AACFS 6th international conference reported by R.Vallings

 

 

http://www.meactionuk.org.uk/aacfsreportbyrvallings.htm

 

 

From 31st January to 2nd February 2003, I was privileged to attend the AACFS 6th International Conference on CFS, FM and related syndromes, held at Chantilly, Virginia. The first day was a clinical conference for physicians working in the field of CFS, followed by a day and a half of research presentations.

 

DAY 1.

 

The conference opened with an introduction and overview by Charles Lapp

(Charlotte,NC) and Leonard Jason (Chicago,IL). Lapp ran through the history of

CFS, which was described by Hammurabi as early as 2000 BC. Jason reviewed the problem of CFS and its definition, citing that 50 million Americans suffer from fatigue, of which 14 million have prolonged fatigue and 8 million have a

diagnosis of Chronic Fatigue. CFS fitting the research case definition probably

affects 800,000 in the USA. He outlined the difficulties in diagnosis and

overlap with major depression. Chronic Fatigue is a diagnostic feature of major

depressive disorder (MDD) with 4 of the minor CFS symptoms occurring

concurrently (unrefreshing sleep, joint pain, muscle pain and impaired

concentration). He then outlined the major distinguishing features between CFS

and MDD and other disorders such as generalised anxiety disorder and

somatization disorder.

 

Epidemiologically, a major study showed that there is a predominance of females

with CFS, and almost double the number of Latinos compared to American whites or Afro-Americans. There was no history of abuse in the majority of cases and in 50% of the cases there was a family history of auto-immune disease. Those with CFS were found to be more functionally impaired than those with Type 2 diabetes, congestive heart failure, MS or end-stage renal disease. Many do however show improvement over 2 years, though the majority do remain significantly impaired. Various physical and psychological scales were discussed to measure outcomes and co-morbidity, including wearing a device to produce actigraphs showing daily activity. Those with CFS particularly showed reduced activity and non-restorative sleep.

 

Lapp then discussed the Fukuda case definition, which is a research definition

with likely future revision. Those with a history of alcohol or substance abuse

should only be excluded for 2 years, and for those with morbid obesity, the BMI

will be raised to >45 for exclusion. (This represents a 5'8" person weighing

more than 300 lb) He then made note of the Provider Education Project. This is

a web based course in CFS for physicians with a competency certificate at the

end.

 

He then reviewed physical examination in CFS pointing out particularly that

lymph glands and skin maybe very tender. Laboratory findings in CFS were

usually essentially normal, though there maybe abnormal immune complexes,

atypical lymphocytes, lowered IgG, small increase in alk phos, elevations in

cholesterol and small increases in ANA and thyroid antibodies. MRI studies of

the brain have demonstrated high intensity T2 weighted lesions, but these do

occur in other diseases and are non-diagnostic. SPECT scans to demonstrate

function show decreases in cerebral blood flow with exercise, often worse 24

hours later.

 

There was acute onset in 85% cases, and in 72% the main precipitating factor was infection, with a small number of cases following trauma, surgery, childbirth,

allergic reaction and emotional trauma. He reviewed possible causes of CFS,

including various infectious agents, immunological defects leading to T cell

activation, increases in cytokines and decreased NK cell function, HPA axis

dysfunction with lowered cortisol levels and orthostatic intolerance. 92% of

patients with CFS can become syncopal with orthostatic intolerance, and as well

as having a drop in BP, symptoms may come on after a delay of 15 minutes.

 

A diagnostic decision making model was then presented with a useful flow chart

for physicians.

 

The differential diagnosis covered a very wide range of diseases, and the

audience participated in discussion of the characteristic diagnostic features of

other conditions such as:

 

Evidence of a tick bite and presence of arthritis in Lyme disease

Optic neuritis and ocular nerve disorders in MS

Butterfly rash and arthritis in SLE

Genital infection followed by arthritis (particularly in heel and

lower spine) in Reiter's disease

Skin discoloration and immediate light headedness on tilt in Addison's disease

SSA antibodies in Sjorgren's syndrome

Hypercalcaemia with polyuria in parathyroidism

High ferritin levels in haemochromatosis

Gluten sensitivity and low ferritin in coeliac disease

Raised SGOT in hepatitis etc etc.

 

Lab tests for all of the above should be performed according to the symptoms and

history. Further investigation should be pursued if the ESR is elevated as that

is not characteristic of CFS, when it tends to be low.

 

A diagnosis of fibromyalgia (FM) is made if there is widespread pain of at least

3 months' duration coupled with tenderness in 11 of the 18 classical tender

point. Gulf War Illness (GWI) tends to overlap with CFS but there are important

differences, such as gastrointestinal, respiratory and skin symptoms, which are

uncommon in CFS. The 1999 case definition for Multiple Chemical Sensitivity

(MCS) was presented. The main symptoms are cognitive impairment, mood disorder, disequilibrium, respiratory problems, headaches, nausea and fatigue. Symptoms are reproducible with repeated exposure and tend to improve when incitants are removed. There is considerable overlap between MCS and CFS with 30% of those with MCS fulfilling the criteria for CFS.

 

 

Lapp then presented his stepwise approach to the management of CFS:

 

1. Education

 

 

2. Activity - balancing light activity with rest and increasing the level of

activity slowly over time.

 

 

3. Nutrition - avoiding malnutrition, minimising sugar, caffeine, alcohol and

tobacco, keeping fats low if suffering from diarrhoea and avoiding dairy

products and or/gluten for 5 days to see if there is any improvement.

