A Unified Mechanism for Functional Neurological Symptoms

Lead Research Organisation: St George's University of London
Department Name: Molecular & Clinical Sci Research Inst

Abstract

From the earliest medical records to the present day, doctors have separated out a group of patients from those with a typical "organic" cause for their physical symptoms. These patients have had many labels: "hysteria","conversion", "medically unexplained", "functional". Patients with functional symptoms are seen across primary care and all medical specialities, but are particularly common in neurological practice. Here they make up about 16% of those seen in neurology outpatient clinics, making functional neurological symptoms (FNS) one of the commonest diagnosis of neurology outpatients. People with these symptoms are, as a group, as disabled and experience as poor a quality of life as patients with Parkinson's disease or multiple sclerosis. Despite this, clinical services for such patients are poorly developed, research into causes of symptoms and treatment is very limited, and attitudes in society and within medicine to patients with functional symptoms are often poor.

With this work, we want to test a new theory for how functional symptoms can arise from the brain. One of the difficulties in understanding functional symptoms is that the brain and the rest of the nervous system appears to be intact, despite severe symptoms. Indeed in patients with some types of symptoms, for example people with limb weakness, it is possible to demonstrate on examination that the apparently weak limb can generate normal power, even though the patient cannot get this to happen him or herself. We believe it is vitally important for research and development of better diagnosis and treatment for us to understand how functional symptoms are produced by the brain. We have previously developed a theory that we believe provides a reasonable mechanism for how symptoms are produced. We have already gathered evidence that supports this theory in patients who have functional symptoms affecting movement (e.g. weakness, tremor) and sensation (e.g. numbness). We now want to move forward and test if this theory can also account for symptoms experienced by people with chronic fatigue syndrome and non-epileptic attack disorder.

Chronic fatigue syndrome is a disabling condition characterised by persistent fatigue in the absence of a clear medical cause. We believe that fatigue in chronic fatigue syndrome may occur because of abnormal activation of a network of structures in the brain that are usually involved in signalling the presence of infection and inflammation in the body and which give rise to a common set of symptoms experienced by everyone (and indeed across species) when infection or inflammation occur (known as the "sickness response"). This sickness response is usually short-lived, but we believe that the system could be abnormally activated in people with chronic fatigue syndrome in the absence of any ongoing infection or inflammation in the body.

Non-epileptic attack disorder is a common cause of fit-like episodes which can be prolonged and very frequent. We know that these attacks are different from epilepsy, as there is no epileptic activity on brainwave (EEG) recordings performed during such attacks, but it is not known what is happening in the brain prior to and during attacks that could be responsible for the symptoms. We believe that changes in the brain's focus of attention in an abnormal way towards the body is an important part of triggering the attacks, and we will test this in our study.

If our theory is correct, then when people get better with treatment then we should see corresponding changes in the way the brain is working. We will therefore test if particular aspects of brain function which our theory predicts are involved in generating functional symptoms become more normal when people with functional symptoms go through successful treatment. This would be a key step in proving or disproving our theory for how functional symptoms can be produced by the brain, and will help with future treatment development.

Technical Summary

Functional neurological symptoms (FNS) are one of the commonest reasons for people to come to see a neurologist - 16% of all new neurology outpatients have these symptoms. Patients with FNS (also known as medically unexplained symptoms, psychogenic symptoms, non-organic symptoms) are typically of working age (average age 40), and 67% remain with persistent disabling symptoms, leading in 50% of cases to cessation of work and in 27% to receipt of illness-related financial benefits.

A major gap in understanding FNS is the absence of a theory to explain how, at a mechanistic level, physical symptoms of the sort seen in FNS could arise from the brain. A secondary effect of this "explanatory gap" is that within FNS, different symptom types are often classified and conceptualized differently, based largely on historical views on aetiology. This fragmentation of FNS is contrary to the very common co-occurrence of different functional symptoms in the same patient which would suggest a shared pathophysiological mechanism for FNS. The aim of the work proposed here is to test a novel pathophysiological theory of functional neurological symptoms. We will build on existing work in patients with functional movement disorders and functional sensory loss to test if this theory can also provide a convincing mechanistic explanation for paroxysmal motor symptoms (non-epileptic attacks) and interoceptive symptoms (fatigue). We will combine this work with experimental studies in patients with functional motor symptoms before and after treatment. This will assess the link between change in clinical symptom severity and change in markers of our proposed pathophysiological mechanism and will demonstrate its relevance to clinical symptomatology and provide potential biomarkers for use in future therapeutic studies.

Planned Impact

1. In the longer term, the key beneficiary of this work will be patients with functional neurological symptoms. We aim here to provide a unified mechanistic account of symptom production. We believe that this will facilitate diagnosis, evaluation of treatment and development of novel treatment. We believe it will be particularly important in helping to rebalance both lay and medical conceptions of functional symptoms which are often polarised between a firmly biological model and a firmly psychological one. We believe that this work can provide a bridge between these models by providing a biologically plausible mechanism for symptom production, but one which is not detached from psychological/cognitive mechanisms and aetiological risk factors.

2. Researchers and clinicians working in the field of functional neurological symptoms and functional somatic symptoms more widely across medical specialities will benefit from this work. At the moment there is a confusing division between researchers and clinicians who work with patients with different functional symptoms, and we believe this work can help unify them behind a common mechanistic account of symptom generation.

