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Diagnosing encephalitis Consider human herpesvirus type 6.

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References
1. Gordon WS. Advance in veterinary research. Vet Res 1946;58:
516 –520.
2. Chandler RL. Encephalopathy in mice produced by inoculation
with scrapie brain material. Lancet 1961;1:1378 –1379.
3. Gajdusek DC, Gibbs CJ Jr, Alpers M. Experimental transmission of a Kuru-like syndrome to chimpanzees. Nature 1966;
209:794 –796.
4. Duffy P, Wolf J, Collins G, et al. Possible person to person
transmission of Creutzfeldt–Jakob disease. N Engl J Med 1974;
290:692– 693.
5. Will RG, Ironside JW, Zeidler M, et al. A new variant of
Creutzfeldt-Jakob disease in the UK. Lancet 1996;347:
921–925.
6. Collinge J, Sidle KCL, Meads J, et al. Molecular analysis of
prion strain variation and the aetiology of “new variant” CJD.
Nature 1996;383:685– 690.
7. Bruce ME, Will RG, Ironside JW, et al. Transmissions to mice
indicate that ‘new variant’ CJD is caused by the BSE agent.
Nature 1997;389:498 –501.
8. Hill AF, Desbruslais M, Joiner S, et al. The same prion strain
causes vCJD and BSE. Nature1997;389:448 –526.
9. Brandel JP, Heath CA, Head MW, et al. Variant Creutzfeld–Jakob disease in France and the United-Kingdom: evidence for
the same agent strain. Ann Neurol 2009;65:250 –257.
10. Prusiner SB. Prions. Proc Natl Acad Sci U S A 1998;95:
13363–13383.
11. Parchi P, Castellani R, Capellari S, et al. Molecular basis of
phenotypic variability in sporadic Creutzfeldt-Jakob disease.
Ann Neurol 1996;39:767–778.
12. Gambetti P, Kong Q, Zou W, et al. Sporadic and familial
CJD: classification and characterization. Brit Med Bull 2003;
66:213–239.
13. Zeidler M, Stewart GE, Barraclough CR, et al. New variant
Creutzfeldt-Jakob disease: neurological features and diagnostic
tests. Lancet 1997;350:903–907.
14. Prusiner SB, Cochran SP, Groth DF, et al. Measurement of the
scrapie agent using an incubation time interval assay. Ann Neurol 1982;11:353–358.
15. Kong Q, Huang S, Zou W, et al. Chronic wasting disease of
elk: transmissibility to humans examined by transgenic mouse
models. J Neurosci 2005;25:7944 –7949.
16. Sanchez-Juan P, Cousens SN, Will RG, et al. Source of variant
Creutzfeldt-Jakob disease outside United Kingdom. Emerg Infect Dis 2007;13:1166 –1169.
17. Chadeau-Hyam M, Alperovitch A. Risk of variant CreutzfeldtJakob disease in France. Int J Epidemiol 2005;34:46 –52.
18. World Organization for Animal Health. Available at: http://
www.oie.int/eng/info/en_esbincidence.htm. Accessed November 26, 2008.
19. Abrial D, Calavas D, Jarrige N, et al. Poultry, pig and the risk
of BSE following the feed ban in France—ecological analysis.
Vet Res 2005;36:615– 622.
20. National Creutzfeldt-Jakob Disease Surveillance Unit
(NCJDSU). Variant Creutzfeldt-Jakob Disease: current data
(December 2008). Available at: http://www.cjd.ed.ac.uk/
vcjdworld.htm. Accessed November 26, 2008.
DOI: 10.1002/ana.21637
Potential conflict of interest: Nothing to report.
Diagnosing Encephalitis?
Consider Human
Herpesvirus Type 6
Despite the best modern diagnostic methods, the causes of
up to 60% of cases of suspected viral encephalitis remain of
unknown origin.1,2 The detection of DNA and human herpesvirus type 6 (HHV-6) antibodies in cerebrospinal fluid
(CSF) of 40% of encephalitis cases, reported in this issue by
Yao and colleagues,3 signifies progress toward solving this diagnostic problem.
Central nervous system (CNS) HHV-6 diagnostic tests are
valued for their ability to distinguish between the presence of
latent virus (as simply HHV-6 DNA in the CNS) and active
viral replication causing disease. The refinements in specimen
preparation, polymerase chain reaction, and serology techniques that Yao and colleagues3 present distinguish latent
and active infection, enabling their report of an association
between HHV-6 and encephalitis in immunocompetent subjects. Because the subjects ranged in age from 1 to 62 years,
presumably, some cases were primary infection and others
reactivation. Yet, individuals in most of the world acquire
HHV-6 through natural circumstances and do not become
sick. What the subjects with encephalitis had in common
besides the virus, the meaning of the authors’ results from a
pathogenesis perspective, will be of interest for future studies.