 

 

4. Specific symptom therapy:

 

 

a) Sleep management - Initially try melatonin, phototherapy or OTC

medication, then clonazepam 0.5mg and/or doxepin 10mg - (clonazepam is

habituating but not addictive). Trazadone 50mg can give improvement in levels

3 - 4 sleep. Hypnotics may be needed by some patients, and Flexeril can be

considered in combination with any of the above.

 

 

b) Central activation - reduced levels of dopamine and serotonin can

lead to sleep disturbance, low pain threshold, loss of motivation and depressed

mood. SSRIs and SNIs (venlafaxine) can be useful as can dopamine agonists such

as wellbutrin.

 

 

c) Autonomic Nervous System dysfunction - treatment aimed at volume

expansion with 2 quarts (2.5L) fluid per day with 1-2 teaspoons of salt daily.

Some will benefit from fluodrocortisone 0.1 - 0.3 mg daily. Vasoconstrictors

such as ephedrine and midodrine can be useful.

 

 

d) Pain control - a review of a personalised algorhythmic approach

was then presented by B Natelson (New Jersey):

 

Stage 1: NSAIDS - celebrex 200mg bd - often not much help.

Plaquenil - raises pain threshold, but has side effects

Tricyclics - amitriptyline 20-50mg, particularly if

there is a sleep problem

Flexeril

Effexor - venlafaxineXR 75 -225 mg daily if depressed

 

Stage 2 Anti-epileptics: Neurontin 100mg daily, increasing to 300mg

qds, can possibly go up to 3 gm daily

Lamotrigine 25mg daily

initially rising to 100mg tds.

Trileptal 150mg bd rising to

600mg bd

Topamax - good if there is a

weight problem

 

Stage 3 Plaquenil - 6 month trial

Tizanidine - 2 - 4mg bd (very expensive)

Mexelitine - 150 - 300mg daily (a local anaethetic)

Lidocaine patches maybe useful for focal pain.

Tramadol - 50mg qds.

 

Stage 4 Opiates - Morphine sulph contin up to 30mg bd

Methadone (cheap but has long half

life)

Prednisone - does not work in FM, but Hydrocortisone

25mg daily is often helpful. A four week trial is worthwhile

 

Several other drugs were then discussed re their relevance in CFS:

dexamphetamine, eldepryl, cylert, methylphenindate, modafinil and a new drug

used for ADD called amoxetine.

 

Disability evaluation of those with CFS was then discussed by C Lapp. He

pointed out that in the US, primary care physicians are faced with the task of

advocating for 800,000 patients with CFS and more than 2 million with FM. Up to 50% of these people are unable to work. Evaluation needs to be done by a

primary carer familiar with CFS. Standardised psychometric and functional

testing instruments need to be used. For presentation to Social Security in the

US, CFS patients must fit the 1994 Fukuda definition, with one or more specific

medical signs clinically evaluated over at least 6 consecutive months (eg

swollen or tender nodes, tender points etc) - and certain specific lab findings

are acceptable. (eg NMH by tilt table testing, abnormal cranial MRI).

Documentation of cognitive and emotional difficulties is also important.

Physicians world wide should be aware of the requirements to keep good notes on relevant issues for these patients.

 

S.Schwartz (Tulsa OK), an infectious diseases physician, then outlined his ideas

as to what to do when "you reach the end of the prescription pad". He uses a "5

points of a star" approach looking at:

 

1. Pain control

2. Improved cognitive function

3. Acceptance, understanding and modification of lifestyle

4. Improved sleep

5. Energy improvement

 

He emphasised particularly that other measures will not work until sleep is

fixed. The aim should be to prevent permanent disability. It is important to

collect as much data as possible before seeing the patient, using appropriate

history forms, looking at impact rather than symptoms, and measuring instruments

designed for the job should be used. Adequate time then needs to be allowed for

the consultation. One should measure what is there rather than what is not.

Such scales should measure fatigue, depression, memory/recall etc. The patient

needs reassurance that he does not have dementia. The patient needs an island of

care including the physician, the nurse and other medical assistants

(physiotherapist and/or occupational therapist, rehab consultant), psychosocial

support persons (psychologist, social worker, neuropsychologist) and possibly an

attorney.

 

Sleep management, graded exercise, goal setting, counselling, CBT and family

involvement all need to be addressed coupled with relearning and restructuring

environment. Vocational rehabilitation should include workplace adaptations,

disability issues and rights. Professionally led support groups are helpful but

patient led support groups can reinforce negative cognition. Schwartz runs an

annual seminar for patients, family and friends.

 

D.Uslan (Seattle WA) a rehabilitation consultant, then outlined his approach to

CFS management. He often uses workbooks and aims to see patients very

regularly. Self management, pacing and education are important, and cultural,

religious and ethnic orientations should be considered. The workplace maybe

"pathological" and leave of absence maybe required. Attention to troubled

relationships, sleep management (avoidance of obsessive thinking), cognitive

rehabilitation (as opposed to CBT) is needed.

 

P.Fennell (Albany NY) then discussed a systematic approach to management of CFS, using her 4-phase theory for psycho-social intervention.

 

1. Crisis

2. Stabilization

3. Resolution

4. Integration

 

Physical/behavioural, psychological and social/interactive features for each

phase were illustrated. Work is aimed at stabilization in each phase. 44

subjects had been studied using the Fennell phase inventory, and the study

supported the distinction between the phases. Assessment and review throughout

the process was discussed.

 

C Lapp (Charlotte NC) then rounded off the formal part of this day with 2 case

presentations which provided interactive discussion, and were examples of how

the Provider Education Project is presented to participants.

