Sequential surface EMG recordings in motor neurone disease. Fasciculations as a biomarker of motor neurone health.

Motor neurone disease (MND) is diagnosed in 1,200 people in the UK every year. It causes progressive paralysis and death on average within three years of symptom onset and there is currently only one licensed drug (riluzole) with only modest survival benefit. Drug trials in MND are time-consuming for patients and expensive for funders. A biomarker of disease activity is urgently needed to accelerate the pace of drug discovery.

MND is caused by the progressive dysfunction and death of motor neurons. Ailing motor neurons in the spinal cord are electrically unstable and spontaneously discharge electrical impulses that cause small groups of muscle fibres to twitch (known as fasciculations). When the motor neuron becomes electrically unresponsive these fasciculations stop and the motor neuron subsequently dies. There is also some experimental evidence that the fasciculations may cause chemical disturbances that hasten the death of motor neurons. These muscle fasciculations can be seen under the skin and are one of the hallmark clinical signs of MND. Thus, recording the site and frequency of fasciculations over time may provide a good measure of motor neuron health.

Conventional electrical testing (needle electromyography, NEMG) involves putting a fine needle deep into muscles to record fasciculations and this can only be done in a hospital. NEMG only detects electrical activity within a minute field, records data for only a few minutes and is quite painful so few patients would tolerate repeated testing. High-density surface EMG (HDSEMG), using a non-invasive sensor that sticks to the skin, can record fasciculations over a field that is 100 times larger than the needle. The test is painless so fasciculations can be recorded over many hours and repeated frequently.

Under the guidance of Professors Chris Shaw and Kerry Mills, eminent in their respective fields of motor neurone disease and neurophysiology, I, as a clinician and neurology trainee, am currently undertaking a six-month preparatory feasibility study at King's College London. In this study, we are making use of commercially available HDSEMG sensors to record fasciculations at rest in patients with MND. We have recruited eight patients and are taking representative recordings from all four limbs simultaneously. The purpose of this study is to ensure this method is comfortable and convenient for patients, and that these preliminary data can be interpreted in the way we expect.

We predict that the site, frequency and shape of fasciculations might provide a more sensitive measure of disease progression in an individual. Once calibrated, this method may then be used to assess the positive impact of a new drug if it reduces the regional spread and frequency of fasciculations. In order to calibrate this technique, we will conduct a 12-month longitudinal study, recruiting 24 patients from the King's College Hospital Motor Nerve Clinic, comprising a mixture of patients with MND and those with benign fasciculation syndrome. Patients in this latter group have fasciculations but do not develop weakness and have normal lifespans. They are therefore an optimal control group. At each visit, we will take resting HDSEMG recordings from all four limbs and perform standard clinical measures of disease progression. In addition to survival, these are the standard tests we use to see whether a drug is working in clinical trials.

Ultimately, through collaboration with Bioengineering colleagues at Imperial College London, we hope to design a wearable ergonomic garment with embedded HDSEMG and remote data transfer capabilities. We envisage testing and calibrating this new equipment against our validated, well-established system. The portability of such a powerful tool will allow the assessment of patients in their own homes, potentially increasing the intensity of objective monitoring. This will prove an invaluable addition to future clinical drug trials.

Aims: To record the site, frequency and morphology of muscle fasciculations in MND patients and controls with benign fasciculation syndrome (BFS). We will compare our data on the disease progression within individual muscles and between anatomical regions with standard clinical measures of disease progression used in drug trials.

Methodology:
Phase 1 - We will conduct a 12-month prospective study, recruiting 24 patients from the King's College Hospital Motor Nerve Clinic, comprising 20 patients with MND and four with BFS. All MND patients recruited will have a diagnosis of probable or definite ALS by the revised El Escorial Criteria.
At each monthly visit, we will take simultaneous 60-minute resting HDSEMG recordings from four muscles (biceps brachii and gastrocnemii). Intervals of one month may not capture the dying process of individual motor units. Therefore, we plan to incorporate a nested component, whereby four MND patients will attend weekly for the first two months.
We will use two TMSi Refa-64 devices using 4x8-array sensors. Sensor placement will be standardized between visits. We will prune the recording to leave only epochs of total relaxation. We will perform standard clinical measures of disease progression at each visit.

Phase 2- Our bioengineer collaborators at Imperial College are currently designing and testing prototypes of the sensors and transmission devices. We hope to validate this new equipment in a small-scale study (six patients), assessed at two time-points three months apart. We hope to test this equipment in our patients' homes and assess the benefit of remote sensing technology.

Medical opportunities: If we can prove that HDSEMG parameters are a more sensitive measure of motor neuron health and accurately predict disease progression, then this technique could be used to rapidly identify positive drug effects and accelerate the process of drug discovery.

Motor neurone disease (MND) is diagnosed in 1,200 people in the UK every year. It causes progressive paralysis and death on average within three years of symptom onset and there is currently only one licensed drug (riluzole) with only modest survival benefit. Weakness starts in one part of the body and it spreads until the person is unable to walk, dress, feed and toilet themselves. Eventually they are unable to swallow and speak, ultimately dying from breathing difficulties. MND is the most common reason people seek euthanasia.

Most drug trials in MND require ~400 patients and cost £10m to complete. Current drug trials test muscle strength, breathing, activities of daily living and survival. These are insensitive and indirect measures of motor neuron health. When motor neurons begin to fail they become electrically unstable causing muscle fibres to contract (fasciculate). By measuring how often and in which muscle groups these fasciculations occur we can track disease progression. We plan to use high-density surface electromyography (HDSEMG) recordings to map the pattern of fasciculations in people with MND over 12 months and compare our results with standard tests of disease progression. To our knowledge, the serial detection of fasciculations in this way over an extended period of time has never been studied before in a MND population.

The most noticeable impact of this research will be on patients with motor neurone disease and their family members. We aim to calibrate a device that can objectify the therapeutic effects of new drugs in a shorter period of time, thereby accelerating effective drug discovery. The technique is non-invasive, comfortable and convenient for patients. Once incorporated into a wearable garment, through collaboration with Bioengineering colleagues, we hope to monitor patients' disease progression at home. This will significantly improve some of the logistical challenges associated with large-scale drug trials, especially in a disease where patients' ability to travel to and from hospital becomes increasingly more restricted. This would influence drug companies' incentives to setup large-scale clinical trials if the feasibility of monitoring disease decline is enhanced.

The assimilation, storage, remote transfer and analysis of large datasets in this study may be applicable to other areas of biological engineering. The development of a new device in the latter phase of the study may have generalizable components to enhance the remote real-time electro-physiological tracking of other diseases. This is analogous to a separate study currently being recruited for at King's. This involves tracking the movement and heart rate of MND patients for 3-day periods every month. These data are periodically relayed to McLaren Applied Technologies and Glaxo Smith Kline, as the sponsors of the study, for analysis. Through collaboration with these commercial companies, the lessons learnt and methodologies used in this study could in the future be similarly utilized for high-density surface EMG tracking.

The potential development of useful prognostic criteria, which can be applied early in the disease process, would help plan future patient management. This would benefit individual patients, the local service provider, as well as more regional or national health commissioners. The distribution and availability of specialist services, such as multidisciplinary MND clinics, community therapy services, respiratory specialists, palliative care and hospice places could be more efficiently managed. This becomes particularly beneficial when patients can be sub-classified into disease stages more robustly, as service requirements inevitably increase as the disease progresses.