Thanks to everyone who came to this three-hour meeting in Burgess Hill, Sussex, on Saturday May 14. The meeting was organised by the Sussex-based ME/CFS charity ReMEmber and there was hardly a spare seat left in the room once we got started! There were presentations by consultant immunologist Dr Amolak Bansal (research) and ME Association medical adviser Dr Charles Shepherd (management).

This is a summary of key points on both research and management – especially those that relate to the way in which some of the current research findings on infection, immune system dysfunction, muscle/mitochondrial function, etc, link in to practical patient management. The summary also includes information from the meeting on the role of stress, activity management and drugs that may affect the underlying disease process in ME/CFS (e.g. antivirals, steroids and rituximab).

The meeting opened with Dr Bansal’s presentation on research.

This was followed by an excellent patient interaction section on what people want to have included in a hospital-based ME/CFS referral service in Sussex.

The final session was devoted to practical aspects of Management.

RESEARCH: DR AMOLAK BANSAL – ME/CFS SERVICE AT ST HELIER HOSPITAL, SURREY

Dr Bansal’s presentation on research concentrated on what he regards as the six key factors that are involved in the perpetuation/maintenance of ME/CFS.

1 INFECTION

In our present state of knowledge, there is little evidence of specific viral infections acting as a perpetuating factors in ME/CFS.

However, there is a specific and subtle abnormality in a key part of the immune system involving what are called natural killer/NK cells (see section 2 on the immune system). This NK cell dysfunction results in a decreased ability to keep latent/dormant infections under control and the consequent reactivation of a latent infection such as Epstein Barr Virus (EBV) – the infection that causes glandular fever.

Most adults (around 90%) acquire glandular fever during childhood and adolescence. There is now good evidence from several research groups (e.g. Loebel et al: www.ncbi.nlm.nih.gov/pubmed/24454857) that this virus (which can remain dormant in the body after the initial infection) becomes reactivated in some people with ME/CFS, possibly as a result of the impaired NK cell activity. This viral reactivation then causes some of the on-going infective type symptoms such as recurrent sore throats etc.

Reactivation of latent EBV infection also raises the question as to whether antiviral treatment – as is used by some doctors in America and occasionally here in the UK – is appropriate in some of these cases.

2 IMMUNE SYSTEM DYSREGULATION

A significant omission in our understanding of immune system dysfunction in ME/CFS is the lack of any robust longitudinal studies that have measured immune system function over the course of time in people with ME/CFS – i.e. at regular intervals from the onset of symptoms.

It is likely that the key immune system abnormalities that have been identified so far (mainly involving NK cells and cytokines) will change over the course of time, especially at times of relapse and improvement/recovery.

Standard blood tests which look at most of the basic components of immune system function – e.g. immunoglobulins and Ig subclasses, complement, anti nuclear antibodies (ANA) – are often reported as being normal in ME/CFS, although atypical lymphocytes (a type of white blood cell) are sometimes found.

So the picture in ME/CFS is not one that is seen in classic immune deficiency diseases like HIV/AIDS. And there are not normally any significant findings that are consistent with an autoimmune disease.

However, as has been widely discussed, several research studies have identified fairly subtle abnormalities in NK numbers and function (NK cells are a first line of defence against infections etc).

And new research indicates that abnormalities in immune chemicals called cytokines, which may then produce low level neuroinflammation, change over the course of time.

Changes in B cell function have also been reported – which directly relates to the use of rituximab (which destroys B cells) as a possible form of treatment for ME/CFS (see later).

Recent research also indicates that the level of a substance called perforin may be reduced in ME/CFS. Perforin is a pore-forming cytolytic protein found in the granules of cytotoxic T lymphocytes and NK cells. It acts at a cellular level to kill viruses that have infected cells.

ME/CFS and perforin: www.ncbi.nlm.nih.gov/pubmed/16297163

3 MUSCLE ABNORMALITIES

There is now a significant amount of research to support a role for muscle/mitochondrial abnormalities in ME/CFS.