 

Opportunity to view the posters (covered later) was then provided, followed by a

dinner symposium at which Trudie Chalder discussed CBT.

 

Dinner Symposium - T Chalder (London UK) acknowledged the physical as opposed to psychological nature of this illness. CBT focuses on educating the patient about the illness and diminishing the focus on symptoms. There should be

concentration on overcoming symptoms rather than looking for a cause of

symptoms. At her clinic patients are seen regularly for 12 sessions or more,

but there is never any pressure brought to bear. The emphasis is on achieving

normality. For example, in sleep management, a sleep diary is kept, with

encouragement to get up early, to keep regular hours and avoid cat naps. An

exercise plan needs to progress very slowly, particularly if the illness is

severe, as there is usually a fear of bringing on symptoms with activity. A

crash and burn approach needs to be avoided. Several short exercise spells each

day are recommended and the length of the spell may only increase in length by 1

minute per week.. Patients may experience worsening symptoms each time the

exercise is stepped up. The patient needs to understand this and realise no

harm is likely. The eventual aim is to return to normal life in a carefully

graded fashion.

 

DAY 2

 

The 2nd day of the conference focussed on research and the first session

covered:

 

EPIDEMIOLOGY - the opening address was given by L Jason (Chicago IL) when he again emphasised the prevalence of fatigue. Many studies have been done looking at prevalence of CFS with wide variation ranging from 7.4 to 2600 per 100,000, but for those meeting the current research definition criteria 1-4 per thousand seems the most likely incidence Latinos represent the highest racial group with CFS in the USA, probably due to poorer health status. Of those with CFS, 41% meet the criteria for MCS, 16% for FM and 5% of those with GWI match the criteria for CFS. Most studies show a female predominance and paediatric prevalence ranges from 60 per thousand to 2%.

 

With so many studies showing different rates there needs to be a standardisation

of diagnostic criteria.

 

W.Reeves (Atlanta GA) said that the research definition is now under review,

including ambiguities associated with exclusionary and comorbid conditions,

using standardised applicable international measuring instruments to measure

intensity and disability associated with fatigue. Exclusions may be permanent

or temporary. Temporary exclusions (until treated) may include sleep disorders,

hypothyroidism, diabetes and morbid obesity with a BMI>40. Major depressive

disorder with psychotic features and PH of anorexia/bulimia are not exclusionary

if there has been resolution for 5 years.

 

Suitable measuring instruments:

 

Psychologica l - SCID or DIS

Fatigue - intensity - CIS or Chalder or Krupp severity scale

Somatic and psych health report - SPHERE - measures anxiety,

depression and fatigue

Functional disability - SF36 or SIF

Sleep - Pittsburg sleep questionnaire, SAQ - to exclude apnoea and

narcolepsy.

Memory and cognition - Cambridge neuro-psych test, RTB , CFI

Pain - SPHERE or McGill pain questionnaire.

 

Where there is a psychological condition in the differential diagnosis, the

patient must have a structured interview with an experienced physician and SCID

or DIS should be used.

 

The symptom list has been re-ordered:

 

Post-exertional malaise

Unrefreshing sleep

Cognitive difficulties

Headache

Myalgia

Joint pain

Sore throat

Tender nodes

 

The most prevalent symptom is non-refreshing sleep.

 

 

In summary, it is mandatory to use a standard definition and standard methods

must be used for assessment. Publications must show how the definition was used

and adequately describe the study subjects.

 

E Unger (Atlanta GA) confirmed that unrefreshing sleep is a defining symptom and the most frequent. This is a chicken and egg situation whereby the poor sleep

aggravates the CFS, which in turn worsens the sleep. Formal studies such as all

night poly-somnography including sleep latency measurement can be used.

 

T Chalder (London UK) presented her paper looking at the rate of CFS in

childhood in a large (4240) London sample. She concluded that CFS was rare in

this age group. 0.19% met the criteria for CFS. 0.4% parents thought their

child had CFS, but there was no overlap between the child's symptoms and

parental labelling. It seems that parents and children have different

perceptions of symptom experience. There was considerable overlap between

fatigue and psychological disorders, and there was frequent maternal

neuroticism.

 

K Busichio (Newark NJ) looked at physical impairment in CFS. Her group found

that fatigue was only modestly associated with physical functioning in 102 women with CFS (average age 40). Pain was a better predictor of work impairment in CFS-only and FM/CFS patients.

 

BIOCHEMISTRY

 

R Suhadolnik (Temple Univ) gave an overview of the biochemistry and genetics of CFS, which he explained encompassed a huge overlap of all disciplines. He

acknowledged the many people who had contributed to the many advances in the

understanding of CFS. He then outlined the various biochemical processes which

had been shown to be altered in CFS. Immune activation and NK cell decrease

seem to be evident in most patients.

 

1. Oxidative stress - described using the peroxynitrite model, whereby

elevated levels of various cytokines cause elevation of nitric oxide. This can

decrease NK cell function, and also leads to mitochondrial dysfunction and HPA

and other organ dysfunction causing fatigue and many other symptoms. He showed

that there was an increase in markers of oxidative damage. The oxidative stress

can thus damage muscles and the ATP generated system.

 

2. 2-5A/RNaseL abnormalities have been shown in CFS, particularly in the

severely ill. 37kDa RNaseL is found in PBMCs in CFS in Suhadolnik's and de

Meirleir's studies and not in healthy controls, depressed or FM patients. He

stressed that there was no time lapse in the examination of the US samples,

which W Behan has cited as a risk for false positives .

