OVERVIEW: NANCY KLIMAS, M.D. LECTURE
Nancy G. Klimas, M.D. is a director of the Department of Immunology
of the University of Miami School of Medicine, a member of the CFS Working
Group there as well as a board member of the American Association of Chronic
Fatigue Syndrome and the co-editor the Journal of Chronic Fatigue Syndrome
put out by The Haworth Medical Press. She is also an AIDS researcher and
clinician. The following is a summary of a lecture she gave this past spring
to an attentive audience of PWCs. CFIDS will be referred to as CFS in this
Dr. Klimas began by explaining the revised
case definition (1994, Fukada, Straus, et al) where 4 of the 8 symptom
criteria were taken from studies by Anthony Komaroff, M.D.:
The last symptom is the answer to disability.
Dr. Benjamin Natelson proved the derogatory effects of exercise to PWCs
in a study. He administered an IQ test to both PWCs and a sedentary control
group. Then the group used a treadmill and took the IQ test again. The
control group's IQ improved but the PWC's IQ dropped 20 to 30 points! Twenty-four
hours later, the IQ tests were repeated and the PWCs drop persisted. "That's
real! That's impressive! That's quantifiable!" said Dr. Klimas. She uses
this to fight for her patient's disability.
memory or concentration impairment (PWCs thoughts are easily disrupted)
tender lymphadenopathy (tender lymph glands)
myalgia (pain in the muscle)
arthralgia (pain in joints)
new type of headaches
post-exertional malaise for more than 24 hours
Fibromyalgia Syndrome (FMS) is "often lumped
together with CFIDS, but that's not entirely appropriate," she said. It's
an overlapping illness, but more than half of the PWCs meet FMS criteria.
FMS CASE DEFINITION (1990 American College of Rheumatology):
And 11 or more of 18 specified tender points along with general pain. Those
FMS patients who have something in addition to CFIDS are told they have
"idiopathic FMS" but "idiopathic FMS is CFIDS!"
widespread pain for more than 3 months
pain left and right sided
pain above and below waist
FMS has been "a known entity for 25 years and
clinicians are more comfortable with it...so it has been a wee bit more
respected...but not much," said Dr. Klimas. "In fact, it is easy to find
high tech scientific studies in CFS, but hard to find them in FMS." FMS
strikes 1% of the population, takes up 15% of a rheumatologist's case load,
and greater than 80% are female. CFIDS is found in at least 3 per 1,000
(Buchwald, et al) or 37 per 100,000 (Lloyd, et al in an Australian study).
The pathogenesis that Dr. Klimas believes is
responsible for CFS begins with a genetic predisposition. The person then
experiences a triggering event which, in turn, leads to immune activation,
cellular dysfunction, and viral reactivation. The proof of genetic involvement
is the HLA typing done in CFS and FMS:
Although the pathogenesis of CFS begins with a
genetic predisposition, this does not mean that everyone with a predisposition
will get CFS. A trigger begins the body's plunge into the world of CFS.
Without this gene plus a virulent trigger, Dr. Klimas believes that a person
would not get CFS. This is not unheard of. Reiter's syndrome is an example
of an illness that takes a genetic predisposition.
CFS: HLA DR4, DR3, DQ3 (Keller, et al, 1993)
FMS: None found in study of 60 patients (Honen, et, al, 1992)
Chronic Lyme: HLA DR4 (antibiotic resistant arthritis), HLA PR2 (Steere,
et al, 1990)
Do viral infections trigger FMS or CFS?
Under the current definition of CFS, Lyme was
the trigger and chronic Lyme is considered CFS. Thus, Lyme is another overlapping
illness. Viral infections in CFS are fairly common with 60-80% describing
an acute onset. Some begin with acute EBV (Epstein-Barr Virus) while others
begin with acute B. burgorferi or acute CMV (cytomegalo virus). All are
followed by CFS. The EBV titers in CFS are not that much higher than an
average person, but knowledge of HHV-6 is incomplete although it seems
interesting. In AIDS, HHV-6 helps HIV to replicate and could be a co-factor
in CFS as well. HHV-6 also reacts on the NK (natural killer) cell. "Both
of them have the same brain power, but sure as heck not the same fuel,"
said Dr. Klimas, alluding to the funding of AIDS research vs. CFS research.
11-20% of HIV patients have FMS
acute coxsackie virus includes chronic FMS
acute parvovirus includes FMS 18% of 293 FMS patients describe an infectious
onset (Goldenberg, 1993) which is a tiny number in comparison to CFS
B. burgdorferi is known as a triggering agent (77 to 800 "chronic Lyme
patients actually had FMS" (Hsu, et al) while 43 of 77 prior Lyme documented
patients had CFS.
Dr. Klimas finds both similarities and differences
in Gulf War Illness (AKA Gulf War Syndrome). Complaints of fatigue are
found in 60% (vs 100% PWCs) with diarrhea the next most common complaint.
Rashes are also common at time of onset. She wanted to study GWI, but her
grant request was not funded. Dr. Klimas found it most interesting that,
although there were a high number of females in the Gulf War, the majority
of those with GWI are male.
After a quick tour of the immune system, Dr.
Klimas illustrated how T-cells get the message if a "bug" enters the body.
In AIDS, over 90% of the T-cells are killed off which makes the person
get sick and die. A PWC has 100% of their T-cells activated, but a healthy
persons immune system is only 60-80% activated. If a healthy person, for
an example, cuts their finger, they'll feel pain in that finger. A PWC,
on the other hand, has so many of their T-cells activated that the same
finger cut will be felt in the brain and the whole body! This is a result
of the overactivation found in CFS.