3. This work will benefit patients with other neurological and general medical disorders. About 12% of patients with neurological illness also have functional symptoms. This phenomenon, often known as "functional overlay" is often not highlighted as an additional cause of disability in patients with neurological illness, perhaps due to continued focus on specific aetiological risk factors (e.g. childhood emotional trauma, recent life events) as the cause of functional symptoms. These factors, while important in some, are neither necessary nor sufficient for functional symptoms to develop. Our work, based as it is on providing a mechanistic understanding of functional symptoms, may help to change attitudes to functional overlay in neurological and general medical practice, could help provide an experimental rationale for assessment of such symptoms in patients with neurological and other disorders, and could aid proactive identification and treatment of functional symptoms when thy occur in the context of other illness.

Publications

10 25 50
 
Description Development of Neuropscyhiatry Specification for NHS England
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description NICE Guideline Proposal
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description Service development in FND
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Participation in a advisory committee
 
Description Training of Healthcare professionals in FND
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact Through multiple speaking engagements, locally, regionally, nationally and internationally I have presented the case for inpriovements in diagnosis and care for people with FND.
 
Description Doctoral College PhD Studentship
Amount £80,000 (GBP)
Organisation University of Surrey 
Sector Academic/University
Country United Kingdom
Start 10/2018 
End 09/2021
 
Title Automated EEG analysis pipeline for non-epileptic attacks 
Description With collaborators a the university of Surrey we have developed an EEG analysis pipeline which is specifically designed for video telemetry data to assess group spectral alterations that may be related to the presence of non-epileptic attacks/seizures. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2019 
Provided To Others? No  
Impact Increased speed of data analysis - suitability for "big data" analysis 
 
Description Sussex CFS Service 
Organisation Brighton and Sussex University Hospitals NHS Trust
Country United Kingdom 
Sector Public 
PI Contribution We have brought the opportunity for the Sussex CFS service to be involved in our research
Collaborator Contribution They have helped us in determining the best way to recruit patients with CFS and to ensure that we are recruiting appropriate patients to the study
Impact None Yet
Start Year 2017
 
Description Telemetry Service at Kings 
Organisation National Institute for Health Research
Department NIHR Biomedical Research Centre (Guy's, St Thomas' and KCL)
Country United Kingdom 
Sector Hospitals 
PI Contribution We have brought our ideas regarding the potential utility of looking at EEG in people with non-epileptic attacks to determine EEG features predicting onset of attacks
Collaborator Contribution They have provided access to a unique database of prolonged EEG recordings in patients with epilepsy and non-epileptic attacks recorded in their own homes.
Impact We have now performed extensive data classification and analysis on this EEG dataset, and we are making significant progress with these data to our aim of determining EEG correlates of non-epileptic attacks.
Start Year 2016
 
Description University of Brighton Sports Science Department 
Organisation University of Brighton
Department Faculty of Science and Engineering
Country United Kingdom 
Sector Academic/University 
PI Contribution We have provided expertise in the specific problems faced by people with Chronic Fatigue Syndrome, in particular post-exertional malaise, which is a novel area of research for the department of sports and exercise science. Through the collaboration they will have the opportunity to integrate fMRI with measurements of exertion.
Collaborator Contribution They have provided essential expertise in the development of an exercise protocol suitable for studying post-exertional malaise in people with chronic fatigue syndrome.
Impact This collaboration has allowed us to develop a suitable ethics application for the chronic fatigue syndrome aspect of this study, and will improve the scientific validity of the planned experimental work.
Start Year 2016
 
Description University of Surrey Department of Biomedical Engineering 
Organisation University of Surrey
Department Department of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution We have brought our ideas regarding the potential use of EEG in detecting features that predict the onset of a non-epileptic attack.
Collaborator Contribution They have brought the potential of specialised EEG analysis techniques, for example measurements of entropy, to our study, which we hope may be of use in determining features that predict the onset of non-epileptic attacks.
Impact None yet
Start Year 2016
 
Description Application for NICE guidlines for Functional neurological disorder 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Together with medical colleagues and the patient charity FNDHope I have opened discussions with NICE about the development of NICE guidelines for Functional Neurological Disorder. We are meeting with the head of guideline in April.
Year(s) Of Engagement Activity 2019
 
Description FND Workshops 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact I participated in a patient workshop for patients and family members with functional neurological disorder. The event was organised with one of the main patient charities for functional neruological disorder: FNDHope. I am participating in a similar workshop later this year for another patient charity: FND Action.
Year(s) Of Engagement Activity 2016
 
Description Founder member of the International Functional Neurological Disorder Society 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I was integral to the formation of the new International Functional Neurological Disorder Society. We have planned our first congress in Boston in 2020.
Year(s) Of Engagement Activity 2019
 
Description NHS England Public Consultation Exercise 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact I have instigated and led a patient consultation exercise for NHS England regarding service development for people with FND - this has involved patient/carer workshops to discuss proposals and to get feedback on proposals so as to develop them further.
Year(s) Of Engagement Activity 2018
 
Description Neuropsychiatry Specificaiton for NHS England 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact I was involved in the working party developing the new national (NHS England) specification for Neuropsychiatry services, the bulk of which relates to assessment and treatment of FND.
Year(s) Of Engagement Activity 2018
 
Description Patient Charity Engagement 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact I am on the medical advisory board for FND Hope and FND Action and am aregular contributor to their patient engagement events including webchats and online interviews
Year(s) Of Engagement Activity 2018,2019
URL http://www.FNDHope.orgwww.FNDAction.org.uk
 
Description Spotlight on Science 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Lecture on perception and movement control linked to functional neurological symptoms
Year(s) Of Engagement Activity 2019