616 OND patients, 322 were female (52%), a lower percentage
than MS patients (63%). The OND patients were generally older.
As HZ increases with age, this alone makes the increased HZ
in the young MS group even more significant. The most common
features of the two groups were: they live in the same community,
and both attend neurological or neurosurgical physicians.
Herpes
zoster among the MS patients was defined in two ways: those
with a positive history of herpes zoster (72/633); and those
with a positive and/or probable history of herpes zoster (106/633).
An objective was to determine the age of onset of HZ among
the MS groups and therefore only MS patients with a positive
HZ history were assessed for this. The survey included the
question of whether the HZ preceded or followed the diagnosis
of MS because many MS patients receive corticosteroids or
other immune system modifying medications.
The
rate of HZ in the MS group with a positive and/or probable
history of HZ was 106/633 (16.8%). In a practice-based survey,
without reference to any other disease, the reported rate
was 192/3534 (5.4%),8 and in a group of patients
with other neurological diseases it was 42/616 (6.8%) (Table
2). The HZ rates in the MS group compared to the OND group
stratified by age groups and sex are homogeneous, giving an
odds ratio of 2.61:1. In the study of Hope-Simpson8 case ascertainment
was by personal contact in a 3500 member rural and urban practice
panel over 15 years.
The
incidence of HZ (positive only) among MS patients was 232.5
per 100,000 patient-years, giving an odds ratio of 1.86:1
relative to the population-based study of Ragozzino et al.9
in Rochester, Minnesota.
The
age of onset of HZ in the MS group with a positive history
of HZ is markedly different from the report of Ragozzino et
al.9 shown in Table
3A. The data consist of number of male and female cases
of expected HZ by decades based on a population-based survey
compared to the observed number from the current survey. Both
male and female rates of HZ are significantly different throughout
all decades. For males less than age 35 chi-sq = 10.92 for
2 degrees of freedom, p = 0.0042. For females chi-sq = 19.67,
p = 0.00005.
For
males, 90% (10/11) of the episodes of HZ occurred before age
35 and prior to the diagnosis of MS, while for females 55%
(12/22) occurred prior to MS (Table
3B). In a comparison of the mean age of individual patients
at onset of HZ in the MS group versus the patients with other
neurological diseases, the findings were: males MS 35.6 years
vs. OND 47.4 years, p = 0.042; and females MS 38.5 years vs.
OND 51.9, p = 0.0051.
In
Table 3B the age specific HZ rates are listed for the 633
MS patients included in the current study. Compared to the
expected linear increasing trends described in a practice-based8
and a population-based survey,9 rates for males
less than 35 and for females less than 44 years of age exceed
expectations. From 45 the trend is as expected for both sexes.
Age specific HZ rates for the OND controls, on the other hand,
reflect a linear increasing trend.
The
number of MS patients with two or more positive episodes of
HZ was 11/72 or 15.3% vs. 9/192 or 4.7% in a practice-based
survey.8 Odds ratio 2.42 (0.99, 5.92) p = 0.053.
In a population-based survey9 the rate for patients with two
or more episodes of HZ was 33/590 (5.5%), odds ratio for MS
patients 2.73 (1.32, 5.64) p = 0.0070.
Concerning
the MS patients with HZ and those without, there was no significant
difference between these two groups in the age at diagnosis
of MS, age at time of survey, or sex proportions.
Discussion
There
is general consensus that a childhood environmental factor
exists in multiple sclerosis. The purpose of the current study
was to enquire if there was any relationship between one of
the manifestations of varicella zoster virus infection, namely
herpes zoster, and MS.
This
study showed that a significant number of patients with MS
have a different history of HZ than the non-MS population.
Herpes zoster is more common in MS, occurs at an earlier age,
and has more repeated attacks than in the non-MS population.
The
other relationships between MS and the varicella zoster virus,
i.e., ages of onset, geography and climate, have been described
elsewhere.2,3,5-7
The
distribution of HLA antigen frequencies in the geographic
area of this study has not been published. However, the data
compiled by the local Organ Transplant, Immunology Laboratory
reveal frequencies of antigens A2 (22%), B7 (16%), and DQ1
(60%). This information is derived from tissue typing of over
200 donors and 200 recipients and are averages for the two
groups.11 A distinctive and isolated racial group,
the Hutterite Brethren, have highly significantly less varicella,
herpes zoster, and MS than their neighbours.6 Nevertheless,
they have gene frequencies of greater than 10% for antigens
A3, DR2, and DQ1.12 The paucity of varicella and
herpes zoster, and the accompanying low varicella antibodies,13
are due to the Hutterite practice of confining their children
exclusively to the Colonies for educational purposes up to
age 14. After this age the rate of varicella in the larger
community is very small.14 Whether raising children
in this restricted environment has anything to do with their
significantly lower rate of MS as adults is unknown.
Conclusions
This
paper adds evidence to a possible relationship between herpes
zoster virus infection and multiple sclerosis. It is part
of a number of studies that support this possible relationship.
These are:
1)
In North America where varicella is common so is multiple
sclerosis and where varicella is less common so is multiple
sclerosis.5 There are no reports or areas where
MS is common and varicella is rare.
2)
There is a north to south diminishing gradient of both diseases
in North America. For example, at latitude 52 degrees N, MS
is 11 times more common than at latitude 30 degrees N. The
frequency of varicella at these two latitudes parallels the
MS rates.
3)
In some tropical countries where multiple sclerosis is almost
unknown, varicella is an adult disease of low contagion, unlike
northern North American varicella.7
4)
A racially exclusive group (the Hutterite Brethren) that by
geographic location and genetic make-up should have a high
incidence of multiple sclerosis have a statistically significant
lesser amount of the disease and less varicella and herpes
zoster.6
5)
A possible explanation for the above is the fact that Hutterite
children are kept on the Colonies for educational purposes
and are relatively free of varicella until age 14. At this
age varicella in Canada is finished as an epidemic disease.14
6)
In addition to the population-based epidemiological information
in 4 (above), a varicella zoster virus antibody study of Hutterites
and controls revealed that many Hutterites are VZV seronegative.13
7)
Finally, the present paper adds one more apparent connection
between MS and a VZV manifestation. Perhaps the potential
or actual MS patient has less ability to contain the varicella
zoster virus than the rest of the population. May the VZV
act as an antigen mimic in these patients, as well as provoking
herpes zoster in some of them at an unusually early age? Whatever
the mechanism or relationship between the VZV and MS is it
true that no one will develop MS if they have not had a prior
VZV infection?
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