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Signs and Symptoms in the Eyes

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In the early 1990s, two reports appeared in the scientific literature reporting ocular (eye) symptoms in ME/CFS.
In the first, a research group in Boston, Massachusetts (Optometry & Vision Science 1992) surveyed 190 patients and 198 healthy controls by written questionnaire and found a range of symptoms to do with dysfunction of the eyes, including sensitivity to light (photophobia) and problems with accommodation probably associated with the ocular muscles. In the study, 24.7% of patients had reduced or stopped driving because of eye problems compared with only 3% of controls. In the second study (Journal of the American Optometry Association 1994) all of the 25 consecutive CFS patients reported eye symptoms; the most common clinical findings were abnormalities of the pre-ocular tear film and ocular surface (19 patients), reduced accommodation for age (18 patients) and dry eyes (9 patients).
Then, in the decade 2000–2010, two further reports appeared. The first was a case-control study (Annals of Ophthalmology 2000) in which the 37 patients had significant eye impairments compared with controls; the impairments included foggy/shadowed vision and sensitivity to light, and there were associated problems of eyeball movement (oculomotor impairments) or tear deficiency. The second, from Russia (Vestnik Oftalmologii 2003) reported vascular pathology of the eye in 70.2% of the 218 ME/CFS patients, and “dystrophic pathology” in 52.8%.
The astounding thing is that these 4 smallish studies represent (almost) the sum total of research into eye problems in ME/CFS in the past 30 years, even though eye symptoms are a concern to many patients today. Indeed, around three-quarters of the 2,073 consecutive patients described in the Canadian review of 2003 specifically reported sensitivity to light and dullness of vision to be significant problems.
Astonishing, isn’t it? But, as we’ve said before, time marches on but sometimes it can seem to stand very still indeed where research into ME/CFS is concerned!

Psychosocial Limitations

The cognitive-behavioural model of ME/CFS postulates that fear-based avoidance behaviour and physical deconditioning can explain many of the symptoms and impairments associated with the illness. However, a thoughtful essay by Dr Fred Friedberg of Stony Brook University, New York (Bulletin of the IACFS/ME 2009) has examined the assumptions underlying this model and raised important critical issues. His central thrust is that although cognitive behavioural therapy (CBT) has a role in reducing symptoms and improving functioning, important matters surrounding the clinical trial evidence remain to be resolved.
First, there is considerable doubt about whether avoidance behaviour and physical deconditioning are indeed causal factors in the illness; for example, there is evidence to show that ME/CFS patients are not exercise phobic, and are not more physically deconditioned than comparable healthy people. Again, evidence from a recent systematic review (Cochrane Collaboration 2008) has indicated that approx. 40% of patients benefit from CBT, while the placebo response rates in ME/CFS intervention trials have averaged 20%. This indicates that while CBT appears to be superior to placebo, less than a majority of patients actually benefit from it, an important concern that is not commonly addressed. Another point highlighted by Dr Friedberg concerns the true clinical significance (rather than statistical significance) of self-reported "improvements" measured in trials of CBT; it is not clear in many cases whether these represent illness improvement or simply better coping or some combination of the two. And, crucially, it is important to know whether real world clinical improvements occurred, e.g. whether patients’ activity levels actually increased, or whether their employment status changed for better. As he points out, it is time for an objective, balanced assessment of the effectiveness of CBT.

A HOT New Therapy?
One symptom commonly reported by patients with ME/CFS is orthostatic intolerance, which is characterised by fainting or a loss in consciousness when standing up, and is caused by abnormalities in the body’s neurological system. An individual with orthostatic intolerance is unable to compensate for the changes in blood pressure that occur when they stand up, and this leads to a temporary lack of blood flow to the upper body and head.
Home orthostatic (or tilt) training (HOT) is a technique which has proved to be effective for the treatment of orthostatic intolerance in patients with neurally mediated hypotension, which may share other features with ME/CFS. Patients are asked to stand and lean with their upper back against a wall and their feet placed 15 cm away from the wall. They do this for up to 30 or 40 minutes, or until they experience symptoms, and then repeat the procedure once or twice a day for several weeks. The idea is that this repetition conditions them over time.
A research team from the National Institute for Health Research in Newcastle wondered whether HOT may be a simple, non-invasive treatment for the symptoms of orthostatic intolerance in patients with ME/CFS. A total of 38 patients completed either a regime of HOT (40 minutes once a day for 6 months), or a sham regime in which they stood for only 10 minutes while exercising their calf muscles. The results have been published in the European Journal of Clinical Investigation, and showed that patients who completed HOT did not experience such a big drop in blood pressure while standing as those who completed the sham treatment. They also tended to show an improvement in their fatigue at the end of six months.
The investigators concluded that a course of HOT may well be an effective strategy for improving the quality of life of patients with ME/CFS, although a large-scale clinical trial is needed to confirm this, and individuals should probably not undertake the therapy by themselves without the advice of their doctors.

“A Virus With Shoes”

While some might dispute the late comedian Bill Hicks’ view of humanity as a virus with shoes, there is no question that the theory of a viral cause for ME/CFS is one that has legs! Many patients can trace their illness back to some kind of viral infection, and the recent finding  that two-thirds of patients in Western USA tested positive for the infectious retrovirus XMRV has given this particular theory a good pair of running shoes as well. However, plenty of other viruses have been implicated in ME/CFS, and a recent study from Belgium, published in the journal In Vivo, has turned the spotlight on some of these.
Associations between the illness and a number of viruses (including human herpesvirus-6, Epstein-Barr virus and parvovirus B19) have been reported  before. However, the results have been inconsistent because it is very difficult to detect active, pathological viral infections, and to distinguish between active and latent viruses. While active viral infections may not be detectable in the blood, they might persist in other tissues such as the gastrointestinal tract, making this potentially a good site to investigate.