In relation to ME/CFS, muscle has two functions that could be involved in symptom development:

First is that muscle and muscular activity is an important source of endorphins – the body’s ‘feel good’ chemicals that also have pain-relieving properties. So lack of muscular activity in ME/CFS, and the consequent decreased production of endorphins, could play a role in pain production.

Second is the production of something called brain-derived neurotrophic factor (BDNF) that helps to increase mental processing and is also involved in the repair of nervous tissue. Reduced BDF could therefore play a role in cognitive dysfunction (problems with memory, concentration) and any recovery process that could be taking place within the nervous system.

BDNF and skeletal muscle: www.ncbi.nlm.nih.gov/pubmed/19387610

Dr Bansal said that, although there were defects in the PACE trial, it did raise the issue of the beneficial affects of physical activity and exercise.

4 NEUROENDOCRINE (brain hormone) DYSFUNCTION AND STEROID RESISTANCE

Stress can affect the production of hormones in the body – especially the stress hormone, cortisol – through its effect on the hypothalamus and the hypothalamic-pituitary-adrenal axis (cortisol is produced in the adrenal glands).

Dr Bansal spoke about some of the recent research work that his group has been doing on steroid receptors and steroid resistance at a cellular level in ME/CFS (some of which has been funded by the MEA Ramsay Research Fund) and the interesting results they are coming through. As this work has not yet been published, I will not report on the preliminary findings that were mentioned on Saturday.

As far as the use of steroids as a possible form of treatment, the results from small clinical trials using low doses of hydrocortisone have not been very useful.

However, there are indications that some people with ME/CFS report improvement when given much higher doses of steroids. The downside here is that the almost inevitable side-effects of using longer term high dose steroids outweigh any possible benefits.

A component of dark chocolate may be a simple and safe form of treatment where stress is a factor. Abstract: www.ncbi.nlm.nih.gov/pmc/articles/PMC4350893/

5 ACUTE AND CHRONIC STRESS

Stress, both acute and chronic, can play an important role in ME/CFS because it has a direct effect on several of the factors involved in the perpetuation of symptoms – immune system dysfunction, neuroendocrine dysfunction and autonomic nervous system dysfunction in particular – as well as helping to maintain the sleep disturbance that occurs in ME/CFS.

Cortisol, the hormone produced by the adrenal glands in response to stress, plays an important role in dampening down the body’s inflammatory response mechanisms (which is why steroids are used to reduce systemic inflammation). So lowered levels of cortisol (as can occur in ME/CFS) could increase the likelihood of an on-going inflammatory response.

Cortisol also affects immune system function – cellular immunity in particular – and chemical neurotransmitter systems, including 5-HT (hyroxytriptamine).

Chronic stress can also have a significant adverse effect on the conductivity and communication systems in the brain, especially in the hypothalamus (which plays a key role in control of most hormonal systems in the body) and the amygdala, both of which have been implicated in ME/CFS.

More info on the amygdala: http://neuroscience.uth.tmc.edu/s4/chapter06.html

Consequences of chronic stress can include a heightened sense of anxiety and cognitive dysfunction. There is also research which indicates that chronic stress may be implicated in the reduction of brain volume as has been reported in some of neuroimaging studies in ME/CFS.

And a past history of chronic stress, which may be relevant in some people with ME/CFS, can make it more difficult for people to cope with a major stressor in the future. In the case of ME/CFS, this could therefore act as a predisposing factor when a major stressor (i.e. an infection) appears and triggers the illness.

6 UNREFRESHING/POOR QUALITY SLEEP

As already noted, any form of chronic stress, is going to have a direct effect on the quality of sleep and may therefore help to perpetuate any existing sleep problems – non restorative sleep; fragmented sleep, daytime sleeping – that are common in ME/CFS.

Sleep also plays a very important role in repairing and restoring the normal physiological homeostatic mechanisms in the body.Iin particular, it ‘resets’ the hypothalamic thermostat.

The hypothalmus is the tiny gland deep in the brain that acts as thermostat for appetite, temperature control, respiration (which may help to explain why rapid, shallow breathing is found in some people with ME/CFS) and bowel movements, all of which can be affected in ME/CFS.

