Thursday, October 25, 2007

Article & response

ARTICLE:

http://www.eastbourneherald.co.uk/features/ME-more-sufferers-more-support.3418542.jp

*ME: more sufferers, more support (Eastbourne Herald, 25 October 2007)*

Joanne Smith

How a local man used his own experience to bring chronic fatigue syndrome
patients together to talk

Oliver Rooke was 19 when he was struck down by glandular fever.

The Seaford resident was studying at Kent University when he first became
ill.

He said, "I went to the university doctor and did some tests and they came
through positive for glandular fever. She said to rest for about four - six
weeks and it would just pass."

But Oliver, now 31, was so ill that a couple of months later he had to leave
his course because he was suffering continuously from mental tiredness.

A year later he was diagnosed with Chronic Fatigue Syndrome (CFS).

Oliver said, "The unique thing about CFS is it's an umbrella term for lots
of things which may have different causes. Mine was triggered by glandular
fever and it can be triggered by stress or trauma."

The illness, which is also known as ME (Myalgic Encephalomyelitis) and can
affect anyone of any age, meant he was unable to return to university.

It is estimated that around 250,000 in Britain are affected by this illness
of unknown cause, which has many different names and symptoms.

Oliver said, "It's a case of managing the symptoms, managing day to day and
trying to live with the illness.

"They set up a clinic in Haywards Heath a couple of years ago that is seeing
patients who have been referred by GPs because they recognise the cases are
increasing."

Oliver's illness has affected him in that he sometimes has difficulty with
concentration, for example, reading a book, watching a TV programme or
playing a board game can be challenging for him. But other sufferers find
they are physically tired rather than affected mentally and may even
struggle to get out of bed.

Oliver says the best way forward is to keep positive and pace yourself when
doing various activities.


He is currently kept busy with running the Defenders of the Ouse Valley and
Estuary (DOVE) website and is a volunteer for Newhaven Community Employment
Partnership (NewCEP), which aims to assist local people to access work,
learning and volunteering opportunities.

Because of his illness Oliver decided to set up a local branch for fellow
sufferers two-and-a-half-years ago.

He said, "There were groups in existence in the area through the Sussex
ME/CFS Society (a registered charity). There were groups in Lewes and
Eastbourne and I went to a few of these and I thought I would try to start a
local group operating in Seaford to see what the reaction would be.

"In the early days it was quite small but as time has gone on it has
gradually grown and is now quite popular."

The group, which meets once a month at Nott's Coffee House in the town, chat
to each other about their symptoms and how they have been coping.

"It's general support, having someone to listen to and talk to.

"It's good for people because often others they speak to do not thoroughly
understand the illness and how it affects them."

Oliver, who is hoping to eventually work full-time in a job that is
computer-related, has been referred to the clinic in Haywards Heath where
various activities he does are being assessed.

The aim is to build up activities to a level he can manage without
stretching himself.

He added, "I think awareness is better now and this is particularly down to
the numbers of sufferers, more and more people are starting to suffer with
it and seeing their doctors and talking to their friends about it. There are
more people who know someone with ME or who have ME.

"I have to try and look at things, things could be worse and so I have got
to try and look at the positive and think of what I can do rather than what
I can't do.

"There are some people who can't get out of bed and are worse off than me."

Anyone who would like more information can call the information line on
01273 674828 or visit the website www.measussex.org.uk Or you can contact Oliver direct on 01323 896741 or e-mail him oliver@seaford.me.uk

RESPONSE:

It is illogical to consider M.E. (Myalgic Encephalomyelitis ) as, both,
synonymous with Chronic Fatigue Syndrome (CFS) and, at the same time, as an
illness subsumed under its umbrella; it can't be both. In fact, it is
neither. M.E. is a discrete neurological illness
and trying to treat them
the same is doing nobody any good. It is because chronic fatigue patients
are being added to M.E. sufferers and them all being thought of as people
with M.E . that the number is, erroneously, thought to be increasing (ME:
more sufferers, more support, Eastbourne Herald, 25 October 2007).

