QUESTIONS and ANSWERS with Dr Nancy Klimas

From Wellington Patient Lecture date 8th September 2006

By Jill Diprose



What is HHV6 virus ? and what is the therapy?

HHV 6 is a virus, there are two  types  - a and b. We are talking  about type a. It is the virus that causes measles in childhood, usually lasts maybe 3 days. Therefore all of us have had it, and it  is usually held in check our immune system.

Some believe it to be the set up virus for epilepsy and there is  large body of work implicating it in MS (at least in a subgroup). They are just beginning clinical trails of therapy at the NIH for MS.

Now HHV6 is being studied in CFS and  it appears to be playing a role in at least  a  subgroup of CFS patients. Remember Peterson and Knox had showed it in spinal fluid. HHV6 definitely shouldn't have been there and the big gun treatments for the virus are valid in those proven cases.

The exciting new research was the work by Dr Jose Montanya at the University of Stanford . He is new to the CFS world and his first study was based on serology .ie high antibody levels (4 fold + incr  to both HHV6 and EBV) . He  was using the new oral valgancyclovir. It was a great small study, titres went down,  9/12
patients improved  meaning they went back to work.

He is now funded and up and running doing a phase 2 trial (i.e. having a placebo control arm). It is after phase 3 trails that a medicine is able to be called "standard of care" and be released general use.

Check out HHV6 Foundation Website at
http://www.hhv-6foundation.org/. They are a committed group of researchers doing great work and raising money for research.
The researchers  intend to make testing available in the near future.


How do you prove disability/severity  which test is best from the list of about 30 tests that I've been looking at on a website.  Is SPECT the best test?

SPECT shows lots of aberrant things but Dr Klimas said she wouldn't use it to prove disability, as it is costly.

Dr Klimas proves CFS disability from:

     *   Immune Activation Panels : (DR, CD26      expression, TH2 cytokine shift, proinflammatory  cytokine expression TNF-a, IL-1, IL6)

     *   + Functional defects : (NK cell dysfunction,      CD8 abnormalities, decreased perforins,     granzymes, macrophage abnormalities,
     antibody production.)



Q. Are these available in New Zealand?

A. "Putting panels together shouldn't be a problem". These kinds of tests are not routine, but they should be do-able by immunologists here. The subtle endocrine abnormalities  low cortisone, small adrenal gland. Cognitive Assessment  psychological  tests to confirm a drop in IQ (can be done with reference to occupation and past employment proficiency records  superior intelligence back to average intelligence for example). Tests can show  - Short term memory problems;
attention loss; concentration loss ; reduced  ability to process complex numbers i.e. problems with "working memory".


The problem is that you need a pre illness reference or the fact that your job has to require that you need a certain level of competency. Sleep studies. (very objective  very little stage 3 and 4 sleep, often stuck in stage one or alpha sleep stage alpha wave intrusion pattern) 5.  Viral serology is sometimes helpful eg
elevated antibodies to HHV6, EBV MRI scans  show higher number of   hyperintensity white spots  areas of inflammation.
Normals have say 5, CFS patients 20-30. Tilt table (very objective)


So given the evidence of an inflammatory response, wasn't the old name, ME,  better than CFS?

Sure, ME is a much better name. The problem is that we've fought so hard in the US to get recognition as CFS, and there is a social security ruling under that name, that changing it now would cause a lot of issues. I'm just trying to get slash(/) ME into it. i.e. CFS/ME


Does duration of the disease matter in terms of likelihood of recovery?

Two  issues:

1. There seems to be a myth around that says that the longer you've had CFS, the less likely you are to recover. Nancy said she hasn't seen a study that shows this. (The problem is that the issue HASN'T actually been studied at all)

2. But on the other hand Nancy thinks duration does matter in terms of doing studies. There are inevitably going to be differences between a  person who has been ill 20 years versus a person who has been ill for 2 years . There could be a host of other contributing factors in the longer term patient, but that
doesn't mean they can't get better especially with newer treatments. Studies should be comparing apples with apples, not apples with apples + a whole host of other things.

The big compounding factor she mentioned was menopause. There has not been one study on the effect of female hormones in this illness, yet we know as clinicians that the illness shifts in nature/severity in the peri-menopausal woman, is different again in menopause, and different again post menopause.

Should we use hormone replacement therapy post menopause?

