Clinical FeaturesNeurology

Current Management of MND

Motor Neuron Disease (MND), also known as Amyotrophic Lateral Sclerosis (ALS) is characterized by combined upper and lower motor neuron degeneration with progression to death within 3 years. There is now compelling evidence to indicate that MND should be classified as a heterogenous neurodegenerative disorder that primarily affects upper and lower motor neurons (corticospinal and anterior horn cells) but that also involves other parts of the neuroaxis. There is now extensive evidence from clinical, imaging, pathology and genetic studies of extensive overlap between ALS and Frontotemporal dementia (FTD). Indeed, up to 70% of incident MND patients develop cognitive and behavioural impairment, with 13% of patients presenting with co-morbid behavioural variant FTD. The most common cognitive impairment presents as executive and language function, with relative preservation of spatial domains. Social cognitive and behavioural change is common, and apathy occurs in up to 70% of patients.

There is no individual test that provides a definitive diagnosis of MND. All investigations are aimed at confirming the presence of upper and lower motor neuron degeneration, while excluding other conditions that could mimic the clinical presentation, such as motor neuropathies (e.g. multifocal motor neuropathy with conduction block), cervical myelopathy with polyradiculopathy, multiple sclerosis and other rare metabolic conditions. Neuroimaging is performed to exclude structural pathology, and neurophysiological studies are performed to confirm the presence of acute and chronic denervation, the absence of sensory findings, and to ensure that mimic syndromes are excluded.

A series of diagnostic criteria have established for ALS/MND – the most recently published being the Gold Coast Criteria, requiring progressive upper and lower motor neuron signs in at least region, and exclusion of other possible causes (BOX 1). However, there remains an urgent need for diagnostic biomarkers for MND. Candidate markers include neurofilaments which are elevated in CSF and blood in MND, altered levels of circulating microRNA, imaging and neurophysiology based technologies, although additional studies are required before these can be used in clinical practice. For most patients, definitive diagnosis takes 12 -15 months, and most patients are seen by 3-5 different healthcare professionals before the diagnosis is entertained. “Red Flags” that should alert the clinician to the possibility of MND include progressive painless loss of function in bulbar or limb regions, unexplained weight associated with dyspnoea, and the presence of progress dysarthria with associated tongue fasciculations. A number of initiatives to increase awareness have been launched, including a recent policy paper presented to the European parliament in September 2023 https://www.

In Ireland, the diagnosis and management of MND has been included as part of the HSE Modernised Care pathways who/strategic-programmesoffice-overview/modernised-carepathways/. The pathway provides a streamlined approach from first symptom of MND through to ongoing management integrated by the specialist multidisciplinary team at the national centre for ALS/MND in Beaumont Hospital, with outreach to community and palliative care services, and with extensive links to the Irish Motor Neuron Disease Association.


The epidemiology of MND has been tracked in Ireland since 1994, using the Irish ALS/MND population based register. Ongoing surveillance has shown that the mean age of onset of MND is in the early 60s. Although the disease can occur throughout life, the peak age of onset is in the early 70s. There has been slight increase in both the mean and peak age of onset in the past 10 years, the reasons for which are not clear, but may related to the improving overall health of the population. The incidence in Ireland is also increasing, partly as a result of the ageing population. At present, there are approximately 140 new diagnoses every year. The prevalence in Ireland is 8.5/100,000, or approximately 450 people living with the condition. Based on data from the Irish ALS/ MND Register, we estimate that the overall lifetime risk in Ireland for developing ALS is approximately 1:350.


Population based studies have suggested that the development of the disease occurs in 6 steps, the first of which is genetic predisposition, and the remainder are probably environmental factors that have not been fully elucidated. MND is sometimes segregated into “familial” and “sporadic” subtypes of disease, although heritability studies indicate that genetic factors account for up to 51% of overall risk. These genetic factors include single genes of major effect, and/or a polygenic risk that most likely interacts with as yet unknown environmental factors.

In Ireland around 15-10% of probands report a family history of MND or FTD, albeit with incomplete penetrance in the majority of kindreds. Within populations of European origin (Europe and USA) four genes account for up to 70% of all cases of “familial” ALS, namely C9orf72, TARDBP (coding for TDP43), SOD1 and FUS. In Ireland, the C9orf72 variant comprising a hexanucleotide repeat expansion, accounts for around 10% of all ALS, and 50% of the familial form of the disease. The prevalence of the remaining gene variants is extremely low.