HHV-6 is one of the more recently identified herpesviruses. It was first isolated in 1986 from human peripheral
blood mononuclear cells of patients with lymphoproliferative
disorders4 but is now recognized as one of the most widespread of human herpesviruses. The lifetime consequences of
infection with HHV-6 are still not well known.
Most HHV-6 infections are benign, self-limited illnesses,
leading to its reputation as ubiquitous commensal. Primary
infection with HHV-6 usually occurs during infancy, as horizontal transmission through saliva. Most children are seropositive by age 2 years; worldwide, more than 90% of adults
have antibodies to the virus. Primary HHV-6 infection produces an acute nonspecific febrile illness, or fever followed by
a maculopapular rash beginning on the trunk and spreading
outward.5 Primary HHV-6 in adults, which is rare, causes a
mononucleosis-like syndrome.6
Now, two variants, HHV-6A and HHV-6B, with different biological, epidemiological, and perhaps, disease associations are known.5 Both HHV-6A and HHV-6B have been
isolated from blood of infected children, and both have been
recognized as brain commensals or normal brain flora.7–9
HHV-6B is the main agent that causes exanthem subitum.
Diseases linked to HHV-6A have been less clear. Confirmation of a causative role for HHV-6 in a particular illness,
except for exanthem subitum,10 has been slow or inconclusive because HHV-6 is widespread in the world population
and latent in blood leukocytes.
Historically, primary HHV-6 infection has been linked to
CNS syndromes and complications. Primary HHV-6 infection of either children or adults may cause CNS infection,
Solbrig: Encephalitis and HHV-6
235
because infected lymphocytes and monocytes arrive at the
CNS from the bloodstream. The clinical consequences of
HHV-6 CNS infection range from asymptomatic to febrile
convulsions and meningoencephalitis. A syndrome of seizures, ataxia, encephalopathy, opsoclonus-myoclonus, and
cranial neuropathies has been described with both types A
and B.11 HHV-6B has been isolated from peripheral blood
leukocytes and CSF of children with primary infection and
febrile seizures.7 HHV-6B encephalitis with seizures has been
reported in previously healthy neonates.9 HHV-6A, possibly
the more neurotropic variant, can be isolated more frequently from CSF than from saliva or peripheral blood leukocytes.12
After primary infection, the role of HHV-6 infection in
neurological disease is incompletely understood. The HHV-6
literature grows each year with the search for active infection
or reactivation in brain in patients with encephalitis, multiple sclerosis, progressive multifocal leukoencephalopathy, febrile seizures, and epilepsy using markers of infection: serology, antigen detection, polymerase chain reaction
amplification of HHV-6 DNA, or virus isolation. In Yao
and colleagues’3 study, documentation of pre-existing serum
antibodies at the start of the syndrome to distinguish primary infections and reactivation could have predictive value
for course or outcome, as well as descriptive value.
As with all herpesviruses, HHV-6 is able to perform two
distinct genetic programs: lytic replication and latency.5 After
HHV-6 exposure and primary infection, the virus establishes
lifelong latency. Sites of HHV-6 latency, where viral genome
integrates into host cell DNA, include lymphoid cells, bone
marrow, salivary glands, kidney, lung, and the CNS.5 Although HHV-6 DNA can be found at low levels in normal
brains, reactivation is thought to have a role in development
or expression of neurological disease in some patients. Reactivation of virus can occur after stem cell or bone marrow
transplant, during immunosuppression, pregnancy, hypersensitivity syndromes, critical illness, and acute infection with
other viruses (measles, influenza, dengue).13 Limbic and
rhombencephalitis syndromes have been described, and
HHV-6B proteins have been detected in hippocampal astrocytes in postmortem tissue of a limbic encephalitis patient.14
If many of the adult cases that Yao and colleagues3 reported
were reactivation, what were the triggers or comorbid conditions?
The fact that HHV-6 goes latent has generated extensive
literature concerning what constitutes infection. Yao and colleagues3 pair polymerase chain reaction testing of CSF for
nucleic acid sequences of two proteins encoded by the lytic
program with detection of virus-specific IgG and IgM antibody in CSF, as evidence of active replication and, therefore,
infection. The authors report their techniques recover cellfree viral sequences in CSF, which is important because viral
sequences in cell-free compartments would measure productive virus and exclude CSF inflammatory cells as the ones
harboring HHV-6 genome. A comparison of CSF white
blood cell counts with viral load would strengthen the case
for HHV-6 and true brain infection.