RITUXIMAB

During the Question and Answer session Dr Bansal provided a comprehensive update on the current situation regarding the proposal to carry out a clinical trial of rituximab here in the UK to see if this could replicate the benefits that have been reported from the Norwegian trial.

However, feedback relating to people in the UK who have been treated with rituximab in America, as well as US citizens who have been treated with rituximab, has been nowhere near as positive as the results that have been reported from Norway. Consequently, questions are now being asked as to how a UK trial could/should proceed and whether this is the right time to commence a UK trial.

Dr Bansal noted that it is possible that the failure of these people to respond to rituximab could be explained by different trigger factors being involved in the Norwegian population, and/or that there is something different about the patient selection process in Norway.

These concerns and uncertainties about the UK trial are due to be discussed with US colleagues shortly.

Dr Shepherd pointed out that the MEA Ramsay Research Fund still has around £60,000 of ring-fenced money to help fund a UK clinical trial of rituximab – if a suitable protocol can be developed by the group concerned (which includes Dr Bansal) and there is a definite intention to move forward with a clinical trial, and a formal application is received.

However, if a UK trial of rituximab is not going to take place, or it is going to be delayed until the results from the phase 3 clinical trial in Norway are published, the MEA Ramsay Research Fund will have to reconsider our position. This is because we have other requests for funding, including a commitment to keep the ME Biobank going for the next two years (at a cost of around £40,000 per year), which will need to be taken into consideration.

Most recent MEA statement on Rituximab:

www.meassociation.org.uk/2015/09/our-60000-rituximab-fund-is-still-available-for-a-clinical-trial-12-september-2015/

INTERACTIVE SESSION: WHAT DO PATIENTS WANT FROM A GOOD HOSPITAL BASED ME/CFS REFERRAL SERVICE?

Moderated by Bill and Janice Kent from ReMEmber

Members of the audience listed all the key components that they want to see included in a hospital based referral service for people with ME/CFS:

1. All patients to be examined by an expert consultant physician

2. Prompt referral and accurate diagnosis

3. A domiciliary service for the severely affected

4. A clinical nurse specialist for the severely affected

5. A specialist occupational therapist

6. A dedicated service for children with ME

7. Recognition from all these practitioners – and GPs – that this is a biomedical condition

8. Compulsory re-training for all healthcare professionals who provide services to ME patients

9. Better access. Some clinics are located upstairs in buildings without lifts, and some have no parking facilities (or inadequate parking)

10. Access to a specialist doctor for more than the 12 months currently offered before being referred back to their GP who is probably not knowledgeable

11. An annual review like that offered by Stoke Mandeville to spinal injury patients… This would allow ME patients to contact their ME unit (e.g. by phone) if they should encounter problems their GP can’t help with.

MANAGEMENT: DR CHARLES SHEPHERD

Using the MEA Management File on ’10 Key Aspects of Management’ as a basis for this presentation, CS went through what he regards as the 10 key components that need to be included in any patient management programme.

1 EARLY AND ACCURATE DIAGNOSIS (EAD)

Dr Shepherd summarised the information in the new MEA information leaflet on EAD for patients and doctors – this can be downloaded (free) from the MEA website:

www.meassociation.org.uk/shop/management-leaflets/the-importance-of-early-and-accurate-diagnosis/

He emphasised that:

• doctors do not have to wait six months before they can diagnose and treat people with ME/CFS – in most straightforward cases this can and should be done by three to four months from onset of symptoms

• there is a list of essential baseline ‘blood test’ investigations that should always be checked before a diagnosis of ME/CFS is confirmed

• there are a number of other investigations that should be arranged in patients where a symptom is atypical or is more severe than would be expected in ME/CFS (e.g. significant joint pain, severe sleep disturbance)

• obtaining an early and accurate diagnosis has many advantages – most important being the development of an individual management plan once a diagnosis (or working diagnosis) has been confirmed

2 FIND A GOOD DOCTOR

Obviously, this is far easier said than done!

DrShepherd covered ways in which people can change their GP or move to another GP practice and said that the Countess of Mar has established through a parliamentary question that people can ask to be referred to a specialist of their choice outside their local area.

