Prospective Study Of Human Herpesvirus Six In Multiple Sclerosis
National Multiple Sclerosis Society Grant PP0618
Final progress report
January 30, 2000
Lorri J. Lobeck, M.D.
Department of Neurology
Medical College of Wisconsin
Konstance K. Knox, Ph.D. and Donald R. Carrigan, Ph.D.
Institute for Viral Pathogenesis
Scientific Summary of Research Progress
The purpose of this study was to validate the use of peripheral
blood specimens in detecting active human herpesvirus six (HHV-6.)
infections in patients with Multiple Sclerosis (MS). Prior to this
study, central nervous system and lymphoid tissues had been assessed
and confirmed the presence of active HHV-6. Use of these tissues
for routine study has limitations because of the need for invasive
procedures to obtain tissue. We have been successful in determining
the presence of active virus in samples of blood from individuals
Forty patients, with MS, had blood samples drawn at the time of
a clinical relapse. A second specimen was to be drawn four to six
weeks later. Cross sectional data is available on 37 patients. Paired
specimen data is available on 30 patients. These data include patients
with two specimens that were either positive or negative for the
presence of active virus on both specimens. Seven patients do not
have paired sample data, as they either had indeterminate specimens
or failed to return for the second blood sample to be obtained.
Indeterminate samples were those which were lost due to culture
toxicity. The remaining three patients had either two indeterminate
specimens or had one indeterminate specimen and failed to return
for the second blood sample. The conclusions reviewed below include
the cross sectional data and paired specimen data.
The cross sectional study of the incidence of HHV-6 viremia is illustrated
in Figure 1. Data from normal control subjects includes 50 healthy
blood donors from the Kansas City Blood Bank and 11 healthy laboratory
donors. The current study population is indicated as patients seen
at the Medical College of Wisconsin Multiple Sclerosis Clinic. Another
group of patients has been assessed in St. Lukes Medical Center
in Kansas City, Missouri. The findings confirm the presence of active
virus in the peripheral blood of patients with MS.
The clinical features of patients participating in the study are
reviewed in Figure 2. This cross-sectional data incorporates the
patients viral status at the time of the first blood sample only.
Some patients began immunomodulator therapy after the first sample
was obtained, but prior to the second. No significant clinical differences
were evident between the patients who tested positive or negative
for the virus on the first blood sample.
Figure 3 illustrates data from paired specimens. A significant number
of patients who were viremic at the time of a clinical relapse demonstrated
a lack of viremia when tested 6 to 10 weeks later. Future investigations,
to include more frequent samples, would provide insight into the
timing and pattern of the HHV-6 viremia.
Figure 4 illustrates the change in clinical status between the time
of the first and second blood sample in those patients with paired
specimen data. As would be expected, patients with relapsing MS
often experience improvement in their symptoms, although not always
a return to the pre-relapse condition.
The profile of HHV-6 viremia in paired specimens is further illustrated
in Figure 5. The majority of those patients testing positive on
the first sample, tested negative on the second, while those negative
on the first were most often negative on the second sample.
While the original proposal was to obtain samples 4 to 6 weeks apart,
some samples were delayed. This delay led to a fortuitous observation
that, as illustrated by Figure 6, more closely spaced samples tended
to test alike, and those separated by more time were more likely
to be different. This observation raises further questions about
the episodic nature of HHV-6 viremia in patients with MS. More frequent
and consistent sampling of individuals with MS should define the
pattern of viremia.
In conclusion, this project has been successful in demonstrating
the presence of active HHV-6 infection in the blood samples of individuals
with Multiple Sclerosis at the time of clinical relapse. The virus
was not detected in blood samples of normal controls. In addition,
several observations are described that suggest viremia is episodic
and variable in patients with MS. As a result, we feel additional
studies into the pattern of viremia are necessary to gain further
understanding of these observations. Further, we feel the use of
viral culture for HHV-6 should be incorporated into trials of anti-viral
agents for patients with MS as the presence or absence of virus
in peripheral blood may provide insight to which patients are most
likely to respond to treatment.
Release for the Public
Researchers at the Medical College of Wisconsin and the Institute
for Viral Pathogenesis have demonstrated the presence of active
human herpesvirus-6 infections, as measured by viral cultures, in
patients with Multiple Sclerosis coincident with new clinical relapses.
Prior to this study, the active virus infection had been detected
in specimens of brain or lymphoid tissue in some patients. The invasive
nature of these techniques led to the search to find other ways
to identify the active virus infection. These findings will hopefully
lead to other studies investigating the role of this virus in Multiple