More MS news articles for April 2002
Herpesvirus Six and Multiple Sclerosis: Clinical Treatment and Relationships
K.K. Knox¹, L.J. Lobeck², E.F. Maas², and D.R. Carrigan¹.
Institute for Viral Pathogenesis¹, 10437 Innovation Drive, Milwaukee,
Wisconsin and Department of Neurology, Medical College of Wisconsin²,
9200 W Wisconsin Ave, Milwaukee, WI 53226
Presented at the 54th American Academy of Neurology Annual Meeting;
Several laboratories, including our own, have presented data linking
the pathogenesis of MS to active HHV-6 infections. Blood samples were obtained
at the time of new clinical relapse in patients with relapsing-remitting
MS and assessed for active HHV-6 infection by plasma PCR. Then, several
weeks later (mean interval:68 days), a second blood sample was obtained
from the same patients and assessed for active HHV-6 infection. Patients'
changes of Expanded Disability Status Scale (EDSS) from the relapse and
treatments at the time samples were obtained were noted. Five of
39 (13%) patients had at least one sample positive for active HHV-6 infection.
Variant typing of the positive samples was possible with 3 of the 5 positives,
and 2 were HHV-6 variant A. Four of the five (80%) positive samples
were obtained at the time of relapse whereas only one (20%) positive was
observed in a patient after relapse. The HHV-6 positive patients
suffered a larger change in their EDSS (mean EDSS change of 1.4) than the
HHV-6 negative patients (mean EDSS change of 0.7). It was also found that
the patients receiving either beta interferon or glatirimar acetate (copaxone)
were less likely to be HHV-6 positive (2/30; 7%) than the patients receiving
no treatment 3/9; 33%). Since the majority (>75%) of the patients
on therapy were receiving beta interferon, the decreased positivity
for active HHV-6 may reflect the known antiviral properties of beta interferon.
Patients And Methods
In a recently published study, Knox et al. (Clin Infect Dis 2000; 31:894-903)
identified, by means of a rapid culture assay, active HHV-6 viremia in
54% (22/41) of patients with MS. HHV-6 viremia was not detected in
61 healthy controls.
Additional studies [Lobeck et al.; American Academy of Neurology, 2000]
demonstrated a significant relationship between active HHV-6 viremia, as
detected by a rapid culture assay, and disease relapse in patients with
relapsing/remitting MS.MS patients.
Based on these findings and the tropism of HHV-6 for blood leukocytes,
the possibility was raised that the CNS lesions of MS are the result of
invasion of the CNS by HHV-6 from the peripheral blood.
Patients and Controls
Thirty-nine patients, with relapsing remitting MS had blood samples drawn
at the time of a clinical relapse.
No patients were receiving corticosteroids when the specimens were drawn.
Most patients received corticosteroid treatment after onset of their disease
A second blood specimen was drawn from 36 of the same patients six
to ten weeks later after the relapse had resolved.
Any treatment that the patients were receiving at the time of the first
blood specimen was noted. Also, the changes in the patients' Expanded
Disability Status Scale (EDSS) score due to the disease relapse were determined.
46 control plasma specimens were obtained from six healthy donors over
a mean period of 140 days (range 62 days to 183 days).
Detection of Active HHV-6 Infections by Plasma PCR
DNA was purified from plasma samples by means of a commercially obtained
kit [QIAmp DNA Blood Mini Kit; QIAGEN Inc.; Valencia, California].
DNA PCR was performed using a hotstart taq DNA polymerase system [TaqBead
Hot Start Polymerase; Promega Corp.; Madison, Wisconsin]. The HHV-6 specific
primer pair used has been described in detail previously (Drobyski et al;
NEJM 1994; 330:1356-1360). This PCR system can detect approximately
200 viral genomes per ml of plasma (5 genomes per PCR reaction).
Quantitation of the PCR reaction was accomplished by amplification of a
quantitative DNA target control. The HHV-6 variant involved in the
positive samples was determined by means of variant specific restriction
Incidence of Active HHV-6 Infections in MS Patients at Time of Relapse
Compared with Healthy Control Individuals.
Results are summarized in figure below.
Significantly increased incidence of active HHV-6 infection was observed
with both rapid HHV-6 culture and plasma PCR.
Rapid culture was significantly (p < 0.004) more sensitive than plasma
PCR at detected the active HHV-6 infections.
Characteristics of the MS patients who were positive for
active HHV-6 Infection by plasma PCR (Table Below).
Patients 1 through 4 were positive for active HHV-6 infection at the time
of disease relapse.
HHV-6 positive patients did not significantly differ from HHV-6 negative
patients with respect to age, gender, disease duration or disease type.
Viral loads varied from 9000 genomes per ml to 500,000 genomes per ml.
Two of the three viruses typed as to variant were HHV-6 variant A.
Relationship Between Positivity for Active HHV-6 Infection
by Plasma PCR and Treatment Regimens
Relationship Between Positivity for Active HHV-6 Infection
by Plasma PCR and Change in EDSS score by Disease Relapse
Relationship Between Tumor Necrosis Alpha (TNFa) And Active HHV-6
Infection in MS Patients
Patients with MS have significantly elevated levels of TNFa mRNA in their
peripheral blood leukocytes (p < 0.0001) and TNFa protein in their plasma
(p < 0.005) compared to healthy controls.
No relationship was observed between TNFa mRNA or protein and active HHV-6
The major findings of these studies can be summarized as follows:
Cross sectionally, at least 13% of patients with definite MS have active
systemic infections with HHV-6 as detected by plasma PCR.
The proportion of MS patients with active systemic infection with HHV-6
is disproportionately high at the time of clinical relapse.
The majority of the active HHV-6 infections in MS patients involve the
A variant of the virus.
The viral loads in the sera of the HHV-6 positive patients range from 10,000
to 500,000 viral genomes per milliliter.
Patients with active HHV-6 infections at the time of relapse show a greater
degree of residual disability than HHV-6 negative patients.
Patients who are receiving beta interferon or copaxone therapies are at
reduced risk for active HHV-6 infections.
© 2001, 2002 Institute for Viral Pathogenesis