 

3. p68 kinase (PKR) - PKR mRNA expression has been shown to be increased in

CFS leading to increased PKR protein activity.

 

4. Apoptosis - (programmed cell death) is evident in CFS

 

5. Skeletal muscle function and mitochondrial function - reduced

intracellular concentration of ATP suggests a defect in oxidative metabolism

with a resultant acceleration of glycolysis in the working skeletal muscles in

CFS. There is also reduced oxidative muscle metabolism (shown by MRI), and

muscle recovery is delayed. Elevated levels of RNaseL are associated with

reduced VO2 max and exercise duration in patients.

 

 

There is evidence for changes in brain metabolism.

 

In addition to altered biochemical processes, there is evidence for some genetic

predispositionto CFS, which coupled with a triggering event can lead to immune

dysregulation. Ongoing twin studies are providing useful information. Vernon

and Behan have both been using micro-arraying techniques for gene expression

profiling.

 

4 papers then followed relevant to Suhadolnik's presentation.

 

S Vernon (Atlanta GA) discussed the utility of the blood for gene expression

profiling and biomarkers in CFS, using micro-array. In her study, she had found

that the results were successful in distinguishing CFS subjects from healthy

controls. Gene activity differences were identified implicating some of the

pathways involved in CFS. She noted that there could be age differences in this

study and that in future there is need to control for all variables. She

stressed that the more genes one can measure the better.

 

W Behan (Glasgow, Scotland) compared the muscle of patients with fatigue due to different chronic diseases using micro-array technology to establish whether or

not there is a common profile of gene expression. She said age matching and

gender was very important. Comparison between the groups identified a range of

genes that were differentially expressed more than 3-fold. Symptoms of fatigue

and myalgia in CFS are similar to that in other common conditions (COPD,CHF).

Studies show profound deconditioning in all groups, but additional mechanisms

must be going on. A large number of transcripts were identified in those

deconditioned but absent in controls.

 

G Kennedy (Dundee, Scotland) provided further evidence for dysfunction in

oxidative pathways in CFS. High levels of isoprostanes were found. 8-iso-PGF2? is a sensitive and reliable measure for oxidative stress in vitro. Viral

infections increase isoprostanes, but the changes shown in the sample of CFS

patients studied were not present in those with organo-phosphate poisoning or

GWI, in which conditions the effects are due to anti-cholinergic effects.

Isoprostanes are potent vasoconstrictors, and this may help to explain some of

the symptoms in CFS.

 

D Racciati (Chieti, Italy) explained how oxidative stress may play a fundamental

role in CFS pathology. The oxidative stress may be a result of elevated

peroxynitrite, leading to a self-perpetuating viscious cylcle mechanism,

producing a chronic pathological condition in response to a trigger such as a

viral infection.

 

INFECTION and IMMUNOLOGY

 

John Hay (Buffalo NY) introduced this session with a presentation showing the

evidence for infection and immunological changes in CFS.

 

INFECTIONS correlate with disease and fatigue and many CFS patients report an

infectious episode at onset. More than 30 infectious agents have been

investigated in the quest for a cause of this illness including picornaviruses,

EBV and retroviruses. Some of the likely organisms leading to CFS-like illness

include:

 

HHV6 and 7 - minimally found in CFS patients and probably not significant

Bornaviruses - ? involved in humans - but found in a small number of CFS

patients.

 

 

Borrelia burg (Lyme disease) - those who are sero-positive are likely to have

symptoms of CFS

 

 

Mycoplasma - Komaroff found no antibodies for these organisms, but Vojdani found 34% positives in CFS patients compared to 8% of controls.

 

 

Parvovirus B19 - a large percentage of people carrying this virus do have

fatigue, but it cannot be diagnosed after the acute phase.

 

He concluded that there was no consistent pattern of infection and a number of

organisms can lead to the CFS state.

 

IMMUNE DYSFUNCTION may be involved, as administration of cytokines gives rise to symptoms similar to CFS. eg parvovirus may cause dysregulation of cytokines (TNF? and IFN?). Other cytokines such as IL -1? and IL-6 were studied. IL-6 was found to be increased following exercise in CFS.

NK cells showed low activity in 25% CFS patients compared with 7% in controls (Whiteside, 1998) but no differences were found in monozygotic twin studies (Sabath, 2002).

 

 

Suhadolnik and de Meirleir found up regulation of the RNaseL pathway in CFS

while Gow et al had no significant evidence for this.

 

ALLERGY - many with CFS report atopy. IgE and CFS were found to correlate in 2 recent studies.

 

AUTO-IMMUNITY is an appealing potential link. Konstantinov (1996) found

significantly increased ANA positives in CFS, but Skower (2002) had less

promising results.

 

In conclusion Hay said that as yet there is no consensus for immune dysfunction

in CFS. Patients need to be divided prior to any data analysis as there are many

routes to this disease making research data potentially difficult to assess.

 

3 further papers were presented at this session.

 

K Maher (Miami,FL) discussed molecular defects associated with CFS, in

particular determining the molecular mechanisms underlying decreased

cytotoxicity. The cytotoxic armamentarium involves perforin, granzyme A and

granzyme B and all are down in CFS. NK cells were also found to contain fewer

molecules of CD11a and CD26, and the cytotoxic protein content of T6 cells was

reduced. Cytotoxic effects may not therefore be NK specific but may encompass

the cytotoxic T cell subset as well.

 

P McGaffney (Minneapolis,MN) found a significant difference in gene expression, detecting 166 genes. In particular the analysis revealed elevated expression of mRNA for IL-1 and the IL-1 receptor,type 2. IL-1 is a very potent inflammatory cytokine and these genes were dysregulated in almost all patients and none of the controls. This may give insight into the pathophysiology of CFS but there is still a long way to go.