Both A and B variants use as a membrane receptor, the
ubiquitous molecule CD46, a member of a family of glycoproteins called regulators of complement activation present on
all nucleated human cells.15 Although both are shown to rep-
236
Annals of Neurology
Vol 65
No 3
March 2009
licate preferentially in human T lymphocytes, CD46 usage
supports the possibility of a broad cellular host range. In addition to T cells, neural cell lines of astrocyte, oligodendroglia, and neuronal origin, as well as primary human oligodendrocytes, are susceptible in vitro.16 HHV-6 antigen has
been found in oligodendrocyte nuclei of multiple sclerosis
patients,17 and HHV-6A DNA sequences associated with
mature viral particles were those detected in CSF of multiple
sclerosis patients.18 HHV-6B has been found in temporal lobectomy surgical specimens from epilepsy patients, together
with evidence of active HHV-6B replication in hippocampal
astrocytes in about two thirds of patients with mesiotemporal
sclerosis.19 Detection of high copy number HHV-6 DNA in
brain biopsy of an encephalitis patient in this study adds to
these neuropathology reports. If additional tissue were available, individual cells containing the viral genome and antigen
could be identified.
In conclusion, Yao and colleagues3 report detection of
HHV-6 DNA species signifying active infection from CSF
from a surprisingly high 40% of encephalitis cases. The result has implications for diagnosis, for use of standardized
molecular and serological tests across laboratories, and for
treatment. Ganciclovir is superior to acyclovir for HHV-6,5
but it treats only lytic phase infection. Finally, the study
shows the value of a large data set and well-characterized
patient registry in studying encephalitis. The banked materials represent a great resource for testing specific hypotheses as
to how virus biology and host mechanisms relate to clinical
disease expression.
Marylou V. Solbrig, MD
Departments of Medicine (Neurology) and Medical
Microbiology, University of Manitoba Winnipeg,
Manitoba, Canada
References
1. Glaser CA, Honarmand S, Anderson LJ, et al. Beyond viruses:
clinical profiles and etiologies associated with encephalitis. Clin
Infect Dis 2006;43:1565–1577.
2. Kupila L, Vuorin T, Vainionpaa R, et al. Etiology of aseptic
meningitis and encephalitis in an adult population. Heurology
2006;66:75– 80.
3. Yao K, Honarmand S, Espinoza A, et al. Detection of human
herpesvirus-6 in cerebrospinal fluid of patients with encephalitis. Ann Neurol 2009;65:258 –269.
4. Salahuddin SZ, Ablashi DV, Markham PD, et al. Isolation of a
new virus, HBLV, in patients with lymphoproliferative disorders. Science 1986;234:596 – 601.
5. Yamanishi K, Mori Y, Pellett PE. Human herpesviruses 6 and
7. In: Knipe DM, Howley PM, eds. Fields virology. 5th ed.
Philadelphia: Lippincott William & Wilkins, 2007:2819 –2845.
6. Akashi K, Eizuru Y, Sumiyoshi Y, et al. Brief report: severe
infectious mononucleosis-like syndrome and primary human
herpesvirus 6 infection in an adult. N Engl J Med 1993;329:
168 –171.
7. Hall CB, Long CE, Schnabel KC, et al. Human herpesvirus-6
infection in children: a prospective study of complications and
reactivation. N Engl J Med 1994;331:432– 438.
8. Tuke PW, Hawke S, Griffiths PD, Clark DA. Distribution and
quantification of human herpesvirus 6 in multiple sclerosis and
control brains. Mult Scler 2004;10:355–359.
9. Zerr DM, Meier AS, Selke SS, et al. A population-based study
of primary human herpesvirus 6 infection. N Engl J Med 2005;
352:768 –776.
10. Yamanishi K, Okuno T, Shiraki K, et al. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet 1988;1:1065–1067.
11. Crawford JR, Kadom N, Santi MR, et al. Human herpesvirus 6
rhomencephalitis in immunocompetent children. J Child Neurol 2007;22:1260 –1268.
12. Hall CB, Caserta MT, Schnabel KC, et al. Persistence of human herpesvirus 6 according to site and variant: possible greater
neurotropism of variant A. Clin Infect Dis 1998;26:132–137.