Disease penetrance in families is incomplete – most recent estimates for C9orf72-related MND are in the region of 20%. This low penetrance is in part explained by evolving evidence that the presence of the repeat expansion, although associated with disease, may a require addition factors for disease to manifest. Irish studies have shown that in families of those with the C9orf72 repeat expansion, the disease may also occur more frequently than expected in family members who do not carry the repeat expansion. Additionally, recent studies from the Irish ALS/MND group has found that cognitive performance of families carrying the C9orf72 variant differs from controls, regardless of the presence of the mutation. This suggest that unaffected family members carry additional factors that increase their risk of both cognitive change and an overall risk of developing MND.

There is also evolving evidence of wider disease “endophenotypes” among family members of MND probands which is most likely genetically determined.

Higher rates of neuropsychiatric disease are reported in some kindreds of those with MND.

These include an increased for psychosis and suicide among first degree relatives. This clustering is not related to the presence or absence of the C9orf72 repeat expansion. The observation of clustering of MND and neuropsychiatric conditions within some kindreds is important for two reasons. Firstly, the observation provides evidence that MND is heterogeneous, as the clustering is not uniformly distributed across all relatives of those with MND, but occurs more frequently among some kindreds. This heterogeneity may be a significant factor in the limited success in development of new therapeutics, as clinical trials to date have not accounted for different patterns of disease pathogenesis.

Secondly, the presence of a family history of neuropsychiatric disorders is likely to reflect a subtype of MND with a specific set of genetic susceptibilities that are shared between ALS and psychiatric conditions . This hypothesis is supported by a combined genomewide association (GWAS) data from the international ALS/MND Consortium with data from the Psychiatric Genome Consortium which has demonstrated a 14% polygenic overlap in the genetic basis of schizophrenia and MND . This suggests the presence of shared pathways of disruption within the brain. The association between MND and neuropsychiatric disorders supports the evolving evidence that both of these conditions can be considered as disorders of neural networking. While there already an extensive literature demonstrating that brain networking is disrupted in schizophrenia, the concept of MND as a “network disorder” is less well established, although evidence imaging and neurophysiologic studies is now compelling.

Management and Treatment

There is currently no effective treatment for MND, and management is symptom based through specialist multidisciplinary clinics. There is strong evidence that attending a specialist clinic improves survival, as patients have access to a multidisciplinary team that provides collective decision making, with multiple experts providing different perspective on the management strategy and care plan. Important interventions include management of weight loss with nutritional support, recognition and management of declining respiratory function, with early introduction of non-invasive ventilation, and management of secretions. The specialist team also supports patients and their family in decision making around end of life, and provides both psychological and practical support to caregivers.

Clinical Trials

To date, Riluzole is only one licensed treatment for MND in Europe. While repeated studies have demonstrated that Riluzole is effective as a disease modifying agent, the effects are modest. Two additional drugs have been licensed for general use in the US and Canada, namely IV Edaravone and Albrioza. Additional Phase 3 trials have been required by the European regulatory agency. These are currently underway, and results will be available by mid-2024. Despite the urgent need for more effective treatments, clinical trials of over 100 other compounds in the past 15 years have failed to demonstrate efficacy, despite positive outcomes in animal models. The reasons for this failure in translation from animal models to human trials are multifactorial, but can be grouped into five major categories, namely: (1) disease heterogeneity, which also reflects our relatively limited knowledge of the interplay between different disease mechanisms in humans;

(2) use of pre-clinical experimental models to incorrectly infer how the disease is likely to develop in humans; (3) an absence of markers of pathogenic mechanisms, markers of disease onset, and quantitative markers of progression; (4) pharmacological challenges of dosing and measures of target engagement and (5) inefficient or poorly designed clinical trials.

New approaches are now underway using better models that are more reflective of the human disease and to provide better biomarkers. New models include induced pluripotent stem cells from patients to explore the specific cell biological processes that are disrupted among affected cell types, and fly, zebrafish and rodent models that have been genetically modified using known human disease-causing variants.