It is widely known and agreed that M.E. is frequently preceded by a virus,
such as glandular fever
, or, sometimes, by a vaccination, such as for TB or
Hepatitis or, perhaps, by chemical poisoning, though it is not certain
whether any of these is the "trigger" or cause. But, since there are no
figures for each of the suspected culprits, of which I am aware, it is
worrying that Oliver Rooke - and he is not alone in doing this - so confidently ascribes it to stress and trauma when, in 19 years, this Research Psychologist and M.E. sufferer has not known of a single one and believes that there is no evidence for any greater incidence of psychiatric history amongst M.E. patients than in the general population. This is a wild assertion that needs either backing with evidence or - as I believe - withdrawing as a myth that is very unhelpful for research and treatment of M.E.

* * *

Again, the flawed notion of stress and emotional illness is allowed to shout down the patients' own reports of "it started with a virus".  Evidence that there is no history of psychiatric problems in the majority of CFS/ME sufferers counts for nothing to the many "experts" who, in actuality, have no clue what they're talking about.

As my own experience demonstrates, if the doctor reads off a long enough list of potential stressors, he will eventually find something to blame your illness on.  Something as common as taking a vacation or changing jobs can be a source of stress; next time you get a cold, you should blame the vacation you took two months ago, and not a virus ... that's what these "experts" want CFS patients to do!

Yet, this Research Psychologist, who certainly knows more about psychological problems than the average MD, states confidently that he knows of NOT A SINGLE CASE of True ME/CFS that had a psychiatric origin.  There are psychiatricproblems which have fatigue as a symptom, but despite the prevailing notion that CFS and depression are identical, the fact is, there are many symptoms of CFS that are simply unheard of in depression, and a cortisol test can quickly prove which of the two a patient is suffering from.  If the patient does not improve when given anti-depressants, then it is quite clear which of the two the patient has ... anti-depressants have repeatedly been proven absolutely useless against CFS/ME.  They will work for someone who has depression who was given an erroneous CFS diagnosis, but not for someone who has that post-viral thing that used to be called Myalgic Encephalomyelitis and was renamed CFS.

If you're talking about the type of CFS that I have, the type of CFS that occurred in Incline Village which formed the basis of the original diagnostic criteria, then there is absolutely no proof whatsoever that stress is a "cause".  As with any illness, stress can make an existing health condition worse, but a stressor that occurs months later clearly is not a "cause" of the initial health problem.

And the big laugh is that while my doctors were telling me to "avoid stress", they were contributing to my stress by refusing to sign the application for disability benefits that would have reduced my financial stress substantially.  They couldn't bring themselves to practice what they were preaching.

Turning the Tide

Thanks to LKW for finding this one!

* * *

 

I wish I could determine precisely when this article was written, as it
would be helpful to know historically how long some, like the author Del
Kennedy, have realized exactly what is going on with the ME and CFS
'blending' these past 20 years (since the USA CDC made up 'CFS' (Fukada, et
al) in 1988.)

