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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
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.
Significantly shorter response
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 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 $1200 US, 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.
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.
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 γ-globulin therapy in their CFS patients who had lower levels of TGF-β1. However a study by G Kennedy (Dundee) showed that their CFS patients had higher levels of TGF-β1 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.
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 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.
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.
VALLINGS, MB BS
Auckland, New Zealand
Copyright © 2003 Rosamund Vallings [Used here with permission.]
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