Targeted Gene Based Therapies

Many of the recently identified genomic variants associated with MND encode RNA binding proteins (e.g TDP-43, FUS, ataxin-2) and stress induced secreted ribonucleases (e.g ANG). We know that a major pathological hallmark of MND is the mislocalisation of the RNA binding protein TDP-43 from nucleus to cytoplasm. This occurs in 97% of patients with MND, leading to both loss and toxic gain-of function. TDP-43 is a regulator of gene expression through RNA splicing, DNA or RNA binding, and protein–protein interactions. It also plays a crucial role in several steps of RNA processing, including mRNA stability regulation, mRNA trafficking, pre-mRNA splicing, and regulation of non-coding RNA translation or function. The latter is thought to lead to cryptic splicing and polyadenylation of premessenger RNAs associated with altered RNA translation of several proteins, leading to random insertion of so-called ‘cryptic peptides’. Incorporation of cryptic exons and formation of aberrant proteins occurs downstream of TDP43 loss of function, including stathmin 2, which is required for axonal regeneration.

Better understanding of these processes has led to exciting new therapeutic approaches using antisense oligonucleotides that target some of these disrupted pathways. Indeed, therapeutic initiatives using antisense oligonucleotides (ASOs) have now entered clinical trials.

These include an anti-sense oligonucleotides (Tofersen) that targets inherited mutations in SOD1. Tofersen have recently been approved by the FDA as an effective treatment of SOD1 related MND. An ASO targeting mutations in the FUS gene (ION363) is currently in phase 1 trial, and additional ASOs in early phase trials include BIIB105 which targets ataxin 2 , and QRL-201, designed to restore the expression of the protein stathmin-2 by suppressing cryptic splicing.

The success of the ASOs in treating some rare forms of MND demonstrates that value of a precision-medicine-based approach towards patient selection for specific treatment. As new and more targeted treatments are being developed, there is genuine optimism that MND may become a chronic rather than a fatal disease. These precision treatments are administered intrathecally by lumbar puncture, and are costly. But if successful they provide proof of principle that strategic targeting of known pathogenic pathways is a real therapeutic option. Notwithstanding, there also remains scope for development of other more conventional (small molecule) approaches toward treatment of MND for which there is no known associated gene variant. Despite the use of better models that can explore the cell biological processes that are disrupted in MND, there is also a need to expand the focus of research from laboratory-based work and animal models to applied clinical research. Direct translation from animal models to humans does not fully take into account the greater complexity of the human nervous system, and individual aspects of a patient, including their genetic makeup, key biomarkers, prior treatment history, environmental factors and behavioural preferences, will all inform how human disease develops and progresses. This in turn influences design and testing of new treatments.

Overcoming the factors that have limited the success of translational medicine requires novel solutions. Because MND is a rare disease, and likely comprises many different subtypes with different pathobiologic mechanisms, an important step is to develop a system that enables collection and uploading of human data at a very large scale, delivering a wealth of new multimodal, multi-sourced clinical phenotype and outcome, imaging, neuro-electric-signaling, biochemical and genomic datasets that will ultimately help to inform how we categorise each patient, and in turn, how we design and test new treatments using a plethora of new and emerging technologies. This is the objective of a novel international academic/ industry initiative. PRECISION ALS ( is funded by Science Foundation Ireland, with participating clinical sites across the EU. The objective is to generated a large repository comprising multimodal data from over 6000 patients within the first 3-4 years, that will help to build a more extensive understanding of the different subtypes of disease, and that will provide well characterised patient cohorts with particular attributes that can be enrolled rapidly in clinical trials. This is a large and complex task, and is mirrored by other initiatives in the US, including the Accelerated Medicine Programme for ALS (AMP-ALS) programme which will be funded by a partnership between the Foundation of the NIH and industry partners. ( )

Taking all of these initiatives together, there are grounds for considerable optimism that new and better targeted treatments will be available to those with MND in the future. And in the meantime, those living with the condition will continue to receive high quality evidence based care, with access to cutting edge clinical trials, as part of the HSE Modernised Care pathway for MND.

Written by Professor Orla Hardiman BSc MD FRCPI FTCD MRIA Consultant Neurologist, Beaumont Hospital, Professor of Neurology, Trinity College Dublin

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