Insights and Outcomes: A Consensus Meeting On Earlier Diagnosis of ALS/MND

Carol Birks, CEO, and Gethin Thomas, Executive Director of Research, MND Australia, recently participated in a meeting with experts from across the world to help improve early diagnosis of ALS/MND.

Earlier diagnosis of MND is very important because it can help give current and future therapies the best chance of stopping, or even reversing, the disease. Carol and Gethin have reported back on major discussion at the meeting, including developments in the criteria and techniques used for MND diagnosis, and ways of assessing upper and lower motor neurons, which are crucial for confirming diagnosis and informing treatment options.

The challenge now is to build on insights generated through discussion. It is hoped that a new consensus paper can help reach scientific agreement on improving earlier diagnosis, and meeting the needs of future clinical trials.

About the meeting

MND Australia was honoured to be invited to attend this potentially historic meeting as a representative of ALS/MND Associations. Supported by the International Federation of Neurophysiologists, World Federation of Neurologists, the ALS Association and the MND Association of England, Wales and Northern Ireland and organised by Professors Matthew Kiernan, Ryuji Kaji and David Burke this meeting involved leading neurologists and neurophysiologists from 11 countries as well as MND Australia and patient and carer representatives from Australia, Sean and Pauline Dorney.

Held over three days in late September, 2019, the aim of the meeting was to improve the ability to diagnose ALS/MND earlier and when clinical symptoms are minimal. Earlier diagnosis gives current and future therapies the best chance of success in stopping, or even reversing, the disease process in the very early stages.

Participants were tasked with looking at methods for demonstrating upper motor neuron (UMN) involvement and developments over the last 10 years that have enhanced the diagnostic value of current Awaji criteria which can now be recommended for inclusion in patient assessments.

Discussions included the diagnostic value of neurophysiological procedures available as well as imaging and genetics to improve early diagnosis and to support a personalised approach for future clinical trials. 

What is Awaji? 

The Awaji criteria were published in 2008 based on a meeting in 2006 and focus solely on lower motor neuron (LMN) features in assisting clinicians to make a diagnosis of ALS/MND. The aim was to further enhance the El Escorial Criteria developed in 1990 and published in 1994.

The El Escorial Criteria were revised in 2015 and, along with the Awaji Criteria, remain the gold standard for the diagnosis of ALS/MND.

The El Escorial Criteria involves clinical examination as well as evidence of progression and abnormal EMG (electromyography) findings to enable clinician to diagnose the type of ALS/MND their patient may have.

The Awaji Criteria recommended that neurophysiological data should also be incorporated as evidence of LMN involvement and this has had a dramatic influence on early diagnosis and recruitment into trials. However, the authors of this criteria noted that “methods of detection of upper motor neuron (UMN) abnormality appear sensitive but require further study, particularly regarding their value when clinical signs of upper motor involvement are uncertain.”

The Awaji Criteria are over 10 years old and now is the time to review whether advances in techniques to measure UMN involvement should be included in diagnostic criteria and whether LMN criteria can be further refined.

Why is assessing UMN and LMN involvement important?

Upper motor neurons (UMN) carry impulses for movement from the brain to the spinal cord. UMN’s connect with the lower motor neurons (LMN) in the spinal cord which then transmit the impulse to the muscles and trigger movement. If UMN’s are involved symptoms will include weakness, spasticity and over active or over responsive reflexes. If LMN’s are involved symptoms will include muscle weakness and wasting, fasciculations (muscle twitching) and weak or absent reflexes.

Most people with ALS will have a mixture of UMN and LMN symptoms. Other forms of motor neurone disease might have involvement of just UMN’s or just LMN’s, at least initially. Determining and monitoring UMN and LMN involvement is important for confirming diagnosis, assessing prognosis and determining treatment options.

What was discussed? 

The first day focused on neurophysiological biomarkers to assist with diagnosis, prognosis and monitoring disease progression especially in clinical trials. The desperate need for more effective treatments remained front and centre over the two day meeting. All agreed on the need to accelerate testing of new therapies and in order to do that reliable and objective biomarkers to supplement clinical outcome measures such as the ALS FRS are vital.

The group noted that there had been a lots of progress on this front since 2006 but the search for a perfect biomarker continues. Current biomarkers include brain imaging techniques such as MRI and PET scans, electrophysiological biomarkers such as motor unit number estimation (MUNE) and transcranial magnetic stimulation (TMS), biochemical biomarkers such as plasma creatinine and plasma uric acid and the newly reported biomarkers including neurofilaments and urinary p75.

Lively debate ensued regarding the merits and otherwise of these techniques. The need to be innovative and to review what could be done better was a common theme. There was consensus that all clinical trials should also be testing the various biomarkers currently available. There was acute awareness that over the next five years there could well be a therapy available for some types of ALS/MND and it will be vital to ensure people have access as early as possible in the disease process. For some people with the familial form a reliable and objective biomarker could pick up disease progression before the person experiences any symptoms.

Discussion on Day 1 progressed to review what a clinician can do with routine diagnostic equipment and the effectiveness of new methods in assessing and measuring LMN involvement and fasciculations. The final session on genetics highlighted the acceleration in discovery of disease causing mutations and increased understanding of the many variants which may or may not lead to a person developing ALS/MND.  Familiarity and genetics could be included in El Escorial Criteria but great care would need to be taken in the definitions, the accuracy of the testing and interpretation of the data.

The final word on Day 1 went to Sean Dorney who expressed his admiration for the robust debate. Sean, ABC Foreign Correspondent to PNG for over 17 years, reflected on his diagnostic experience. A weakness in his big toe prompted his GP to refer him to a foot doctor, who then referred him to a neurologist who then referred him to an MND specific specialist in Brisbane. He encouraged everyone present to keep fighting on to increase understanding of this very complex disease, keep researching and keep discussions going to help accelerate solutions.

Day 2 discussions focused on upper motor neuron changes and whether ALS/MND should be classified as a brain disease. The diagnostic equipment available to support assessment of UMN involvement were reviewed and discussed. Some interesting questions were posed and hotly debated:

1. ALS is a clinical syndrome not a disease? 
2. ALS has a focal clinical onset?
3. Spread in ALS is non-random?
4. Is lower motor neuron predominant ALS a better term than progressive muscular atrophy (PMA)? 

These discussions questioned whether we should unify behind the term ALS as a unique clinical syndrome and what, if any, benefits there would be in selecting patients for clinical trials from an ALS syndrome point of view as opposed to a clinical phenotype point of view. 

Next steps?

Development of an ALS consensus paper(s) to improve earlier diagnosis and meet the needs of future clinical trials.