Certainly it's been clear to serious ME advocates like myself that others
before us and around the world have fought the good fight all along, against
the ever-increasing and skewed vested interest efforts. LKW

~~~

Turning the Tide

All over the UK, there are thousands of people debilitated and disabled by
this horrific disease, some bedbound, some in wheelchairs, many in constant
pain. But because their condition cannot yet be detected in a test-tube at
the local pathology lab, all of these desperately ill and suffering people
are labelled liars or loonies; all of the scientific evidence that there is
a real illness at work is dismissed out of hand; and those who highlight
this grotesque injustice are labelled paranoid and hysterical.

The history of the cover-up of ME by the Medical Establishment over the last
45 years is a nightmare story like no other. Quiet, painstaking scientific
research has been stonewalled by the Medical Establishment in favour of
contemptuous power-politics : denigration by design. If this were a
scientific debate, there would be no contest. ME Denial is a political
issue.

What makes the battle over the recognition of ME so significant is that we
seem to have a situation where the majority of the medical profession have
lost the humility to say "we don't know", and are prepared instead to defend
against any suggestion that there might be any ailment that they cannot yet
detect 'in a test tube'
on a per-patient basis. Technology has not only come
to dominate intellectual endeavour in the field of medicine; it seems to
have displaced it. 'Somatoform disorder' (psycho-somatosis or now,
'functional somatic syndrome') is the dustbin diagnosis at the end of a
battery of tests. Any other diagnosis requires positive evidence; the
diagnosis of somatoform disorder requires none. This is not science, and
should never be allowed to masquerade as such.

It seems to me that the only way out of the present impasse is to ensure
that every study into the cause or treatment of ME is conducted exclusively
with the most severely disabled sufferers. We have to get back to basics :
back to the original definition of ME - Melvin Ramsay's
. I am sure there are
many people whose lives have been devastated by this disease who would yet
fall outside Ramsay's narrow definition of ME. Many would fall within it in
the morning, and outside it in the afternoon, or vice-versa; my own
condition used to fluctuate between extremes.

But the more exclusive our definition, the more the psychiatrists' absurd,
nightmare bangwagon will be confronted with reality. Let's make them face
the truth. Let's put those in wheelchairs first.


Chronic Fatigue Syndrome is a term introduced in 1988 (32 years after the
discovery of ME) by the U.S. Centres for Disease Control (CDC). It was felt
at first by many British ME sufferers to be transparently contrived in order
to denigrate our illness and downgrade its priority below a level that might
warrant serious funding of research. Unfortunately, the two major British ME
charities were of another opinion.

NOTE: ME was 'discovered' earlier; it was 'formally recognized' later on
then. LKW


Everything that has happened since then has confirmed this first grassroots
impression. The new name was followed by new and ~broader~ diagnostic
criteria, until it became possible to conduct a study into CFS that might include not one single genuine ME sufferer.

Now there is a move to group a whole host of ludicrously unrelated
conditions (IBS, CFS, PMT, FMS, Temporomandipular Joint Pain, Tension
Headache, Atypical Chest Pain, MCS and Globus Hysterictis) together under an
even larger umbrella - "functional somatic syndromes". It's high time we
threw a spanner in the works of this drivel-factory; it's time we returned
to Ramsay.

Magna est veritas et praevalebit
(great is truth, and shall prevail).

Del Kennedy

Posted on: http://www.meactionuk.org.uk/tide.html


 

On a Personal Note

David Paulison of FEMA says "Nobody does disasters better than California". Yeah, maybe you and Heckuva-Job-Brownie should come out here and take a few lessons from the masters.

The difference is, our annual disaster drill isn’t a dry run like other states – between the fires and the earthquakes, our annual practice is the real thing, all hands on deck, this one really counts. Our state Office of Emergency Services has matters well under control before FEMA even knows there’s a problem. We don’t just have theory on how to move a thousand trucks of bottled water to the far end of the state; we’ve done it for real and often enough to have experienced all the possible difficulties.

My family in SoCal evacuated sequentially over the past few days: one aunt went to another aunt’s house. From there, they were evacuated to one son’s house, and from there to the other son’s, who wisely lives far enough from the other family members that he’s safe when they’re threatened (and vice versa). All well-planned (the aunts have planned their evacuations for decades, and have used those plans more than once) and orderly. Another cousin loaded the valuables into the RV and is camped out on a beach, again, all according to plan.

When I lived in San Diego, we had a canyon fire come within a mile of our house. Our biggest worry was whether one side of the family would be offended if we refugeed to the other’s family instead. We had a list of what to take with us, and were calmly boxing it up and setting it on the couch, positive that our list contained everything we would need, because it was based on the list my aunt had used for decades of evacuations from her house.