 

The Belgian group used a technique called real-time polymerase chain reaction to measure viral DNA in gastrointestinal biopsies from 48 ME/CFS patients and from 35 control subjects (who were either healthy or suffering mild gastrointestinal symptoms). Most of the viruses investigated were detected in a similar proportion in both groups, but the exception was parvovirus B19, which was detected in 40% of ME/CFS patients but in only 15% of control subjects. This virus is known to be linked to a number of diseases and conditions, including “fifth disease” (fever, malaise and a skin rash most commonly seen in children), anaemia and a form of arthritis. This study provides further evidence of its association with ME/CFS in at least a subgroup of patients, and parvovirus B19 may therefore potentially be a cause of gastrointestinal symptoms in the illness. We wait with interest to see how these investigations develop.

Kissing Disease

Infectious mononucleosis (IM) is a widespread disease caused by the Epstein-Barr virus, and often known as glandular fever or colloquially as kissing disease (because it is spread by mouth). Its symptoms include fever, sore throat and fatigue, but another potential complication is the development of ME/CFS in the longer term. Previous studies have suggested that as many as 12% of adults can develop ME/CFS after suffering from IM, but the equivalent figures for adolescents are unknown. 
A research team from Chicago set about filling this knowledge gap by conducting a prospective follow-up study, the results of which have been published in the journal Pediatrics. A total of 301 adolescents (aged 12 to 18 years) with IM were telephoned 6 months after their diagnosis to find out about recovery. A medical evaluation was conducted in those 70 adolescents who had not fully recovered and in 50 who had, and they were then followed up again at 12 and 24 months. A diagnosis of CFS was made if the participant fulfilled the Fukuda criteria, and in the absence of a recognised underlying condition. 
Six months after being diagnosed with IM, 13% of the original sample of 301 adolescents were found to meet the criteria for ME/CFS. Most individuals recovered over time, and the figures dropped to 7% by 12 months and 4% by 24 months. All those who still had the illness at 24 months were female and most reported less severe symptoms than they had experienced at 12 months.

IM does therefore appear to be associated with the development of ME/CFS in adolescents, and girls may be at a greater risk. While much more remains to be known, including the various factors that might predict long-term illness, it is certainly encouraging that most children made a full recovery within 2 years.

Immune Links Between ME/CFS and Cancer 
Cancer fatigue is a well-recognised, often intense symptom experienced both during and after treatment. Since cancer and ME/CFS share both fatigue and severe disability, researchers in Antwerp speculated that there could be other links between the two pathologies, particularly as regards immune abnormalities. 
The key findings of their in-depth review, published in Anticancer Research in 2009, were that both conditions share abnormalities in the RNase L antiviral pathway and in the major intracellular mechanism NF-κB which regulates inflammatory and oxidative stress (Table). In addition, natural killer cell malfunction has long been recognised as an important factor in the development and reoccurrence of cancer, and this has also been documented repeatedly in people with ME/CFS. The researchers point out that these immunological problems are clearly apparent and quite similar in both diseases. 
While there are clear differences between cancer and ME/CFS – most prominently in cause, illness progression and mortality – the researchers are nevertheless intrigued by the shared immune abnormalities. It may be that these overlapping immune dysfunctions are involved in shaping some of the symptoms shared by both illnesses.
 


Factor

ME/CFS

Cancer

Ribonuclease L (RNase L)

Increased activity, leading to increased apoptosis

Decreased activity, leading to decreased apoptosis

Nuclear factor kappa beta (NF-κB)

Increased activation

Increased activation

Natural killer cells

Decreased activity

Decreased activity

Bacteria in your Guts?

Various gastrointestinal and neurological problems that are common in people with ME/CFS are surprisingly similar to the symptoms of “D-lactic acidosis”. This condition arises from bacterial fermentation of carbohydrates in the gastrointestinal tract, leading to increased lactic acid levels in the blood. Could there be an overgrowth of Gram-positive anaerobic lactic acid bacteria in the guts of ME/CFS patients too? 
Scientists at the University of Melbourne in Australia examined the faeces of 108 ME/CFS patients and 177 healthy controls for the presence of the most common of the 500 different bacterial species that inhabit the human gut.
Their recent paper in the journal ‘In Vivo’ reported significantly increased levels of aerobic Gram-positive intestinal bacteria in the ME/CFS group than the controls, particularly Enterococcus and Streptococcus species which are the common aerobic bacteria in humans.   
Moreover, the organisms found in the patients produced significantly more lactic acid (p<0.01) than those from the healthy subjects, indicating that acidosis was at least a possibility in ME/CFS.
The researchers postulate that increased colonisation by Enterococcus and Streptococcus could heighten intestinal permeability, assisting the absorption of D-lactic acid into the bloodstream. Increased gut permeability might also aid the release of endotoxins from the bacteria themselves, leading to inflammation, immune activation and oxidative stress, which are prominent features in a large subset of ME/CFS patients. 
While the cause of the increased colonization remains unclear, the researchers point out that eradication of all bacteria is not the answer; indigenous bowel microflora has both positive and negative impacts on health, and the balance of “good” to “bad”  bacteria is important. And their next experimental step is to measure D- and L-lactic acid accumulation in the biofluids of ME/CFS patients to confirm whether D-lactic acidosis really is a factor. If so, existing interventions, such as short-course antibiotics, alkalinizing agents, a low carbohydrate diet or dietary glucose restriction might prove to be useful.

 

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