 

R.Suhadolnok (Temple Univ) enlarged further on the biochemistry and clinical

differences. His team studied 3 groups: CFS patients, healthy controls and those

with depression. He had again found a close association between the upregulated

2-5A/RNaseL immune defence pathway and the clinical presentation of CFS. These markers can be used together with clinical parameters to identify CFS patients and to identify homogenous subsets within the population. This would thus prove useful in studying treatment methodologies for various subsets.

 

TREATMENT

 

B Natelson ( New Jersey) introducing this session explained the trials and

tribulations of drug research in CFS. One could compare an assortment of

biological functions between patients and healthy controls, or one could use a

trial of a specific pharmacological agent. Such a trial may give a clue as to

cause.

 

3 trials using phenelzine, selegiline and ambrotose only showed minor

statistical improvement. He reported on a larger trial using Modafinil, a drug

used to combat fatigue and sleepiness in conditions such as narcolepsy and MS.

It was thought it could have a role in CFS. A double blind, placebo-controlled

trial in moderately ill patients was performed. The trial lasted 4 weeks and

the dose was increased from 100mg daily to 200mg over the first few days. Drop

out rate was 20% mainly due to adverse effects such as headache and nausea. The

trial was conducted in 6 sites and many measures were studied. No significant

improvements were seen. There was a tendency for slight improvement on the drug and in 2 sites there was an amazing placebo effect! The subtle therapeutic

effects were not backed up by research.

 

A number of factors deemed to be important for future research emerged from this

study:

 

1. Choose only those reporting sudden onset consistent with viral illness

2. Psychiatric diagnoses should be excluded.

3. Those with MCS or FM should be excluded as they have higher levels of

comorbid psychopathology.

 

This will ensure a more homogenous sample. It may also be preferable to use

only one site.

 

O Zachrisson (Goteborg,Sweden) presented a randomised controlled studyon the use of staphylococcus toxoid in FM/CFS. His group found that over 6 months there was significant improvement. There was good tolerability with only 10% dropout. 65% of the CFS group improved significantly, but there was worsening of symptoms on withdrawal. The symptoms that improved were: fatigue, sleep, cognition, sadness and irritability. The antibody response was related to the clinical response. Maintenance treatment is needed to prevent relapse and this agent is no longer on the market as it contains a preservative which breaks down to mercury and salicylate.

 

D Clauw (Washington DC) had studied the effectiveness of aerobic exercise and

CBT in 1000+ Gulf War veterans with chronic multisystem illnesses. Patients

were excluded if they already had an exercise plan. 4 groups were studied:

usual care, exercise alone, CBT alone and a CBT+exercise group. Physical

functioning was not significantly improved in any of the 4 treatment groups.

However both exercise alone and CBT+exercise improved fatigue, cognition,

distress and mental health functioning. Affective pain was improved with CBT

alone and CBT+exercise, but 3 other pain measures were not improved.

 

C Lennartson (Stockholm, Sweden) studied the effects of low intensity interval

training in 30 women with CFS. 20 were in the training group, which involved

walking (15-30 min), stretching and relaxation. 10 were controls. Rest periods

were included. 5 dropped out of the training group. This type of light

intensity training was found significantly to be useful for those with CFS,

and this exercise did not appear to exacerbate symptoms, so that patients could

continue the programme without fear of relapse.

 

PSYCHO-SOCIAL ISSUES

 

T Chalder (London,UK) introduced this session and gave an over view of her

thoughts on Chronic Fatigue. She described labelling difficulties with

medically unexplained illnesses. eg psychosomatic, somatization, hysteria,

conversion disorder etc. She preferred to divide these illnesses in terms of:

 

Functional - absence of pathology but with physiological processes not clearly

understood.

Medically unexplained

Miscellaneous eg FM,IBS,CFS.

 

She suggested we should try to study the physiological mechanisms alongside

cognitive and behavioural factors. Precipitating factors such as life events,

social support, lack of fitness and coping ability are determinants in the level

of fatigue. She has used several different questionnaires to determine the

level of fatigue, and found that the perceived lack of practical rather than

emotional support was predictive of fatigue level. She noted that CBT could

target the cognitive and emotional effects.

 

T Giesecke (Washington DC) had looked at the roles played by biological,

psychological and cognitive factors in subsets of patients with FM. 3 groups

were identified: a) Those with FM with extreme tenderness and no identifiable

psych/cognitive contribution. b) Those who are moderately tender with normal

mood and c) those where mood and cognitive factors contribute considerably to

tenderness.

 

R Taylor (Chicago IL) evaluated the effects of an empowerment orientated

rehabilitation programme on QOL and outcomes related to symptoms and disability.

 

These programmes which were consumer driven were found to be effective.

Patients set their own goals and determined steps. They also took primary

control over evaluation.

 

D Williams (Michigan MI) had worked with Gulf War vets with chronic multi-system illness. The aim was to improve symptoms and physical functioning using 12 weeks of aerobic exercise and CBT alone or in combination. Results had been

less than expected despite some improvement. Results were more specifically

analysed looking at functional status, mental health, pain, fatigue and memory.

Sex, mood disorders, personality disorders, disablility issues and dolorimeter

threshold were all associated with negative changes in outcome. Tender point

count was predictive of positive outcome in both exercise and CBT.