Tuesday, October 23, 2007

More evidence it's a virus, not psychological

Source: Journal of Clinical Virology Vol. 37 Supplement #1, pp. S33-S38 Date: December 2006 URL: http://www.sciencedirect.com/science/journal/13866532

Use of valganciclovir in patients with elevated antibody titers against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) who were experiencing central nervous system dysfunction including long-standing fatigue

Andreas M. Kogelnik(a), Kristin Loomis(b), Mette Hoegh-Petersen(c), Fernando Rosso(a,c), Courtney Hischier(b), Jose G. Montoya(a,c,*) a Stanford University School of Medicine, Stanford, CA, USA b HHV-6 Foundation, Santa Barbara, CA, USA c Palo Alto Medical Foundation Research Institute, Palo Alto, CA, USA * Corresponding author. E-mail address: gilberto@stanford.edu (J.G. Montoya).

Abstract

Background Twelve patients with long-standing symptoms of central nervous system (CNS) dysfunction were found to have elevated antibody titres to human herpesvirus-6 (HHV-6) and Epstein-Barr virus (EBV). All patients had four or more of the following neurocognitive symptoms: impaired cognitive functioning, slowed processing speed, sleep disturbance, short-term memory deficit, fatigue and symptoms consistent with depression.

Objectives We sought to determine whether elevated antibodies to EBV and HHV-6 indicated chronic viral activation in patients with CNS dysfunction and if their symptoms could be improved by suppressing viral activity with oral valganciclovir.

Study design Patients with high IgG antibody titers against HHV-6 and EBV who were suffering from central nervous system dysfunction and debilitating fatigue for more than one year (median 3 years, range 1-8 years) were treated with 6 months of valganciclovir in an open label study.

Results Nine out of 12 (75%) patients experienced near resolution of their symptoms, allowing them all to return to the workforce or full time activites. In the nine patients with a symptomatic response to treatment, EBV VCA IgG titers dropped from 1:2560 to 1:640 (p=0.008) and HHV-6 IgG titers dropped from a median value of 1:1280 to 1:320 (p=0.271). Clinically significant hematological toxicity or serious adverse events were not observed among the 12 patients.

Conclusion These preliminary clinical and laboratory observations merit additional studies to establish whether this clinical response is mediated by an antiviral effect of the drug, indirectly via immunomodulation or by placebo effect.

1. Introduction

Chronic fatigue syndrome (CFS) is a clinically defined condition characterized by severe disabling fatigue and a constellation of symptoms that prominently feature self-reported impairment of concentration and short-term memory, sleep disturbances, and musculoskeletal pain. Patients suffering from CFS typically experience these symptoms for 6 months or longer. Suggested etiologies of CFS include, but are not limited to: viral or bacterial infections, endocrine-metabolic dysfunction, immunological imbalance, neurally mediated hypotension and depression (Afari and Buchwald, 2003; Fukuda et al., 1994). Most prior studies have found laboratory evidence that EBV and HHV-6 are reactivated more often in patients with CFS than in healthy control subjects or disease comparison groups, but causal inferences have not been made from such an association.

Epstein-Barr virus (EBV) and human herpesvirus type 6 (HHV-6) are enveloped double-stranded DNA viruses belonging to the herpesviridae family. Both viruses are lymphotropic and neurotropic, and both are capable of producing latent infections with immunomodulatory effects (Ambinder, 2003; Ambinder and Lin, 2005; Krueger and Ablashi, 2003). Furthermore, in vitro studies of co-infection with both viruses have revealed that a significant interplay may occur between them (Cuomo et al., 1998; Flamand et al., 1993). The clinical consequence of this interaction remains unknown. However, it has been suggested by various investigators that infection with EBV and/or HHV-6 may trigger or contribute to the pathogenesis of certain diseases including chronic fatigue syndrome (Bertram et al., 1991; Sairenji et al., 1995) and multiple sclerosis (Hollsberg et al., 2005).

The seroprevalence in the adult population for EBV and HHV-6B is about 90% and most people undergo asymptomatic seroconversion. The high seroprevalence in the general population complicates the interpretation of serological tests in diagnosing reactivation of either virus. Unlike many other viruses, the DNA for EBV and HHV-6 are difficult to detect in either the peripheral blood cells or serum except in cases of primary infection or acute reactivation. Most (Ablashi et al., 2000; Manian, 1994; Natelson et al., 1994; Patnaik et al., 1995) but not all (Buchwald et al., 1996) studies that have examined antibody titers to HHV-6 and EBV in CFS patients have found that there is a significant difference between patients and controls: Manian found 55% of CFS patients had EBV VCA antibodies of 1:320 or above compared to 15% of controls (Horwitz et al., 1985). Sairenji et al. found that CFS patients had elevated antibodies to EBV, HHV-6, human herpesvirus 7 (HHV-7) and ZEBRA (a protein of the immediate early EBV gene BZLF1) compared to healthy controls (Sairenji et al., 1995). Highly elevated early antigen (EA) antibodies are considered indicative of active infection for both EBV and HHV-6. Both Patnaik and Ablashi found elevated antibodies to the HHV-6 EA antibody in CFS patients compared to controls (Ablashi et al., 2000; Patnaik et al., 1995).