After the big heart/stroke scare with HRT last year a lot of Dr Klimas's patients came off HRT. Within 9 months they were all begging to go back on it. Clearly not having the hormones made them "much, much worse". It begs the question that whilst well women can come off HRT, what does it mean to a body with ME
and messed up hormones? What does it tell us? Nancy goes on  patient report, tries to keep to lowest doses, checks lipids, watches weight  and other risk factors etc. But basically said she doesn't have guidelines because yet again there is no good research  to go from.


Why is there a Type 2 shift?

By measuring the number of Type 1 lymphocyte cells and comparing them to Type 2 lympocyctes, we find more of the Type 2. We also find a fewer numbers and poorer functioning
Natural Killer cells which is an outcome of this shift. We proved  that this was implicated in the symptomatology of the illness by the self autologous infusion (the proof of principle study) experiment where people were reinfused with the corrected ratio and their symptoms improved, especially their cognitive
symptoms. Why the immune response is being pushed this way is at the heart of the cause of the illness.


What are the consequences of this Type 2 shift?

A lot of pro-inflammatory immune activation is not held in check and this gives rise to a host of symptoms. The NK cell reduction implies reduced surveillance of viral, bacterial and neoplastic (cancer) cells.

Doctor Mary- Ann Fletcher then spoke about a study that they have just got funding for, where they are going to track patients over time with ME/CFS looking for a biomarker. She said that the problem has always been that patients are not all in same state when bloods are drawn for study.

They are going to measure blood parameters at 4 points in time

. Once at start, once at finish and 2 times in between where the patient themselves classify themselves as feeling "well" and then at "sickest". This they hope will try to catch what it is that is fluctuating and hopefully detect either a biomarker or proxy biomarker. Once a biomarker is elucidated, then self report
outcome measures (that are problematic) don't have to be used all the time and good "hard" data gets generated.

Witness the self report problem from  the Growth Hormone study - which showed improvement in patients as they went back to
work, but because "quality of life questionnaire" was used as outcome measure  the study showed no benefit. All that good
work has now stopped, all because the outcome measure didn't measure the appropriate thing.


Is the immune activation the reason I don't get colds anymore?

Well, who knows? You certainly have a lot of immune activation and it is possible that maybe the high levels of interferon that are present are fighting the cold virus off before you know it. But clearly the antiviral activity isn't good enough in other respects because we are seeing the re-activation virus problems. Also it maybe that you don't contact many small children with colds because you don't get out as much.


How does gluten sensitivity relate to CFS?

Gluten sensitivity can sometimes be a problem alongside CFS but this is very rare. Gluten sensitivity is measurable and should be screened for at diagnosis and treated (i.e. gluten avoidance diet). If a person does have it, it will be causing a degree of immune activation and so reducing that activation is a good
thing to do  but please don't cut out wheat etc if you don't have gluten sensitivity.


You mentioned the Holter monitor, can you explain what does a holter monitor test for in CFS?

A holter-monitor  is a device that cardiologists use . It is portable and patients wear it all day and all night and it measures every beat your heart makes .( normally 24 hours). It is usually used to check for arrhythmias.

It can be used as a cheap  alternative to the tilt-table test to show autonomic dysfunction/involvement .

If the r-wave shows a pattern of stretched activity , then scrunched activity (wide, then narrow) then this means your heart
is filling irregularly and thus an autonomic problem exists.



Does melatonin help sleep?

Yes patients report that it does. You have to get good quality as it is a hormone and it should be prescription. Often the over-the
-counter stuff is not what it says. I am glad to see here in NZ it is on prescription  this means you are getting a reputable brand.

Remember what I said about alpha trappers  don't take diazepam/valium derivatives (exceptions  Clonazapam, Ambiem). Low dose tricyclics often helpful for both keeping people asleep as well as for the pain relieving- her favourite is Doxepin as it has strong antihistamine effect; she doesn't like
Amitriptyline as much. Doxepin comes in liquid and can be titrated to the best dose to suit each person.



So, one of the first things you would suggest is a sleep study?

Sure thing.  Good sleep is the first step for all patients.   Don't you all find that if once in a while you wake up refreshed you have a good day to follow? We want to aim for good sleep and the newer sleep medications (as discussed eg Xyrem) seem to be working really well, much better than anything we've had
before , for this disorder of lack of stage 4 sleep.


Hypersomnia  can I oversleep?

Yes, certainly people can oversleep. Some of my patients do and it isn't normal.  The normal band is 7-9 hours (9 hours better). Getting a sleep study in this situation is also correct procedure. Sometimes though extended sleep is what helps patients.