New MEA information leaflet covering Specialist Referrals: www.meassociation.org.uk/shop/management-leaflets/specialist-referrals/

3 DRUGS THAT CAN HELP WITH SYMPTOMS

Whilst we do not have a safe and effective form of treatment for the underlying disease process in ME/CFS, there are a number of over-the-counter and prescription-only drugs that can be helpful in the management of specific ME/CFS symptoms – in particular, pain, irritable bowel syndrome symptoms and sleep disturbance (as emphasised by Dr Bansal in his presentation).

In relation to sleep: In addition to simple self-help measures, there are a number of drugs that can be helpful in managing the various types of sleep disturbance that occur in ME/CFS, as well as complications of sleep disturbance that may occur such as myoclonus (sudden jerking movements) and restless legs syndrome. These are amitriptyline, short-acting hypnotics, and melatonin.

The MEA has information leaflets covering the practical management of sleep disturbance and restless legs syndrome: http://www.meassociation.org.uk/shop/management-leaflets/sleep-disturbance/

In relation to pain, over-the-counter painkillers are often infective in relieving muscle, joint or nerve pain in ME/CFS. But there is a ‘step ladder’ of prescription-only drugs that can be very helpful where pain is a significant factor. Examples include low dose amitriptyline, gabapentin or pregabalin and duloxetine. Non-drug approaches such as acupuncture or a TENS machine are also worth considering in some cases.

MEA information leaflet on Pain Management: www.meassociation.org.uk/shop/management-leaflets/coping-with-pain/

There are also plenty of simple self-help strategies that can help to relieve other common symptoms such as sore throats and symptoms relating to orthostatic intolerance or hypotension (lowered blood pressure on standing).

4 BALANCING ACTIVITY AND REST

Following on from the muscle research referred to by Dr Bansal, that muscle activity is involved in the production of both endorphins (which reduce pain) and BDNF (which helps with nervous system repair), we clearly need more research into finding the ways that people with ME/CFS can carry out some form of very flexible and gradually increasing physical activity that is going to harness the benefits of physical activity but is not going to induce post-exertional malaise/symptom exacerbations at the same time.

CS referred to the results of the MEA report on patient evidence relating to safety and efficacy of CBT, GET and Pacing and the controversies surrounding the PACE trial.

MEA report: www.meassociation.org.uk/how-you-can-help/introduction-to-our-cbt-get-and-pacing-report/

Pacing is the form of activity/energy management that is favoured by the vast majority of people with ME/CFS and this needs to take account of stage, severity and variability of ME/CFS. Activity management also needs to cover emotional and mental energy.

The MEA has information leaflets covering both Activity/Energy Management and Pacing: www.meassociation.org.uk/shop/management-leaflets/energy-management/

5 DEALING WITH EMOTIONAL AND MENTAL HEALTH ISSUES

As with any chronic debilitating condition, some people with ME/CFS will go on develop mental health problems, including clinical depression during the course of their illness.

Depression needs to be recognised and treated where it occurs.

Symptoms which are more consistent with clinical depression than feeling fed up – which is quite common in ME/CFS – include:

• Worthlessness or loss of self-esteem

• Anhedonia – loss of interest

• Constant fatigue

• Tearful

• Suicidal thoughts – must be taken seriously

• Suicidal intentions

The MEA has an information leaflet covering depression and the use of antidepressants in ME/CFS: htwww.meassociation.org.uk/shop/management-leaflets/antidepressants/

Taking up Dr Bansal’s remarks on role of acute and chronic stress, it is equally important to try and deal with any factors that are causing chronic stress.

The MEA has an information leaflet covering the management of stress in ME/CFS: www.meassociation.org.uk/shop/management-leaflets/coping-with-stress/

6 EMPLOYMENT AND EDUCATION

Dr Shepherd referred to the fact that ME/CFS is covered by both the Disability Discrimination Act and the 2010 Equality Act. Both of these have important implications for modification to hours, duties, etc.

The MEA has a new booklet covering all aspects of Employment and Occupation Health: www.meassociation.org.uk/shop/management-leaflets/employment-advice/

We also have a leaflet covering tuition and exam modification for students with ME/CFS: www.meassociation.org.uk/shop/to-whom-letters/exam-arrangements/

7 STATE BENEFITS

Following the departure of Ian Duncan Smith from thew Department of Work and Pensions, Dr Shepherd reported that he understands from his Westminster briefings that there are no current plans for further major reforms involving ESA or PIP.

