I was privileged to attend the AACFS 6^th 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.

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.  

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.

The 2^nd 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 emphasized 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:

            Psychological - 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.

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.

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-PGF_2α  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.

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.

T Chalder (London,UK) introduced this session and gave an over view of her thoughts on Chronic Fatigue.  She described labeling difficulties with medically unexplained illnesses. eg psychosomatic, somatization, hysteria, conversion disorder etc.  She preferred to divide these illnesses in terms of:

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 program 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.

D Peterson (Incline Village NV) introduced this session 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.

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 levels 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.

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.