Is Yoga good for me?

Tighter abs and a strong 'core' really helps. Pilates is great  as it works on the core. The largest vein in the body runs through the lower abdomen  the vena cava. If you can tighten the muscles around these veins you will help stop the massive pooling in this blood bed that occurs (ie if you can tighten around the pipe). Get
a low key video  of Pilates for mat exercises (not ball or anything else). If you can get through a 1/2 hour video, in 10minute chunks, throughout the day then that is great. Remember try to work on :

1.      strength (sand bag weights, upper body one day, lower   body the next)
2.       tone (Pilates)
3.       aerobic exercise (in 5min bursts)

5mins on, 5 mins rest, etc or swimming ( swimming doesn't create any orthostatic constraints, you should be able to go longer maybe?) . Don't work to build up aerobic work each week, this will eventually cause relapse. We just want you to try to keep a certain amount of cardiac work.

If you have fibromyalgia you are doing yourself no favours if you don't stretch every muscle in your body twice a day (a physio should be able to teach you how to do this)


So, we have low blood volume. Could you explain the study you were doing that addressed this and why you said you thought you'd undershot the mark?

OK  a normal person has 4.5 litres of blood. My CFS patients averaged a litre less. Blood is made out of red cells +plasma
(fluid). There is a hormone (called erythropoietin)  produced by your kidney that tells your bone marrow to make red blood cells

So to increase volume you need more red cells, plus more fluid.

We wrote a grant to study just this, but the NIH would only give us the funding to study just adding red blood cells alone (via erythropoietin). This was very scarey because there was a chance of effectively thickening the blood too much. We had to  draw blood every week to check this and I had patients increase
salt. I monitored very carefully. By adding just the red blood cells we managed to bring volumes up by maybe 1/2 litre. I feel really frustrated because the study may not show great results, but I know it could have been designed better ( meaning  the volume needed adding too), and I think there is a story there , but this
may put off the NIH from funding us further in this area.

I will be reporting the final results of this study at the up coming  conference in Jan. The majority of patients I think gained some benefit  we'll see when I get the data. Patients with CFS don't placebo respond as much as other illnesses and my sense is that patients found it "somewhat helpful"- if we'd been able to
volume expand who knows??


Should I drink more to keep my blood volume up?

No drinking excessive amounts  may make things worse. If you overhydrate it causes your kidneys to diuresis (i.e. it has a diueratic effect) and you pee more and volume drops further. If you have low blood volume you need to take the medications like Florinef plus salt. If you have been avoiding salt and you
have low blood pressure please eat more salt "I give you permission to eat potato chips". There is enough salt in one bag of potato chips to bump up your blood volume. About quarter to half tsp a day extra is all it takes.


Should people with ME give blood?.

No I don't think it's a good idea  for two reasons

a . Most patients are 1 litre low in blood (most of Dr Klimas's patients at around 3.5l instead of 4.5l why would you want to take out another litre!

b. To my mind, there are no studies to prove that ME is not  infectious  so we can't say with complete certainty that an infection will not be passed on. "I wouldn't want your blood, you can keep your blood to yourself for now"


Where do you think that the brain dysfunction comes from?

That's hard to say, the sudden 'brain fog' would seem to be a blood pressure/volume issue. Other stuff is probably a combination of volume and inflammatory response in the brain.


What about the headaches?

a.   The sinus 'thickening across the head' is a fibro type headache. Fibro pain meds should help.

b.   The new onset migraine is more of a vascular (blood pressure) problem. Treat as for migraine  sometimes that works well.


The last slide you mentioned about the Japanese study's  can you explain again?

There are three very good Japanese studies underway. One in particular is very exciting using Neurotropin (usually used in
Sympathetic Reflex Dystrophy  an autonomic disorder with pain).
In  a very small study it resolved all symptoms. The data is to be presented at upcoming conference in Fort Lauderdale in
January. The Japanese are spending more money on CFS than any other country at the moment!


What is folinic acid and have you got any comment on the recent study using it?

Hadn't seen study, but folinic acid is downstream product of folic acid, and the folate pathway was one of the pathways that came out as relevant in the gene assay studies.  Usually folinic acid is used as a rescue therapy in chemotherapy patients. It is used to bypass enzymes in the pathway that are knocked out due to
chemotherapy. If the folate pathway is screwed up it would make sense to investigate.