He stressed the importance of stating whether people can carry out the various descriptor tasks for ESA and PIP reliably, repeatedly, safely (to you and to others) and in a timely manner, as well as the need to gather as much written supportive medical evidence (from anyone involved in your care) during the application process.

People with ME/CFS should appeal if an ESA or PIP application is refused because there is a high rate of success on appeal.

The MEA has detailed guidance on how to fill in ESA and PIP paperwork.

In addition, people with ME/CFS are eligible to claim a Blue Badge if they meet the mobility criteria. Unfortunately, government guidance to local councils is often misinterpreted to mean that they cannot grant a Blue Badge to people with ME/CFS.

MEA guide to ESA: www.meassociation.org.uk/shop/benefits-leaflets/esa-guide/

MEA guide to PIP: www.meassociation.org.uk/shop/benefits-leaflets/pip-guide/

MEA guidance on Blue Badge applications: httpwww.meassociation.org.uk/shop/to-whom-letters/blue-badge-evidence/

8 SOCIAL CARE AND SUPPORT

People with severe ME/CFS are often entitled to social care but are not receiving a social care package.

Dr Shepherd referred to the All Party Parliamentary Group (APPG) on ME inquiry into Social Care and the excellent work that has been done by Catherine Hale in identifying the problems that exist.

The MEA has an information leaflet on social care, and how to apply for a social care assessment. This is written by our professional adviser on social care, Cathy Stillman-Low:

www.meassociation.org.uk/shop/benefits-leaflets/help-social-services/

9 VITAMINS MINERALS AND SUPPLEMENTS

There is currently very little sound research evidence to demonstrate that mineral or vitamin deficiencies occur in ME/CFS.

One important exception is the possibility of vitamin D deficiency in people with moderate or severe ME/CFS who are housebound and not being exposed to sunlight and may also have dietary modifications/restrictions.

The National Osteoporosis society (NOS) guidelines (UK, 2013) and the Institute of Medicine (US) classify vitamin D results as follows:

• 25-hydroxyvitamin D of less than 30 nmol/L is deficient

• 25-hydroxyvitamin D of 30-50 nmol/L may be inadequate in some people

• 25-hydroxyvitamin D of greater than 50 nmol/L is sufficient for almost the whole population.

There is also very little evidence from clinical trials to show that vitamins, minerals and supplements are of any significant benefit in ME/CFS.

Possible exceptions include carnitine, eicosapentaenoic acid (EPA) and Ubiqinone 10 (Co-Enzyme Q10) where a small clinical trial was published in May. For more information see:

www.meassociation.org.uk/2016/05/tgi-friday-our-weekly-round-up-of-recently-published-research-abstracts-6-may-2016/

Exclusions diets, including the FODMAP diet, may be helpful where there are irritable bowel syndrome type symptoms but more radical changes to diet can cause more harm than good.

Do not go ‘gluten-free’ until a screening test has excluded coeliac disease.

10 ALTERNATIVE AND COMPLEMENTARY SECTOR (ACM)

As with orthodox medicine, the ACM sector does not have a safe and effective form of treatment for ME/CFS.

Acupuncture for pain or meditation for stress may be helpful and approaches such as homoeopathy are worth considering if you have faith in this approach.

Dr Shepherd cautioned against spending large amounts on money in the ACM sector on unproven tests and treatments.

MEA leaflet on common ACMs: www.meassociation.org.uk/shop/management-leaflets/alternalternative-approaches/

FURTHER INFORMATION

ReMEmber website: www.remembercfs.org.uk

ME/CFS Service at St Helier Hospital: www.epsom-sthelier.nhs.uk/chronic-fatigue-syndrome

ME/CFS Sussex Service: htwww.sussexcommunity.nhs.uk/services/servicedetails.htm?directoryID=16292

Dr Charles Shepherd

Honorary Medical Adviser, The ME Association

16 May 2016