HHV-6 and EBV infections can cause immunosuppression and HHV-6 can impair immune response to fungal infections (Cermelli et al., 2006; Sauce et al., 2006; Smith et al., 2005). We suspected that their symptoms could be the result of an immune dysregulation triggered by EBV and HHV-6, especially when reactivated jointly. Alterations in the immune system such as aberrant cytokine profiles have been proposed as the central abnormality in patients with other viruses such as parvovirus B19 (Kerr et al., 2003). Latent EBV and HHV-6 virus can also alter cytokines and induce sickness behavior (Glaser et al., 2006; Yoshikawa et al., 2002).

Valganciclovir is the only known antiviral drug with efficacy against both EBV and HHV-6 that can be administered orally. It has the potential for toxicity, but our experience in using the drug to treat reactivation of viral infections in immunocompromised patients (Gao et al., 2003; Montoya et al., 2001; Montoya, 2004) with minimal adverse effects has made us comfortable with this treatment. If patients are supervised properly, the risk of significant side effects is greatly reduced and antiviral treatment is manageable. We hypothesized that a long course (i.e. 6 months) of valganciclovir could effectively decrease or stop ongoing viral replication of both HHV-6 and EBV and result in a sustained clinical improvement (decrease in antibodies or resolution of lymphadenopathy and fatigue).

2. Materials and methods

2.1. Patients

Twelve patients, ages 21-57 (75% female) were referred to the Infectious Diseases Clinic at Stanford University Medical Center between February 2004 and August 2005 because of their history of chronic fatigue syndrome suspicious for infectious etiology. Patients had been seen by at least five other physicians (range 5-20). Other causes of fatigue had been appropriately excluded. The following laboratory tests were within normal limits in each of the patients who were tried on valganciclovir: complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), alanine aminotransferase (ALT), total protein, albumin, globulin, alkaline phosphatase, calcium, phosphorus, glucose, BUN, creatinine, electrolytes, and urinalysis. All patients met the CDC case definition for CFS (Fukuda et al., 1994) and all had neurocognitive complaints that included four or more of the following symptoms: impaired cognitive functioning, slowed processing speed, sleep disturbance, short-term memory deficit and symptoms consistent with depression. In addition, all had a history of a "flu-like" onset.

2.2. Drug regimen, toxicity monitoring, and fatigue evaluation Valganciclovir (VGCV) was prescribed as 900 mg twice per day for three weeks followed by 900 mg every day to complete a total of 6 months on the drug. Ganciclovir was approved in June 1989 by the United States Food and Drug Administration for the treatment and prophylaxis of diseases caused by cytomegalovirus (CMV). Ganciclovir has been used at Stanford Medical Center since 1987 for the treatment of several viral diseases observed in immunocompromised patients (Montoya, 2004). A second oral formulation (valganciclovir or L-valine esther of ganciclovir) was introduced in 1991 and achieves serum levels similar to those reached by the intravenous form.

CBC's were followed twice per week for three weeks, followed by once per week for three weeks, and once per month thereafter until VGCV was discontinued. None of the patients in our cohort was taking drugs with known adverse hematological or renal effects. While on VGCV, patients were instructed to report any new symptoms and on each medical visit they were explicitly asked whether they had experienced fever, chills, unusual bleeding or bruising, infection, unhealed sores or white plaques in mouth, headache, seizures or gastrointestinal symptoms. Pregnancy was not a consideration for any of our patients in the childbearing age; none of them was sexually active. At baseline, and again at each visit, patients were asked to report on their current activity level as a percentage of their pre-illness activity level.

2.3. Serological and molecular testing

In each of the 12 patients, the following serological tests were performed: EBV Viral Capsid Antigen (VCA) IgG and IgM antibodies, antibodies against EBV nuclear antigens (EBNA), antibodies against EBV early antigens (EA), HHV-6 IgG and IgM antibodies and CMV IgG and IgM antibodies (Focus Diagnostics, Inc., Cypress, CA, USA). HHV-6 and EBV testing was done by IFA and CMV tests were done by ELISA. The HHV-6 kits were purchased at Panbio (Columbia, MD) and the EBV kits are FDA approved kits sold by the Products division of Focus Diagnostics. At initial evaluation, each of the 12 patients had a polymerase chain reaction (PCR) test performed in serum for the following viruses: EBV, HHV-6, and CMV.

2.4. Statistical testing

To compare EBV and HHV-6 serologic titers before and after valganciclovir therapy among the 12 patients, paired non-parametric tests were performed (Sign test). To compare demographic and serologic variables between those who responded to valganciclovir and those who did not, the Mann ­Whitney test was used. Statistical analysis was performed using the Epi Info Version 3.3.2.