The PWC has their NK cells barely functioning.
This is why, in Japan, CFS is called Low NK Cell Disease . If it were known
by this name in the United States, she said, "We'd be a lot better off."
She, personally, prefers the name that researcher Dr. Jay Levy coined for
CFS, "Chronic Immune Activation Syndrome (because) it has a kind of ring
Turning to the chronology of CFS, Dr. Klimas
said that beta 2 (microglobulin found in the serum) is higher in PWCs.
Their immune activation is constantly up-regulated. Although it will be
higher during a flare or relapse, it is always high. The TNF (tumor necrosis
factor) is also much higher in PWCs which correlates very strongly with
NK dysfunction. This is a very accurate way to test for CFS. "I could find
90% of my CFS patients using this method of testing," she said. It's pretty
The immune activation is why PWCs "feel so
terrible." If a PWC could shut off their immune system, they'd feel much
better. Steroids accomplish this, but "when a PWC goes off the steroid,
the immune system responds with a vengeance," she said. The proof of immune
dysfunction in CFS includes these important milestones in research:
Chronic Immune activation (Klimas, etal, 1989, Landay and Levy, 1990, Straus
Lymphocyte dysfunction (Califori, etal, 1993, Straus, etal 1993, Linide,
Cytokine dysregulation (Patarca, etal, 1993, Stause, etal 1993, Linde,
Humoral dysfunction (Komaroff, etal 1988, Read etal. 1995)
In contrast, FMS needs much more work in the area of immune dysfunction.
The studies for FMS citing immune dysfunction include:
IL-2 dysregulation (Harder, etal 1991)
reduced NK cell activity (Russel, etal 1988)
abnormal lymphocyte (Russel, etal 1988)
The cognitive dysfunction found in CFS
takes specific testing that can be found by a cognitive psychologist using
psychometric testing. The dysfunctions are found in concentration, attention,
distractibility, and logical memory. The cognitive problems are different
in FMS, Lyme (delayed recall), MS, and depression. This has been documented
by Kaplin (1992), Krupp (1994), Riccio (1992), and Millon (1989). Is there
a mind-body connection in CFS, as the government keeps suggesting in every
one of their CFS publications? Dr. Klimas reminded those in the audience
that she is an immunologist that looks at scientifically proven facts.
As far as psychosocial interplay that psychiatrists have persisted in studying
in great depth in CFS, Dr. Klimas stated, "I don't feel the mind has any
idea what the body is doing." There is certainly interplay between the
neurotransmitters (incorrect messages sent) and the (resulting) neuroendocrine
dysfunction, but it has nothing to do with any psychological problem.
The autonomic dysfunction found in CFS
is suggestive of a parasympathetic predominance. "Basically, " Dr. Klimas
explained, "this means that when a person stands up after being prone for
awhile, the heart says, 'I need more blood", and the heart is giving enough
blood. But then the parasympathetic system says "O.K., now drop the pressure.
(A cardiologist will go beserk if testing this...and finds this important...calls
it neurocardiogenic sycope.") This is good to use for objective evidence
if someone is going for disability, but Dr. Klimas sees no other reason
to test for this abnormality. When treated for this, many PWCs feel better
because Florinef keeps the heart full. "Water retention is really the theory,"
she said and some medications, such as Paxil and Prozac also help with
"The immune system and the autonomic
system are completely tied up to work together," Dr. Klimas continued.
When a PWC is tilt-table tested, the pulse falls which is known as bradycardia.
This is a phenomena not found in anxiety disorders. Sympathetic withdrawal
and parasympathetic stimulation was found in 1995 (Bou-Halaigah, et al
from Johns Hopkins) and reduced vago activity was also found the same year
(Sisto, 1995), but was documented by Kollai in 1992 and in reconditioned
athletes in 1993 (de Gues, et al). Dr Klimas said she studied and published
data on PWCs who were hit by Hurricane Andrew. Their parasympathetic stimulation
made it possible for them to respond to the emergency and feel fine while
they did it but they relapsed dramatically after the event.
Addressing sleep studies in FMS/CFS, Dr. Klimas
said that there was alpha intrusion during delta sleep. This was reported
in both FMS and CFS (Modolfsky), while alpha wave findings in FMS was found
by Ware, Gupta, Herrison and Doherty. Subsequently, 15 CFS patients and
4 with FMS were found to have a problem of alpha wave intrusion that did
not predict either illness nor that of depression (Menu et al, 1994). [Editor's
note: this intrusion means you are not fully asleep when you are supposed
to be.] These studies raised concern about seratonin dysfunction and Modolfsky
postulates a potential IL-1 (interleukin-1) effect. This is why low-dose
anti-depressents can be helpful, such as Doxepin. However, when to take
it depends on whether you're a slow or fast metabolizer. Dr. Klimas thinks
some are trapped in alpha-wave sleep due to pain. She highly recommended
Dr. Pelligrino's book to try and decrease pain (The Fibromyalgia Syndrome
by Mark J. Pelligrino. M.D., Anadem Publishing, Inc., 1995 is available
by mail. Call 800- 633-0050)
Dr. Klimas tries to get her patients off as
many medications as possible. Detoxifying PWCs doesn't make the illness
go away, she said, but it "can put some beauty in life."