 

A Peckerman (New Jersey NJ) found that PTSD contributes to disregulation of

cardiovascular responses to mental and orthostatic stress, leading to more

physical symptoms in Gulf War vets with CSF/ICF.

 

DAY 3

 

CENTRAL NERVOUS SYSTEM

 

D Peterson (Incline Village NV) introduced this sesion and discussed the role of

the brain in medically unexplained illnesses. He described structural and

functional abnormalities. A number of structural abnormalities have been

reported such as "MS-like" changes on MRI and Chiari syndrome, which he

described as rare.

 

Functional abnormalities include:

 

Altered HPA axis

Cognitive impairment

Abnormal sleep patterns

Regional hypoperfusion in the brain (SPECT studies)

Hypo brain metabolism (PET studies)

Autonomic dysfunction (NMH shown using tilt table)

Pertubation of brain hormones in neurotransmitters.

Primary or reactivated CNS infection

 

Abnormal spinal taps often have shown that something abnormal is going on in the brain - one study in children showed that a large cohort of children had

evidence of HHV6A (using culture and PCR) in the spinal fluid, which is unusual

as the childhood illness is usually HHV6B. If there are prominent CNS symptoms, a spinal tap maybe helpful, and studies have shown increased opening pressure, increased total protein and lymphocytosis. He stressed that blood tests for HHV6 are unreliable. Treatment with antiviral agents has proved often dramatic in these cases, who had often been severely ill for a long time.

 

He warned however that these tests are invasive and therapy expensive, and he

presented a useful algorithm for assessment of those in whom these procedures

are worthwhile.

 

B Natelson ( New Jersey NJ) described earlier hypotheses suggesting that some

patients may have covert encephalopathy as had been demonstrated by MRI and

larger ventricular volumes. The more severe the CFS, the larger the volume

tended to be. CFS patients without comorbid Axis 1 psychological disorders also

had more neuropsychological dysfunction than those with psychological disorder

or controls. 44% of those with CFS were found to have spinal tap results in

the abnormal range for protein or WBCs thus supporting the hypotheses that some

CFS patients do have underlying pathologic brain processes responsible for their

symptoms. For those with normal cerebro-spinal fluid (CSF), 29% showed signs of depression within a few weeks, while those with abnormal CSF did not. Further studies will investigate correlation between those with CSF abnormality and psychological and cognitive status.

 

R Gracely ( Michigan MI) found that patients with FM/CFS showed higher

subjective ratings and significantly increased cerebral responses to a constant

pressure stimulus. This was assessed using functional MRI comparing constant

pressure with fluctuating stimulation. In CFS patients there was also unique

activation in the thalamus and putamen consistent with the hypothesis of

augmented pain processing in these patients.

 

A Tomoda (Kumamoto, Japan) discussed his team's work with children, analysing event related potentials (ERPs) using a visual oddball paradigm. The large group of 319 children with CFS studied, plus 264 controls, showed 3 types of abnormalities in this measue.

 

Prolonged response

Significantly shorter response

Normal results

 

These responses appeared to correlate with level of illness.

 

TECHNOLOGY

 

Advances in technology for measuring abnormalities in CFS patients were

discussed by Y.Yamamoto (Tokyo, Japan). He reviewed many different measuring devices now in use leading up to the development of a new behaviour monitor known as an ECOLOG. This is a watch type computer for ecological momentary assessment of mood, physical symptoms and cognitive function. There is a built in actigraph for locomotor activity data. It can operate continuously for more than 30 days. A vast amount of material can thus be analysed and this device seems infinitely superior to those used in the past.

 

K Yoshinuchi (Tokyo,Japan) then explained a study using this device to track

symptoms in CFS patients before and after an exercise test. This provides

further evidence that CFS patients do develop symptoms following exercise and

the onset of symptoms may be delayed.

 

P.Lyden (Michigan MI) reported on a study in patients with FM/CFS using an

actigraph measuring activity over 5 days. Participants rated symptoms 5 times

daily. They tended to have a day of activity followed by 1-2 days of very

limited activity, but there was a lack of correlation between activity and

reported pain or fatigue. She described the actigraph as being useful but not

really adequate. The cost of each watch is about $1200US,.and data analysis is

very costly.

 

PHYSIOLOGY

 

The session was introduced and overviewed by P.Gold (Nat Inst of Mental Health), who showed how HPA function is different between those with CFS and those with depression. In major depression there is elevation of 24 hour plasma cortisol and 24 hour CSF norepinephrine. This is evident usually even in mild

depression. BP is generally also higher in depression. In CFS patients,

cortisol tends to be lower, but it may also be slightly down in those with

depression with severe fatigue, who also often have pain and some immune

activation. IN CFS patients cortisol and ACTH levels are reduced in response to

exercise Catecholamine levels also tend to be lower in CFS.

 

J.Stewart (Valhalla,NY) discussed some of the physiology underlying POTS. He

described 2 groups in relation to metabolic mediated vasodilatation and the

skeletal muscle pump:

 

a) Those with increased flow and lowered resistance

b) Those with low flow and high resistance.

 

Arterial remodelling does not occur in CFS. It maybe that there is a subset of

patients with CFS who would not therefore benefit from support stockings.

 

V.Spence (Dundee, Scotland) reported that cholinergic abnormalities exist in the

peripheral micro-circulation of CFS patients, as evidenced by enhanced skin

vascular responses to graded doses of transdermally-applied acetylcholine. This

has not been shown in other diseases. Acetylcholine leads to release of nitric

oxide, which causes blood vessel dilatation. Nitroprusside also leads to

release of nitric oxide, but administering nitroprusside does not lead to the

same response as acetylcholine, indicating that what is happening is a specific

sensitivity to acetylcholine.