3. Results

As shown in Table 1, of the 12 patients, 9 "responders" had a dramatic improvement in their fatigue and central nervous system symptoms (p=0.007) and 3 "non-responders" failed to report any progress. Central nervous system symptoms such as "brain fog" and other cognitive abnormalities were among the first symptoms to improve. Most improvement of clinical symptoms occurred between weeks 6 and 12. In the first several months, significant improvement was observed in physical activity at home. Subsequently, each of the responders was able to return to work or full time activities. The new level of "near-normal" activity has been sustained for greater than 9 months (up to 31 months) after discontinuation of the drug at week 24 in each of the nine patients.

The mean age of the responders was 35.4 years (range: 14-57) and that of the non-responders 43 years (range: 28-52). Of the 9 responders, 9 (100%) experienced the onset of their chronic fatigue syndrome as a "flu-like" illness and 4 (45%) developed lymphadenopathy. Whereas of the 3 non-responders, only 1 (33%) had a "flu-like" illness at the onset of the disease and 1 (33%) developed lymphadenopathy. The activity level of both responders and non-responders was severely compromised, compared to pre-illness activity level, at baseline (10% in responders, 15% in non-responders).

All of the nine responders experienced an initial worsening of their already severe symptoms. This worsening occurred between weeks 2 and 4, and wassevere enough to make several patients stay in bed for several weeks. In one patient where the WBC differential data was collected, this worsening period coincided with a 25% drop in WBC count and an 80% drop in monocytes. The three non-responders did not experience this worsening in their symptoms.

None of the 12 patients experienced any side effects to VGCV that required its discontinuation or experienced abnormalities in their laboratory tests including clinically significant hematological toxicities.

IgG antibody titers against HHV-6 and EBV antigens at baseline and after valganciclovir therapy for the responders and non-responders are shown in Table 2. In responders, the median HHV-6 antibody titer dropped from 1:1280 to 1:320 (p=0.271) and the median EBV VCA titer dropped from 1:2560 to 1:640 (p=0.008). Two of the 3 non-responders had no significant change in their titers against EBV antigens after VGCV therapy and values were not obtained for the third. Two of the non-responders did not have elevated antibody levels that meet our current threshold for treatment, but had other evidence of a viral syndrome.

Of the 12 patients in our cohort, only one patient had a positive IgM for HHV-6 (patient #8). The 12 patients were negative for EBV VCA IgM antibody. Neither EBV, HHV-6 nor CMV DNA was detected by PCR in the serum; assessment of viral DNA on whole blood was not performed. Seven of the patients had high HHV-6 antibody titers (patients #2-6, 8, 9), five had elevated antibody titers to EBV (#1, 2, 6-8), and three had elevated antibodies to both viruses (#2, 6, 8).

Reduction in IgG antibody titers, duration of fatigue and level of activity change in 9 patients whose clinical improvement was associated with the use of valganciclovir are shown in Table 1. In three of the nine responders the EBV EA antibody dropped by four-fold or more. EBNA antibodies dropped in six of the nine responders. Of the 9 responders, 4 (45%) were positive for CMV IgG and 1 was positive for CMV IgM. Of the 3 non-responders, 2 were CMV IgG positive. Only one patient was positive for CMV IgM antibodies (patient #8).


Footnotes to Montoya Research

4. Discussion

This was an open-label study of valganciclovir (VGCV) in 12 patients with CFS and elevated antibody titers to both HHV-6 and EBV. VGCV treatment was associated with reduction in antibody titers in most patients. A majority of the treated patients also had dramatic improvement in activity level, although three did not. Obviously, a placebo effect is always possible in open-label studies. Many previous treatments had been tried in these 12 patients, without any benefit, suggesting that they were not placebo responders. Moreover, patients with CFS appear to be less likely than patients with other diseases to experience a placebo effect (Cho et al., 2005). Nevertheless, large randomized trials are essential before VGCV therapy is given routinely in patients with CFS and elevated antibody titers to HHV-6 or EBV. Based on our experience, such studies should probably be restricted to CFS patients whose illness began with an acute flu-like illness, which may be a minority of patients with CFS in the community at large (Solomon and Reeves, 2004).

Since HHV-6 is typically acquired by the age of two and EBV is generally acquired in early childhood or as a young adult, we interpreted the elevated titers as a sign of reactivated rather than primary infection. The antibody titers of the patients were considerably higher than those in 12 healthy controls, tested in the same laboratory. However, reference values for antibody titers against HHV-6 and EBV do vary by laboratory and variations of 1-2 dilutions in results on tests run on the same sample are considered common in most commercial laboratories. Focus Diagnostics, the laboratory used by Stanford for the EBV, HHV-6 and CMV serological tests, has a reference range that is higher than what has been reported in the literature (Savoldo et al., 2002; Straus et al., 1985; Tobi et al., 1982). At our request, Focus Diagnostics tested 12 healthy controls and the median titers were 1:80 for HHV-6 IgG and 1:320 for EBV VCA IgG. When fifty laboratory workers were tested at Focus, median values were slightly higher: 1:160 for HHV-6, and 1:640 for EBV VCA.

