A Unified Mechanism for Functional Neurological Symptoms

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.

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.

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.