 

The abnormal peripheral cholinergic activity in CFS may perhaps be related to

altered cholinesterase activity. These effects can be worsened using the drug

Mestinon and Spence had some concerns regarding the use of galanthamine also.

 

K Yoshiuchi (Tokyo,Japan) presented a study which suggested that patients with

CFS without POTS have a change in sympatho-vagal balance in favour of a

sympathetic predominance during head up tilt.

 

D Clauw (Michigan MI) reported on his group's study of catecholamine levels in

response to standardised stressors in FM and CFS patients. Data suggests that

those with CFS/FM have higher catecholamine levels than controls while

performing the same activities. The responses were consistently different for

CFS and FM with individuals with CFS displaying attenuated responses while those with FM showing normal response.

 

POSTER PRESENTATIONS

 

EPIDEMIOLOGY

 

D Keye (Salt Lake City,UT) found that CFS patients frequently do have an

infective episode in the month preceding onset of illness, while those with FM

will have often had metabolic or mechanical injury. A. Logan (Mahwah NJ) showed that of those with CFS of sudden onset, the majority of cases occurred during the influenza season.

 

E Van Hoof (Belgium) had looked at the activity differences between CFS and FM and the data indicated a lack of differences, sustaining the growing awareness

of the great similarity between the 2 syndromes. Her group had also developed a

new questionnaire - the CFS activities and participation questionnaire

(CFS-APQ). It was found to have good internal consistency and validity. C Snell

(Stockton CA) confirmed that those with CFS exhibit non normal responses to

exercise with post-exertional malaise being a major debilitating symptom.

 

 

P.Levine (Washington DC) had looked at the cluster of neurologic symptoms in

Gulf deployed and non-deployed sufferers of CFS. The study showed an even

distribution of these symptoms in deployed and non-deployed, and no specific

aetiology for this cluster of symptoms was identified. Multiple vaccines,

exposure to the Khamisiyah plume and deployment to Kuwait/Iraq maybe

potentiating factors.

 

A Chester (Washington DC) found that those with unexplained chronic fatigue had

more rhinosinusitis symptoms than those with fatigue explained by mental or

physical illness.

 

IMMUNOLGY

 

K Tiev (Montpellier, France) confirmed that a ratio of RNaseL isoforms higher

than 0.4 seems to be sensitive to screen patients with CFS in the absence of

known infection. Further studies using controls need to be done however, as

this has been challenged by Gow et al. K De Meirleir (Belgium) suggested that

RNaseL truncation could lead to dysregulation leading to degradation of cellular

mRNAs which are not normal targets of native RNaseL. W Behan et al

(Glasgow,Scotland) concludes in her studies that if activation of the antiviral

pathway is observed in patients then the data suggests that the patient is

suffering from a current or recent infection, not that the patient has CFS. It

would therefore be inappropriate to use the RNaseL/PKR antiviral pathway as a

basis for a diagnostic test for CFS.

 

M Antoni (Miami FL) describes the picture in CFS as dual immunologic with low NK cell activity and high activation of other aspects of the immune system. K de Meirleir (Brussels, Belgium) also had data confirming immune activation in CFS patients. However immune activation was less controlled in those infected with Mycoplasma than those without. A further poster showed no association between the RNaseL ratio and antibody titres of C.pneumoniae.

 

A small study by T Jhodoi et al (Kumamoto,Japan) showed some clinical

improvement following treatment with low dose ?-globulin therapy in their CFS

patients who had lower levels of TGF-?1. However a study by G Kennedy (Dundee) showed that their CFS patients had higher levels of TGF-?1 with increased neutrophil apoptosis.

 

Patients who had been tested with C.albicans antigen were shown by G Cozon

(Lyon, France) to have delayed reactivity, suggesting that this antibody may be

implicated in the development of CFS in a subgroup of patients, who may

therefore benefit from probiotics and low sugar diet. J Allegre

(Barcelona,Spain) had looked at atopy prevalence in CFS and found no difference between CFS patients and controls.

 

A sleep study presented by E Van Hoof (Brussels, Belgium) showed that immune

alterations may increase the percentage of alpha intrusion due to ant-infectious

activity.

 

PHYSIOLOGY

 

D Cook (New Jersey) found that there were some differences in autonomic function between healthy controls and CFS patients. Exercise exaggerated differences in the reactivity to postural change between the 2 groups, including both periodic and fractal components of heart rate variability.

 

A Peckerman (Newark NJ) found that patients with CFS demonstrated abnormal

breathing adjustments to postural stress. There was inefficient utilization of

respiratory muscles while standing associated with increased light headedness.

Further studies are needed to determine whether the abnormal adjustments were

due to posture itself or to greater energy expenditure required when standing.

 

T Friedman (Los Angeles CA) concluded that CFS patients in his study had defects in the renin-aldosterone axis, .with impaired mineralocorticoid activity,

reduced blood volume and impaired cerebral blood flow. Further studies may

offer unique treatment options.

 

J M Van Ness (Stockton CA) noted the importance of considering gender as a

variable when designing and conducting CFS research as there were noted

male/female differences in his studies on exercise capacity. Exercise testing

was also investigated by K Ambrose (Michigan MI) and she found physical

performance and physiological responses similar for most patients and healthy

controls. She noted that particular subgroups of patients may perform

differently than others and broad generalizations should be avoided. She also

found in a further study that there were differences between the genders on

various tetsts, in that females had altered heart rate variability in FM, CFS

and GWI but males and healthy controls did not. Again the importance of gender

effects must be considered when analysing results.