13. Razonable RR, Fanning C, Brown RA, et al. Selective reactivation of human herpesvirus 6 variant a occurs in critically ill
immunocompetent hosts. J Infect Dis 2002;185:110 –113.
14. Wainwright MS, Martin PL, Morse RP, et al. Human herpesvirus 6 limbic encephalitis after stem cell transplantation. Ann
Neurol 2001;50:612– 619.
15. Santoro F, Kennedy PE, Locatelli G, et al. CD46 is a cellular
receptor for human herpesvirus 6. Cell 1999;99:817– 827.
16. De Bolle L, Van Loon J, De Clercq , Naesens L. Quantitative
analysis of human herpesvirus 6 cell tropism. J Med Virol
2005;75:76 – 85.
17. Challoner PB, Smith KT, Parker JD, et al. Plaque-associated
expression of human herpesvirus 6 in multiple sclerosis. Proc
Natl Acad Sci USA 1995;92:7440 –7444.
18. Rotola A, Merlotti I, Caniatti L, et al. Human herpesvirus 6
infects the central nervous system of multiple sclerosis patients
in the early stages of the disease. Mult Scler 2004;10:348 –354.
19. Fotheringham J, Donati D, Akhyani N, et al. Association of
human herpesvirus-6B with mesial temporal epilepsy. PLOS
Med 2007;4:0848 – 0857.
DOI: 10.1002/ana.21635
Potential conflict of interest: Nothing to report.
Magnetic Resonance
Imaging as a Surrogate for
Treatment Effect on
Multiple Sclerosis Relapses
Despite the fact that acute white matter lesions are responsible for most, if not all, of the relapses in multiple
sclerosis (MS), the reported correlation between active
magnetic resonance imaging (MRI) lesions and relapses
in individual MS patients is weak. The potential reasons for this dissociation are multiple. For example,
most lesions do not appear to affect eloquent regions of
brain; a fact that, in itself, may explain much of the
poor correlation.1 In addition, new lesions may be
small or not associated with significant myelin or axonal injury,2 cerebral redundancy and plasticity may be
able to compensate for injury that does occur,3 and
some lesions that are associated with relapses may be
located in areas (eg, spinal cord or optic nerve) that are
not captured in routine brain imaging. Nevertheless,
the poor correlation of gadolinium enhancement with
relapses at the individual level has caused despair that
these MRI measures could provide a useful surrogate
marker for relapses in drug development.4
In this issue of Annals, Sormani and colleagues5 provide a meta-analysis of all of the published randomized,
placebo-controlled therapeutic trials in relapsingremitting MS that included data on MRI and relapses
(23 trials, 40 contrasts, 6,591 patients). Looking not at
the correlation between active MRI lesions and relapses
within individuals, but rather at the correlation between the effect of therapy on active lesions in clinical
trials and the effect of therapy on relapses in these trials,
they found a strong correlation that accounted for
more than 80% of the variance in the relation. This
successfully resolves the paradox of the only modest
correlation between MRI and relapses found at the “individual level” by demonstrating the expected correlation at the “trial level.”6,7 This strong correlation, obtained in so many different trials with so many
different classes of medication, is important. However,
it would be more important to establish that shortterm effects on MRI correlated strongly (and independently) with long-term outcome; an analysis that was
not attempted in this study.
Drug development in MS is becoming a victim of its
own success. In the United States, six disease-modifying
drugs are approved for treatment of multiple sclerosis
(interferon ␤-1a intramuscularly, interferon ␤-1a subcutaneously, interferon ␤-1b subcutaneously, glatiramer
acetate, natalizumab, and mitoxantrone). The same
number are in phase III trials (alemtuzumab, BG0012,
cladribine, daclizumab, FTY720, laquinimod, and teriflunomide), and many more are in earlier stages of clinical development. Because regulatory approval generally
requires two phase III studies, preferably with more than
one dose arm, showing superiority over placebo and/or
an active comparator, just the phase III studies of a new
drug require approximately 2,000 patients and several
years. Individual trials currently are being performed at
hundreds of sites in dozens of countries around the
world to enroll the required numbers of patients. The
increasing difficulty in finding the required numbers of
patients, the increasing cost of these trials, and the decreasing potential revenues for any individual drug as
more and more drugs are approved are combining to
challenge the feasibility of developing more effective
drugs for MS in the future.
Acceptance of the suppression of active MRI lesions
as a surrogate for the suppression of relapses at the trial
level would help to meet some of these challenges.
However, it would necessitate relaxing some of the theoretical criteria that Prentice8 proposed for surrogate
Arnold and Goodin: MRI and MS Relapse
237
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