Although EBV EA antibodies dropped in three responders, it did not drop in the others, which was contrary to our expectations. Since antibody levels fall slowly over time, these results may understate the full extent of the drop. Antibody measures cannot determine whether a patient has an active viral reactivation. However, the fact that we observed falling EBV and HHV-6 titers concurrent with clinical recovery is significant. Larger studies and standardized assays are necessary to determine how useful these serological assays can be in identifying prospects for treatment. Molecular assays available in clinical laboratories were not informative. None of the responding patients was positive for HHV-6 or EBV DNA using an assay capable of detecting as few as 200 copies/ml. DNA of these viruses is typically detected only during a primary or acute infection. Better biomarkers are needed to identify reactivation of chronic disease and assess response to treatment.

Both HHV-6 and EBV can reactivate in a healthy person in response to an acute illness and normal controls can be found with elevated antibody titers to HHV-6 and EBV, especially in those under the age of thirty who are more likely to have had a recent primary infecton. This makes the assessment more complex and underscores the necessity of a careful evaluation by an experienced clinician, in order to differentiate between transient reactivation due to other illness, asymptomatic elevation of viral titers, and a chronic reactivated viral infection which would deserve treatment.

Clinical evaluation and a history suggestive of a viral etiology must remain the primary determinant for treatment. Treatment cannot be based solely on antibody levels or detection of viral DNA. In cases where humoral immune response is impaired, antibody levels may not be elevated at all or only slightly elevated above the mean. Also, there may be persistent viral infection in the CNS tissue with no trace in the peripheral blood. A prospective placebo controlled trial of valganciclovir is necessary to determine whether a subset of CFS patients would benefit from treatment. The fact that antibody titers to either HHV-6 or EBV dropped four-fold or more in several of these patients suggests (a) some if not all of these patients had active infections and (b) elevated antibody levels can be useful to confirm a suspicion of a chronic infecion that has reactivated.

In this study, treatment with oral VGCV did not produce any serious adverse effects, but it was not without some difficulties. As noted above, all of the responding patients reported some degree of worsening of their condition during their inital month of treatment. This worsening resembled a Jarisch ­Herxheimer-like reaction and included several days of myalgias, chills, headache, worsening of the "brain fog" and fatigue, and skin rash in some patients. The pathology of this response is unclear, but may be mediated by an immune response to transiently increased circulating viral antigen(s).

Adverse events for patients using VGCV is far higher for immunocompromised patients including those with AIDS-associated CMV retinitis and solid organ transplants with CMV disease. Neutropenia was reported to be 27% for retinitis patients (Roche Valcyte product information: (http://www.rocheusa.com/products/valcyte/) and 8% in solid organ transplants (Paya et al., 2004). In this small study, none of our patients experienced any hematological adverse effects or untoward reactions requiring the discontinuation of the VGCV.

Several other limitations of this study need to be acknowledged. We did not test for HHV-7 or distinguish between the HHV-6 A and B subtypes. Also, despite the fact that the improvements in physical activity and cognitive functions were dramatic and impressive, they were self-reported and not objective measurements. We are planning a double-blind placebo controlled trial with more comprehensive evaluation of the functional status of subjects, using established and validated instruments as well as better documentation of viral activity.

In summary, the results of this preliminary study suggest that a subset of patients with CFS and elevated antibody levels to HHV-6 and EBV may have an illness that is caused by reactivation of these viruses, and that is responsive to VGCV antiviral therapy. Further definition of this subset of patients with better and more standardized viral assays is required, as are large randomized controlled trials with long-term follow-up to confirm the possible value of antiviral therapy in patients with CNS dysfunction and symptoms of sustained fatigue. In addition, we propose a new medical term for the syndrome that may best describe our patient cohort: Virus Induced CNS Dysfunction. It may be applied to the subset of CFS patients who have elevated HHV-6 and EBV titers and clinical symptoms of a viral syndrome with neurocognitive complaints and sustained fatigue. Other viruses may also play a role in defining additional CFS patient sets.

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