 

TREATMENT

 

Treatment of CFS patients with Ampligen (200-400mg twice weekly) was reviewed by D Strayer (Philadelphia PA) Significant improvements were seen in physical performance, cognitive function, vitality and physical activity in 81 severely ill patients after 24 weeks' treatment. The treatment was well tolerated and most patients were continuing beyond 24 weeks.

 

A Logan (Mahwah NJ) showed that CFS patients report consumption of a wide

variety of herbal/dietary supplements. The potential for drug interaction is

high and patients need to be aware of telling their doctors what they are

taking. He suggests that further research is needed into which, if any

supplements have benefit in CFS.

 

Mind/Body interventions were also frequently used by CFS patients as shown by A Bested (Toronto, Canada). Again this seems to be an under-researched area

warranting further study of psycho-physiological mechanisms. Eye movement

desensitization as a means of achieving relaxation was demonstrated in a poster

by F Friedberg (New York), and is described as being useful when other

relaxation techniques fail.

 

T Madarame (Tokyo, Japan) had graphic illustrations of the use of moxibustion on "Shitsumin" in 26 CFS patients. It was found to be an effective treatment for

these patients.

 

Administration of Transfer Factor for HHV-6 was illustrated by J Brewer (Kansas City, MO). Patients with CFS and documented HHV6 viraemia improved symptomatically and immunologically after administration, and such treatment may have an important role to play in some with CFS.

 

A study by A Logan (Mahwah NJ) showed that dietary modification was frequent in CFS patients in an effort to deal with possible food sensitivities. The

sensitivities reported appear to be a result of CFS and may exacerbate symptoms,

but research is scant in this area. There appeared to be no significant

connection between pre-illness migraine and food sensitivity reporting.

 

The work presented earlier by O Zachrisson ( Goteborg, Sweden) on the use of

staphylococcus toxoid was further demonstrated in his poster showing that the

greater the serologic response the better the clinical outcome. He also had a

preliminary poster discussing a new Fibro-Fatigue scale to measure outcome

following treatment.

 

BIOCHEMISTRY and CNS

 

G Moorkens (Antwerp, Belgium) looked at serum and RBC magnesium and Vitamin D status in 3 groups: CFS, FM and autonomic dysfunction. A number of patients in each group were found to have deficiencies, and appropriate supplementation may therefore be important for some patients.

 

The cognitive function scale (CFI) was used by G Lange (Newark NJ) to measure

impaired brain function in CFS groups with and without brain abnormalities as

assessed by MRI. Those with brain abnormalities were significantly more

impaired that those without.

 

D Cook (New Jersey NJ) found that CFS patients showed subtle baseline cognitive deficits, but cognitive performance was not worsened by light exercise. Light exercise appears to improve short term memory. Clarification on relationship between cognitive performance and exercise in CFS may be useful in determining prognosis and defining those who may benefit from exercise.

 

M Pall ( Pullman WA) outlined the proposed mechanism of elevated nitric

oxide/peroxynitrite theory of CFS/FM and related conditions, and his poster

reviewed the literature and data thus far.

 

Gene expression profiling using micro-array technology was illustrated by H

Ojaniemi (Stockholm, Sweden)

 

E Georgiades (Glasgow, Scotland) had looked at peripheral and central mechanisms of fatigue in the aetiology of CFS by examining cardiopulmonary and metabolic responses, and the profiles of selected seratoninergic and dopaminergic modulators during symptom-limited exercise and subsequent recovery in CFS compared to controls. The findings supported impaired exercise tolerance.

 

There was heterogeneity in the cardiovascular and metabolic responses arguing

that these peripheral mechanisms have a variable contribution to the underlying

pathogenesis in CFS. More uniform differences were seen between CFS and control subjects in the seratoninergic and dopaminergic modulators and this may reflect a more global involvement of central mechanisms in the premature fatigue that characterises CFS.

 

PSYCHOSOCIAL

 

K de Meirleir (Brussels, Belgium) had evidence for a high rate of kinesiphobia

(fear of movement) in CFS patients. A fear/avoidance behaviour may thus develop as a result of chronic disability. Also from Belgium, E Van Hoof (Brussels) found a strong link between psychological variables and immune parameters. The link could be mediated by cytokines. Sickness behaviour may help the body to recuperate.

 

The poster by K Busichio (New Jersey NJ) stressed the importance of

understanding the neuropsychobiological correlates in finding a cure for CFS.

A study using tryptophan was used to illustrate effects on the

serotoninergic/dopaminergic system. There appears to be a normal relationship

to prolactin release in CFS, since the effects of serotonin on prolactin release

are mediated via a decreased inhibition of the dopaminergic system, and it

maybe that disorders of this system are characteristic of CFS.

 

R Taylor (Chicago IL) introduced their model of Human Occupation for functional capacity assessment in CFS. This model conceptualises occupational

participation as influenced by volition, habituation, performance capacity and

the environment. S Song (Chicago IL) had done a study which suggests that

chronic fatigue syndrome and psychiatrically explained chronic fatigue are not

the same conditions.

 

Findings in a study by S Torres-Harding (Chicago IL) suggest an underlying

family disposition toward the development of both CFS and auto-immune disorders. This is consistent with the hypothesis that CFS represents a dysregulation of the immune system.

 

I would finally like to thank the Associated NZ ME Societies for supporting my

attendance at this excellent conference.

 

ROSAMUND VALLINGS, MB BS

Auckland

New Zealand

 

[Note: Posted here with Dr. Vallings' kind permission.]